Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal. Opioids can cause death and have been used for executions in the United States.

Side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, and euphoria. Long-term use can cause tolerance, meaning that increased doses are required to achieve the same effect, and physical dependence, meaning that abruptly discontinuing the drug leads to unpleasant withdrawal symptoms. The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction. An overdose or concurrent use with other depressant drugs like benzodiazepines commonly results in death from respiratory depression.

Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids. Opioid drugs include partial agonists, like the anti-diarrhea drug loperamide and antagonists like naloxegol for opioid-induced constipation, which do not cross the blood–brain barrier, but can displace other opioids from binding to those receptors in the myenteric plexus.

Because opioids are addictive and may result in fatal overdose, most are controlled substances. In 2013, between 28 and 38 million people used opioids illicitly (0.6% to 0.8% of the global population between the ages of 15 and 65). In 2011, an estimated 4 million people in the United States used opioids recreationally or were dependent on them. As of 2015, increased rates of recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin. Conversely, fears about overprescribing, exaggerated side effects, and addiction from opioids are similarly blamed for under-treatment of pain.

Terminology

Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl; antagonist drugs such as naloxone; and endogenous peptides such as endorphins. The terms opiate and narcotic are sometimes encountered as synonyms for opioid. Opiate is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives. Narcotic, derived from words meaning 'numbness' or 'sleep', as an American legal term, refers to cocaine and opioids, and their source materials; it is also loosely applied to any illegal or controlled psychoactive drug. In some jurisdictions all controlled drugs are legally classified as narcotics. The term can have pejorative connotations and its use is generally discouraged where that is the case.

Medical uses

Pain
The weak opioid codeine, in low doses and combined with one or more other drugs, is commonly available in prescription medicines and without a prescription to treat mild pain. Other opioids are usually reserved for the relief of moderate to severe pain.

Acute pain
Opioids are effective for the treatment of acute pain (such as pain following surgery). For immediate relief of moderate to severe acute pain, opioids are frequently the treatment of choice due to their rapid onset, efficacy and reduced risk of dependence. However, a new report showed a clear risk of prolonged opioid use when opioid analgesics are initiated for an acute pain management following surgery or trauma. They have also been found to be important in palliative care to help with the severe, chronic, disabling pain that may occur in some terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis. In many cases opioids are a successful long-term care strategy for those with chronic cancer pain.

Just over half of all states in the US have enacted laws that restrict the prescribing or dispensing of opioids for acute pain.

Chronic non-cancer pain
Guidelines have suggested that the risk of opioids is likely greater than their benefits when used for most non-cancer chronic conditions including headaches, back pain, and fibromyalgia. Thus they should be used cautiously in chronic non-cancer pain. If used the benefits and harms should be reassessed at least every three months.

In treating chronic pain, opioids are an option to be tried after other less risky pain relievers have been considered, including paracetamol/acetaminophen or NSAIDs like ibuprofen or naproxen. Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids. The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.

Opioids are contraindicated as a first-line treatment for headache because they impair alertness, bring risk of dependence, and increase the risk that episodic headaches will become chronic. Opioids can also cause heightened sensitivity to headache pain. When other treatments fail or are unavailable, opioids may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.

Opioids are being used more frequently in the management of non-malignant chronic pain. This practice has now led to a new and growing problem with addiction and misuse of opioids. Because of various negative effects the use of opioids for long-term management of chronic pain is not indicated unless other less risky pain relievers have been found ineffective. Chronic pain which occurs only periodically, such as that from nerve pain, migraines, and fibromyalgia, frequently is better treated with medications other than opioids. Paracetamol and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives. They are frequently used combined with opioids, such as paracetamol combined with oxycodone (Percocet) and ibuprofen combined with hydrocodone (Vicoprofen), which boosts the pain relief but is also intended to deter recreational use.

Other

Cough
Codeine was once viewed as the "gold standard" in cough suppressants, but this position is now questioned. Some recent placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children. Thus, it is not recommended for children. Additionally, there is no evidence that hydrocodone is useful in children. Similarly, a 2012 Dutch guideline regarding the treatment of acute cough does not recommend its use. (The opioid analogue dextromethorphan, long claimed to be as effective a cough suppressant as codeine, has similarly demonstrated little benefit in several recent studies.)

Low dose morphine may help chronic cough but its use is limited by side effects.

Diarrhea and constipation
In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea. Loperamide is a peripherally selective opioid available without a prescription used to suppress diarrhea.

The ability to suppress diarrhea also produces constipation when opioids are used beyond several weeks. Naloxegol, a peripherally-selective opioid antagonist is now available to treat opioid induced constipation.

Shortness of breath
Opioids may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others. However, findings from two recent systematic reviews of the literature found that opioids were not necessarily more effective in treating shortness of breath in patients who have advanced cancer.

Hyperalgesia

Opioid-induced hyperalgesia (OIH) has been evident in patients after chronic opioid exposure.

Adverse effects

Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction.

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls". As a result, older adults taking opioids are at greater risk for injury. Opioids do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and paracetamol. They are not associated with upper gastrointestinal bleeding and kidney toxicity.

Prescription of opioids for acute low back pain and management of osteoarthritis seem to have long-term adverse effects

According to the USCDC, methadone was involved in 31% of opioid related deaths in the US between 1999–2010 and 40% as the sole drug involved, far higher than other opioids. Studies of long term opioids have found that many stop them, and that minor side effects were common. Addiction occurred in about 0.3%. In the United States in 2016 opioid overdose resulted in the death of 1.7 in 10,000 people.

Reinforcement disorders

Tolerance
Tolerance is a process characterized by neuroadaptations that result in reduced drug effects. While receptor upregulation may often play an important role other mechanisms are also known. Tolerance is more pronounced for some effects than for others; tolerance occurs slowly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more quickly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis (the constriction of the pupil of the eye to less than or equal to two millimeters). This idea has been challenged, however, with some authors arguing that tolerance does develop to miosis.

Tolerance to opioids is attenuated by a number of substances, including:
 calcium channel blockers
 intrathecal magnesium and zinc
 NMDA antagonists, such as dextromethorphan, ketamine, and memantine.
 cholecystokinin antagonists, such as proglumide
 Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.

Tolerance is a physiologic process where the body adjusts to a medication that is frequently present, usually requiring higher doses of the same medication over time to achieve the same effect. It is a common occurrence in individuals taking high doses of opioids for extended periods, but does not predict any relationship to misuse or addiction.

Physical dependence
Physical dependence is the physiological adaptation of the body to the presence of a substance, in this case opioid medication. It is defined by the development of withdrawal symptoms when the substance is discontinued, when the dose is reduced abruptly or, specifically in the case of opioids, when an antagonist (e.g., naloxone) or an agonist-antagonist (e.g., pentazocine) is administered. Physical dependence is a normal and expected aspect of certain medications and does not necessarily imply that the patient is addicted.

The withdrawal symptoms for opiates may include severe dysphoria, craving for another opiate dose, irritability, sweating, nausea, rhinorrea, tremor, vomiting and myalgia. Slowly reducing the intake of opioids over days and weeks can reduce or eliminate the withdrawal symptoms. The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly than methadone withdrawal. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can be treated with other medications, such as clonidine. Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance. While there is anecdotal claims of benefit with ibogaine, data to support its use in substance dependence is poor.

Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.

Addiction
Drug addiction is a complex set of behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages. Addiction includes psychological compulsion, to the extent that the affected person persists in actions leading to dangerous or unhealthy outcomes. Opioid addiction includes insufflation or injection, rather than taking opioids orally as prescribed for medical reasons.

In European nations such as Austria, Bulgaria, and Slovakia, slow-release oral morphine formulations are used in opiate substitution therapy (OST) for patients who do not well tolerate the side effects of buprenorphine or methadone. Buprenorphine can also be used together with naloxone for a longer treatment of addiction. In other European countries including the UK, this is also legally used for OST although on a varying scale of acceptance.

Slow-release formulations of medications are intended to curb misuse and lower addiction rates while trying to still provide legitimate pain relief and ease of use to pain patients. Questions remain, however, about the efficacy and safety of these types of preparations. Further tamper resistant medications are currently under consideration with trials for market approval by the FDA.

The amount of evidence available only permits making a weak conclusion, but it suggests that a physician properly managing opioid use in patients with no history of substance use disorder can give long-term pain relief with little risk of developing addiction, or other serious side effects.

Problems with opioids include the following:

 Some people find that opioids do not relieve all of their pain.
 Some people find that opioids side effects cause problems which outweigh the therapy's benefit
 Some people build tolerance to opioids over time. This requires them to increase their drug dosage to maintain the benefit, and that in turn also increases the unwanted side effects.
 Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.

All of the opioids can cause side effects. Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.

Nausea and vomiting
Tolerance to nausea occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective. Due to severe side effects such as tardive dyskinesia, haloperidol is now rarely used. A related drug, prochlorperazine is more often used, although it has similar risks. Stronger antiemetics such as ondansetron or tropisetron are sometimes used when nausea is severe or continuous and disturbing, despite their greater cost. A less expensive alternative is dopamine antagonists such as domperidone and metoclopramide. Domperidone does not cross the blood–brain barrier and produce adverse central antidopaminergic effects, but blocks opioid emetic action in the chemoreceptor trigger zone. (The drug is not available in the U.S.) Some antihistamines with anticholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective. The first-generation antihistamine hydroxyzine is very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties. Δ9-tetrahydrocannabinol relieves nausea and vomiting; it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting.
 5-HT3 antagonists (e.g. ondansetron)
 Dopamine antagonists (e.g. domperidone)
 Anti-cholinergic antihistamines (e.g. diphenhydramine)
 Δ9-tetrahydrocannabinol (e.g. dronabinol)

Vomiting is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on the chemoreceptor trigger zone of the area postrema, the vomiting centre of the brain. Vomiting can thus be prevented by prokinetic agents (e.g. domperidone or metoclopramide). If vomiting has already started, these drugs need to be administered by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).
 Prokinetic agents (e.g. domperidone)
 Anti-cholinergic agents (e.g. orphenadrine)

Evidence suggests that opioid-inclusive anaesthesia is associated with postoperative nausea and vomiting.

Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.

Drowsiness
Tolerance to drowsiness usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as fentanyl, morphine and diamorphine (heroin) tend to be particularly sedating, while others such as oxycodone, tilidine and meperidine (pethidine) tend to produce comparatively less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Otherwise, treatment with CNS stimulants is generally effective.
 Stimulants (e.g. caffeine, modafinil, amphetamine, methylphenidate)

Itching
Itching tends not to be a severe problem when opioids are used for pain relief, but antihistamines are useful for counteracting itching when it occurs. Non-sedating antihistamines such as fexofenadine are often preferred as they avoid increasing opioid induced drowsiness. However, some sedating antihistamines such as orphenadrine can produce a synergistic pain relieving effect permitting smaller doses of opioids be used. Consequently, several opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), and these may also reduce opioid induced nausea.
 Antihistamines (e.g. fexofenadine)

Constipation
Opioid-induced constipation (OIC) develops in 90 to 95% of people taking opioids long-term. Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a laxative or enemas.

Treatment of OIC is successional and dependent on severity. The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake (around  per day), and physical activity. If non-pharmacological measures are ineffective, laxatives, including stool softeners (e.g., polyethylene glycol), bulk-forming laxatives (e.g., fiber supplements), stimulant laxatives (e.g., bisacodyl, senna), and/or enemas, may be used. A common laxative regimen for OIC is the combination of docusate and bisacodyl. Osmotic laxatives, including lactulose, polyethylene glycol, and milk of magnesia (magnesium hydroxide), as well as mineral oil (a lubricant laxative), are also commonly used for OIC.

If laxatives are insufficiently effective (which is often the case), opioid formulations or regimens that include a peripherally-selective opioid antagonist, such as methylnaltrexone bromide, naloxegol, alvimopan, or naloxone (as in oxycodone/naloxone), may be tried. A 2018 Cochrane review found that the evidence was tentative for alvimopan, naloxone, or methylnaltrexone bromide. Naloxone by mouth appears to be the most effective. A daily 0.2 mg dose of naldemedine has been shown to significantly improve symptoms in patients with OIC.

Opioid rotation is one method suggested to minimise the impact of constipation in long-term users. While all opioids cause constipation, there are some differences between drugs, with studies suggesting tramadol, tapentadol, methadone and fentanyl may cause relatively less constipation, while with codeine, morphine, oxycodone or hydromorphone constipation may be comparatively more severe.

Respiratory depression
Respiratory depression is the most serious adverse reaction associated with opioid use, but it usually is seen with the use of a single, intravenous dose in an opioid-naïve patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can partially block respiratory depression, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application. Newer drugs such as BIMU-8 and CX-546 may be much more effective.
 Respiratory stimulants: carotid chemoreceptor agonists (e.g. doxapram), 5-HT4 agonists (e.g. BIMU8), δ-opioid agonists (e.g. BW373U86) and AMPAkines (e.g. CX717) can all reduce respiratory depression caused by opioids without affecting analgesia, but most of these drugs are only moderately effective or have side effects which preclude use in humans. 5-HT1A agonists such as 8-OH-DPAT and repinotan also counteract opioid-induced respiratory depression, but at the same time reduce analgesia, which limits their usefulness for this application.
 Opioid antagonists (e.g. naloxone, nalmefene, diprenorphine)

The initial 24 hours after opioid administration appear to be the most critical with regard to life-threatening OIRD, but may be preventable with a more cautious approach to opioid use.

Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.

Increased pain sensitivity

Opioid-induced hyperalgesia – where individuals using opioids to relieve pain paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving palliative care, most often when dose is increased rapidly. If encountered, rotation between several different opioid pain medications may decrease the development of increased pain. Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses but some research suggests that it may also occur with very low doses.

Side effects such as hyperalgesia and allodynia, sometimes accompanied by a worsening of neuropathic pain, may be consequences of long-term treatment with opioid analgesics, especially when increasing tolerance has resulted in loss of efficacy and consequent progressive dose escalation over time. This appears to largely be a result of actions of opioid drugs at targets other than the three classic opioid receptors, including the nociceptin receptor, sigma receptor and Toll-like receptor 4, and can be counteracted in animal models by antagonists at these targets such as J-113,397, BD-1047 or (+)-naloxone respectively. No drugs are currently approved specifically for counteracting opioid-induced hyperalgesia in humans and in severe cases the only solution may be to discontinue use of opioid analgesics and replace them with non-opioid analgesic drugs. However, since individual sensitivity to the development of this side effect is highly dose dependent and may vary depending which opioid analgesic is used, many patients can avoid this side effect simply through dose reduction of the opioid drug (usually accompanied by the addition of a supplemental non-opioid analgesic), rotating between different opioid drugs, or by switching to a milder opioid with a mixed mode of action that also counteracts neuropathic pain, particularly tramadol or tapentadol.

 NMDA receptor antagonists such as ketamine
 SNRIs such as milnacipran
 Anticonvulsants such as gabapentin or pregabalin

Other adverse effects

Low sex hormone levels
Clinical studies have consistently associated medical and recreational opioid use with hypogonadism (low sex hormone levels) in different sexes. The effect is dose-dependent. Most studies suggest that the majority (perhaps as much as 90%) of chronic opioid users develop hypogonadism. A 2015 systematic review and meta-analysis found that opioid therapy suppressed testosterone levels in men by about 165 ng/dL (5.7 nmol/L) on average, which was a reduction in testosterone level of almost 50%. Conversely, opioid therapy did not significantly affect testosterone levels in women. However, opioids can also interfere with menstruation in women by limiting the production of luteinizing hormone (LH). Opioid-induced hypogonadism likely causes the strong association of opioid use with osteoporosis and bone fracture, due to deficiency in estradiol. It also may increase pain and thereby interfere with the intended clinical effect of opioid treatment. Opioid-induced hypogonadism is likely caused by their agonism of opioid receptors in the hypothalamus and the pituitary gland. One study found that the depressed testosterone levels of heroin addicts returned to normal within one month of abstinence, suggesting that the effect is readily reversible and is not permanent. , the effect of low-dose or acute opioid use on the endocrine system is unclear. Long-term use of opioids can affect the other hormonal systems as well.

Disruption of work
Use of opioids may be a risk factor for failing to return to work.

Persons performing any safety-sensitive task should not use opioids. Health care providers should not recommend that workers who drive or use heavy equipment including cranes or forklifts treat chronic or acute pain with opioids. Workplaces which manage workers who perform safety-sensitive operations should assign workers to less sensitive duties for so long as those workers are treated by their physician with opioids.

People who take opioids long term have increased likelihood of being unemployed. Taking opioids may further disrupt the patient's life and the adverse effects of opioids themselves can become a significant barrier to patients having an active life, gaining employment, and sustaining a career.

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.

Increased accident-proneness
Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents and accidental falls.

Reduced Attention

Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.

Rare side effects
Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). Both therapeutic and chronic use of opioids can compromise the function of the immune system.  Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996).  Opioids may also inhibit leukocyte migration.  However the relevance of this in the context of pain relief is not known.

Pregnancy

Interactions

Physicians treating patients using opioids in combination with other drugs keep continual documentation that further treatment is indicated and remain aware of opportunities to adjust treatment if the patient's condition changes to merit less risky therapy.

With other depressant drugs
The concurrent use of opioids with other depressant drugs such as benzodiazepines or ethanol increases the rates of adverse events and overdose. Despite this, opioids and benzodiazepines are concurrently dispensed in many settings. As with an overdose of opioid alone, the combination of an opioid and another depressant may precipitate respiratory depression often leading to death. These risks are lessened with close monitoring by a physician, who may conduct ongoing screening for changes in patient behavior and treatment compliance.

Opioid antagonist

Opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose but giving this in small doses until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief. Opioid antagonists remain the standard treatment for respiratory depression following opioid overdose, with naloxone being by far the most commonly used, although the longer acting antagonist nalmefene may be used for treating overdoses of long-acting opioids such as methadone, and diprenorphine is used for reversing the effects of extremely potent opioids used in veterinary medicine such as etorphine and carfentanil. However, since opioid antagonists also block the beneficial effects of opioid analgesics, they are generally useful only for treating overdose, with use of opioid antagonists alongside opioid analgesics to reduce side effects, requiring careful dose titration and often being poorly effective at doses low enough to allow analgesia to be maintained.

Naltrexone does not appear to increase risk of serious adverse events, which confirms the safety of oral naltrexone. Mortality or serious adverse events due to rebound toxicity in patients with naloxone were rare.

Pharmacology

Opioids bind to specific opioid receptors in the nervous system and other tissues.  There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors. Conversely, σ (Sigma) receptors are no longer considered to be opioid receptors because their activation is not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for classical opioids, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for levo-rotatory isomers. In addition, there are three subtypes of μ-receptor: μ1 and μ2, and the newly discovered μ3.  Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics.  These are all G-protein coupled receptors acting on GABAergic neurotransmission.

The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist.  For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the μ1 receptor; respiratory depression and physical dependence by the μ2 receptor; and sedation and spinal analgesia by the κ receptor.  Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ1 and μ2 for example) providing even more [measurably] specific responses.  Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the μ-opioid receptor, while ketazocine exhibits high affinity to ĸ receptors.  It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism.

Functional selectivity
A new strategy of drug development takes receptor signal transduction into consideration. This strategy strives to increase the activation of desirable signalling pathways while reducing the impact on undesirable pathways. This differential strategy has been given several names, including functional selectivity and biased agonism. The first opioid that was intentionally designed as a biased agonist and placed into clinical evaluation is the drug oliceridine. It displays analgesic activity and reduced adverse effects.

Opioid comparison

Extensive research has been conducted to determine equivalence ratios comparing the relative potency of opioids. Given a dose of an opioid, an equianalgesic table is used to find the equivalent dosage of another. Such tables are used in opioid rotation practices, and to describe an opioid by comparison to morphine, the reference opioid. Equianalgesic tables typically list drug half-lives, and sometimes equianalgesic doses of the same drug by means of administration, such as morphine: oral and intravenous.

Binding profiles

Usage

Opioid prescriptions in the US increased from 76 million in 1991 to 207 million in 2013.

In the 1990s, opioid prescribing increased significantly. Once used almost exclusively for the treatment of acute pain or pain due to cancer, opioids are now prescribed liberally for people experiencing chronic pain. This has been accompanied by rising rates of accidental addiction and accidental overdoses leading to death. According to the International Narcotics Control Board, the United States and Canada lead the per capita consumption of prescription opioids. The number of opioid prescriptions per capita in the United States and Canada is double the consumption in the European Union, Australia, and New Zealand. Certain populations have been affected by the opioid addiction crisis more than others, including First World communities and low-income populations. Public health specialists say that this may result from the unavailability or high cost of alternative methods for addressing chronic pain. Opioids have been described as a cost-effective treatment for chronic pain, but the impact of the opioid epidemic and deaths caused by opioid overdoses should be considered in assessing their cost-effectiveness. Data from 2017 suggest that in the U.S. about 3.4 percent of the U.S. population are prescribed opioids for daily pain management. Calls for opioid deprescribing have led to broad scale opioid tapering practices with little scientific evidence to support the safety or benefit for patients with chronic pain.

History

Naturally occurring opioids

Opioids are among the world's oldest known drugs. The earliest known evidence of Papaver somniferum in a human archaeological site dates to the Neolithic period around 5,700–5,500 BCE.  Its seeds have been found at Cueva de los Murciélagos in the Iberian Peninsula and La Marmotta in the Italian Peninsula.

Use of the opium poppy for medical, recreational, and religious purposes can be traced to the fourth century BC, when ideograms on Sumerians clay tablets mention the use of "Hul Gil", a "plant of joy".
Opium was known to the Egyptians, and is mentioned in the Ebers Papyrus as an ingredient in a mixture for the soothing of children, and for the treatment of breast abscesses.

Opium was also known to the Greeks.
It was valued by Hippocrates ( – ) and his students for its sleep-inducing properties, and used for the treatment of pain. The Latin saying "Sedare dolorem opus divinum est", trans.  "Alleviating pain is the work of the divine", has been variously ascribed to Hippocrates and to Galen of Pergamum. The medical use of opium is later discussed by Pedanius Dioscorides ( – 90 AD), a Greek physician serving in the Roman army, in his five-volume work, De Materia Medica.

During the Islamic Golden Age, the use of opium was discussed in detail by   Avicenna ( – June 1037 AD) in The Canon of Medicine.  The book's five volumes include information on opium's preparation, an array of physical effects, its use to treat a variety of illness, contraindications for its use, its potential danger as a poison and its potential for addiction.  Avicenna discouraged opium's use except as a last resort, preferring to address the causes of pain rather than trying to minimize it with analgesics. Many of Avicenna's observations have been supported by modern medical research.

Exactly when the world became aware of opium in India and China is uncertain, but opium was mentioned in the Chinese medical work K'ai-pao-pen-tsdo (973 AD) By 1590 AD, opium poppies were a staple spring crop in the Subahs of Agra region.

The physician Paracelsus (–1541) is often credited with reintroducing opium into medical use in Western Europe, during the German Renaissance. He extolled opium's benefits for medical use. He also claimed to have an "arcanum", a pill which he called laudanum, that was superior to all others, particularly when death was to be cheated. ("Ich hab' ein Arcanum – heiss' ich Laudanum, ist über das Alles, wo es zum Tode reichen will.") Later writers have asserted that Paracelsus' recipe for laudanum contained opium, but its composition remains unknown.

Laudanum
The term laudanum was used generically for a useful medicine until the 17th century. After Thomas Sydenham introduced the first liquid tincture of opium, "laudanum" came to mean a mixture of both opium and alcohol.
Sydenham's 1669 recipe for laudanum mixed opium with wine, saffron, clove and cinnamon. Sydenham's laudanum was used widely in both Europe and the Americas until the 20th century.
Other popular medicines, based on opium, included Paregoric, a much milder liquid preparation for children; Black-drop, a stronger preparation; and Dover's powder.

The opium trade
Opium became a major colonial commodity, moving legally and illegally through trade networks involving India, the Portuguese, the Dutch, the British and China, among others.
The British East India Company saw the opium trade as an investment opportunity in 1683 AD. In 1773 the Governor of Bengal established a monopoly on the production of Bengal opium, on behalf of the East India Company. The cultivation and manufacture of Indian opium was further centralized and controlled through a series of acts, between 1797 and 1949. The British balanced an economic deficit from the importation of Chinese tea by selling Indian opium which was smuggled into China in defiance of Chinese government bans. This led to the First (1839–1842) and Second Opium Wars (1856–1860) between China and Britain.

Morphine
In the 19th century, two major scientific advances were made that had far-reaching effects. Around 1804, German pharmacist Friedrich Sertürner isolated morphine from opium. He described its crystallization, structure, and pharmacological properties in a well-received paper in 1817.
Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery.

The second advance, nearly fifty years later, was the refinement of the hypodermic needle by Alexander Wood and others. Development of a glass syringe with a subcutaneous needle made it possible to easily administer controlled measurable doses of a primary active compound.

Morphine was initially hailed as a wonder drug for its ability to ease pain. It could help people sleep, and had other useful side effects, including control of coughing and diarrhea. It was widely prescribed by doctors, and dispensed without restriction by pharmacists. During the American Civil War, opium and laudanum were used extensively to treat soldiers. It was also prescribed frequently for women, for menstrual pain and diseases of a "nervous character".
At first it was assumed (wrongly) that this new method of application would not be addictive.

Codeine
Codeine was discovered in 1832 by Pierre Jean Robiquet. Robiquet was reviewing a method for morphine extraction, described by Scottish chemist William Gregory  (1803–1858). Processing the residue left from Gregory's procedure, Robiquet isolated a crystalline substance from the other active components of opium. He wrote of his discovery: "Here is a new substance found in opium ... We know that morphine, which so far has been thought to be the only active principle of opium, does not account for all the effects and for a long time the physiologists are claiming that there is a gap that has to be filled." His discovery of the alkaloid led to the development of a generation of antitussive and antidiarrheal medicines based on codeine.

Semisynthetic and synthetic opioids
Synthetic opioids were invented, and biological mechanisms for their actions discovered, in the 20th century. Scientists have searched for non-addictive forms of opioids, but have created stronger ones instead. In England Charles Romley Alder Wright developed hundreds of opiate compounds in his search for a nonaddictive opium derivative. In 1874 he became the first person to synthesize diamorphine (heroin), using a process called acetylation which involved boiling morphine with acetic anhydride for several hours.

Heroin received little attention until it was independently synthesized by Felix Hoffmann (1868–1946), working for Heinrich Dreser (1860–1924) at Bayer Laboratories. Dreser brought the new drug to market as an analgesic and a cough treatment for tuberculosis, bronchitis, and asthma in 1898. Bayer ceased production in 1913, after heroin's addictive potential was recognized.

Several semi-synthetic opioids were developed in Germany in the 1910s.  The first, oxymorphone, was synthesized from thebaine, an opioid alkaloid in opium poppies, in 1914.
Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.
In 1920, hydrocodone was prepared by Carl Mannich and Helene Löwenheim, deriving it from codeine. In 1924, hydromorphone was synthesized by adding hydrogen to morphine. Etorphine was synthesized in 1960, from the oripavine in opium poppy straw. Buprenorphine was discovered in 1972.

The first fully synthetic opioid was meperidine (later demerol), found serendipitously by German chemist Otto Eisleb (or Eislib) at IG Farben in 1932. Meperidine was the first opiate to have a structure unrelated to morphine, but with opiate-like properties. Its analgesic effects were discovered by Otto Schaumann in 1939.
Gustav Ehrhart and Max Bockmühl, also at IG Farben,
built on the work of Eisleb and Schaumann.  They developed "Hoechst 10820" (later methadone) around 1937.
In 1959 the Belgian physician Paul Janssen developed fentanyl, a synthetic drug with 30 to 50 times the potency of heroin.
Nearly 150 synthetic opioids are now known.

Criminalization and medical use
Non-clinical use of opium was criminalized in the United States by the Harrison Narcotics Tax Act of 1914, and by many other laws. The use of opioids was stigmatized, and it was seen as a dangerous substance, to be prescribed only as a last resort for dying patients. The Controlled Substances Act of 1970 eventually relaxed the harshness of the Harrison Act.

In the United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the "British system" of control—which lasted until the 1960s.

In the 1980s the World Health Organization published guidelines for prescribing drugs, including opioids, for different levels of pain. In the U.S., Kathleen Foley and Russell Portenoy became leading advocates for the liberal use of opioids as painkillers for cases of "intractable non-malignant pain".
With little or no scientific evidence to support their claims, industry scientists and advocates suggested that people with chronic pain would be resistant to addiction.

The release of OxyContin in 1996 was accompanied by an aggressive marketing campaign promoting the use of opioids for pain relief. Increasing prescription of opioids fueled a growing black market for heroin. Between 2000 and 2014 there was an "alarming increase in heroin use across the country and an epidemic of drug overdose deaths".

As a result, health care organizations and public health groups, such as Physicians for Responsible Opioid Prescribing, have called for decreases in the prescription of opioids. In 2016, the Centers for Disease Control and Prevention (CDC) issued a new set of guidelines for the prescription of opioids "for chronic pain outside of active cancer treatment, palliative care, and end-of-life care" and the increase of opioid tapering.

"Remove the Risk"
In April 2019 the U.S. Food and Drug Administration announced the launch of a new education campaign to help Americans understand the important role they play in removing and properly disposing of unused prescription opioids from their homes. This new initiative is part of the FDA's continued efforts to address the nationwide opioid crisis (see below) and aims to help decrease unnecessary exposure to opioids and prevent new addiction. The "Remove the Risk" campaign is targeting women ages 35–64, who are most likely to oversee household health care decisions and often serve as the gatekeepers to opioids and other prescription medications in the home.

Society and culture

Definition

The term "opioid" originated in the 1950s. It combines "opium" + "-oid" meaning "opiate-like" ("opiates" being morphine and similar drugs derived from opium). The first scientific publication to use it, in 1963, included a footnote stating, "In this paper, the term, 'opioid', is used in the sense originally proposed by George H. Acheson (personal communication) to refer to any chemical compound with morphine-like activities". By the late 1960s, research found that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed "opioid receptors". The definition of "opioid" was later refined to refer to substances that have morphine-like activities that are mediated by the activation of opioid receptors. One modern pharmacology textbook states: "the term opioid applies to all agonists and antagonists with morphine-like activity, and also the naturally occurring and synthetic opioid peptides". Another pharmacology reference eliminates the morphine-like requirement: "Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists)". Some sources define the term opioid to exclude opiates, and others use opiate comprehensively instead of opioid, but opioid used inclusively is considered modern, preferred and is in wide use.

Efforts to reduce recreational use in the US
In 2011, the Obama administration released a white paper describing the administration's plan to deal with the opioid crisis. The administration's concerns about addiction and accidental overdosing have been echoed by numerous other medical and government advisory groups around the world.

As of 2015, prescription drug monitoring programs exist in every state, except for Missouri. These programs allow pharmacists and prescribers to access patients' prescription histories in order to identify suspicious use. However, a survey of US physicians published in 2015 found that only 53% of doctors used these programs, while 22% were not aware that the programs were available to them. The Centers for Disease Control and Prevention was tasked with establishing and publishing a new guideline, and was heavily lobbied. In 2016, the United States Centers for Disease Control and Prevention published its Guideline for Prescribing Opioids for Chronic Pain, recommending that opioids only be used when benefits for pain and function are expected to outweigh risks, and then used at the lowest effective dosage, with avoidance of concurrent opioid and benzodiazepine use whenever possible. Research suggests that the prescription of high doses of opioids related to chronic opioid therapy (COT) can at times be prevented through state legislative guidelines and efforts by health plans that devote resources and establish shared expectations for reducing higher doses.

On 10 August 2017, Donald Trump declared the opioid crisis a (non-FEMA) national public health emergency.

Global shortages
Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. As of 2002, seven countries (USA, UK, Italy, Australia, France, Spain and Japan) use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication. The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of poppy-based drugs. The World Health Organization is now working with administrations from various countries to train healthworkers and to develop national regulations regarding drug prescription to facilitate a greater prescription of poppy-based medicines.

Another idea to increase morphine availability is proposed by the Senlis Council, who suggest, through their proposal for Afghan Morphine, that Afghanistan could provide cheap pain relief solutions to emerging countries as part of a second-tier system of supply that would complement the current INCB regulated system by maintaining the balance and closed system that it establishes while providing finished product morphine to those in severe pain and unable to access poppy-based drugs under the current system.

Recreational use

Opioids can produce strong feelings of euphoria and are frequently used recreationally. Traditionally associated with illicit opioids such as heroin, prescription opioids are misused recreationally.

Drug misuse and non-medical use include the use of drugs for reasons or at doses other than prescribed. Opioid misuse can also include providing medications to persons for whom it was not prescribed. Such diversion may be treated as crimes, punishable by imprisonment in many countries. In 2014, almost 2 million Americans abused or were dependent on prescription opioids.

Classification
There are a number of broad classes of opioids:
 Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine which have a different mechanism of action
 Esters of morphine opiates: slightly chemically altered but more natural than the semi-synthetics, as most are morphine prodrugs, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;
 Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine;
 Fully synthetic opioids: such as fentanyl, pethidine, levorphanol, methadone, tramadol, tapentadol, and dextropropoxyphene;
 Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.
 Endogenous opioids, non-peptide: Morphine, and some other opioids, which are produced in small amounts in the body, are included in this category.
 Natural opioids, non-animal, non-opiate: the leaves from Mitragyna speciosa (kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.

Tramadol and tapentadol, which act as monoamine uptake inhibitors also act as mild and potent agonists (respectively) of the μ-opioid receptor. Both drugs produce analgesia even when naloxone, an opioid antagonist, is administered.

Some minor opium alkaloids and various substances with opioid action are also found elsewhere, including molecules present in kratom, Corydalis, and Salvia divinorum plants and some species of poppy aside from Papaver somniferum. There are also strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids.  Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics there are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction.  Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine or some other antihistamines.  Tricyclic antidepressants have painkilling effect as well, but they're thought to do so by indirectly activating the endogenous opioid system. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. It has recently been discovered that most or all of the therapeutic efficacy of paracetamol is due to a metabolite, AM404, which enhances the release of serotonin and inhibits the uptake of anandamide.

Other analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Recent investigations discovered opioid receptors on peripheral sensory neurons. A significant fraction (up to 60%) of opioid analgesia can be mediated by such peripheral opioid receptors, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain. Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.

It was discovered in 1953, that humans and some animals naturally produce minute amounts of morphine, codeine, and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to endogenous opioid peptides.  Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.

Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid analgesic effect at all despite their structural similarity to other opioids; instead they are potent NMDA antagonists and sigma 1 and 2-receptor agonists and are used in many over-the-counter cough suppressants.

Salvinorin A is a unique selective, powerful ĸ-opioid receptor agonist. It is not properly considered an opioid nevertheless, because:
 chemically, it is not an alkaloid; and
 it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.

Endogenous opioids

Opioid-peptides that are produced in the body include:

 Endorphins
 Enkephalins
 Dynorphins
 Endomorphins

β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus, in the brainstem and in immune cells, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neo-endorphin is also expressed in POMC cells in the arcuate nucleus.

met-enkephalin is widely distributed in the CNS and in immune cells; [met]-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. leu-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors.

Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.

Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors.

Opium alkaloids and derivatives

Opium alkaloids
Phenanthrenes naturally occurring in (opium):

 Codeine
 Morphine
 Thebaine
 Oripavine

Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

Esters of morphine

 Diacetylmorphine (morphine diacetate; heroin)
 Nicomorphine (morphine dinicotinate)
 Dipropanoylmorphine (morphine dipropionate)
 Diacetyldihydromorphine
 Acetylpropionylmorphine
 Desomorphine
 Methyldesorphine
 Dibenzoylmorphine

Ethers of morphine

 Dihydrocodeine
 Ethylmorphine
 Heterocodeine

Semi-synthetic alkaloid derivatives

 Buprenorphine
 Etorphine
 Hydrocodone
 Hydromorphone
 Oxycodone (sold as OxyContin)
 Oxymorphone

Synthetic opioids

Anilidopiperidines

 Fentanyl (see also list of fentanyl analogues)
 Alphamethylfentanyl
 Alfentanil
 Sufentanil
 Remifentanil
 Carfentanyl
 Ohmefentanyl

Benzimidazoles

Benzimidazoles opioids are also known as nitazenes.

 Metodesnitazene (Metazene)
 Etodesnitazene (Etazene)
 Metonitazene
 Etonitazene
 Etonitazepyne
 Etonitazepipne
 Isotonitazene
 Clonitazene

Phenylpiperidines

 Pethidine (meperidine)
 Ketobemidone
 MPPP
 Allylprodine
 Prodine
 PEPAP
 Promedol

Diphenylpropylamine derivatives

 Propoxyphene
 Dextropropoxyphene
 Dextromoramide
 Bezitramide
 Piritramide
 Methadone
 Dipipanone
 Levomethadyl acetate (LAAM)
 Difenoxin
 Diphenoxylate
 Loperamide (does cross the blood–brain barrier but is quickly pumped into the non-central nervous system by P-Glycoprotein.  Mild opiate withdrawal in animal models exhibits this action after sustained and prolonged use including rhesus monkeys, mice, and rats.)

Benzomorphan derivatives

 Dezocine—agonist/antagonist
 Pentazocine—agonist/antagonist
 Phenazocine

Oripavine derivatives

 Buprenorphine—partial agonist
 Dihydroetorphine
 Etorphine

Morphinan derivatives

 Butorphanol—agonist/antagonist
 Nalbuphine—agonist/antagonist
 Levorphanol
 Levomethorphan
 Racemethorphan

Others

 Lefetamine
 Meptazinol
 Mitragynine
 Tilidine
 Tramadol
 Tapentadol
 Eluxadoline
 AP-237
 7-Hydroxymitragynine

Allosteric modulators
Plain allosteric modulators do not belong to the opioids, instead they are classified as opioidergics.

Opioid antagonists

 Nalmefene
 Naloxone
 Naltrexone
 Methylnaltrexone (Methylnaltrexone is only peripherally active as it does not cross the blood–brain barrier in sufficient quantities to be centrally active. As such, it can be considered the antithesis of loperamide.)
 Naloxegol (Naloxegol is only peripherally active as it does not cross the blood–brain barrier in sufficient quantities to be centrally active. As such, it can be considered the antitheses of loperamide.)

Tables of opioids

Table of morphinan opioids

Table of non-morphinan opioids

See also
 Froehde reagent
 Opiate comparison
 Opioid epidemic
Opioid tapering

References

External links
 Opioid Withdrawal Symptoms —Information about Opioid and opiate withdrawal issues

 World Health Organization guidelines for the availability and accessibility of controlled substances
 CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016
 Reference list to the previous publication
 Links to all language versions of the previous publication
 Video: Opioid side effects (Vimeo) (YouTube)—A short educational film about the practical management of opioid side effects.

Morphine
Articles containing video clips

Opioid


Paramount+ er bandarísk streymisveita í eigu Paramount Pictures og CBS sjónvarpsstöðinni. Á veitunni má finna efni frá Paramount, CBS og Nickelodeon. Streymið er ekki aðgengilegt á Íslandi.

Streymið opnaði upprunalega 28. október 2014 undir merkjum CBS sjónvarpsstöðvarinnar en nafninu var breytt í Paramount+ þann 4. mars 2021.
Streymisveitur
Stofnað 2014
Paramount

Paramount+


Sinteza Rapsodia—Anotimpurile este un proiect de rock simfonic al formației Phoenix, care combină suita "Ciclul anotimpurilor" de pe albumul Cei ce ne-au dat nume cu Rapsodia română nr. 1 în La major a lui George Enescu. Proiectul constă în prelucrarea în stil rock a compoziției orchestrale a lui Enescu și interpretarea sa pe fragmente și intercalat cu creații sau prelucrări folclorice ale grupului Phoenix, ce alcătuiesc muzica discului Cei ce ne-au dat nume din 1972. "Inițial, am dorit să cântăm ambele «Rapsodii» ale lui George Enescu, dar deocamdată ajunge prima. În plus, se leagă cel mai bine de «Cei ce ne-au dat nume». Între stilul muzicii noastre și capodoperele lui Enescu există similitudini, în primul rând din punct de vedere folcloric", spunea Nicu Covaci.

Premiera
Spectacolul aferent acestui proiect a avut premiera pe 1 decembrie 2009, la Sala Palatului din București, și a presupus colaborarea formației cu un cor și cu câțiva muzicieni din zona muzicii clasice. Despre invitații care au fost pe scenă alături de Phoenix, liderul Nicolae Covaci declara, în seara spectacolului: "Am chemat niște oameni să ne ajute să facem o sinteză frumoasă, să fie convingătoare. Avem un cor – Accapela se cheamă, avem un oboist care cântă și la saxofon sopran – Adrian Petrescu, avem un pianist clasic – Nicușor Dumitru. Și gașca mare Phoenix."  Alături de Covaci, ceilalți componenți ai formației care au participat la acest concert sunt: Bogdan Bradu, Cristi Gram, Volker Vaessen, Dzidek Marcinkiewicz, Ionuț Contraș și Ovidiu Lipan Țăndărică, ultimul dintre ei, spunând, cu această ocazie: "Se va cânta un melanj între Enescu, partitură de pian, piese de pe albumul «Cei ce ne-au dat nume», care sunt piese de un rock românesc profund."  Chitaristul Cristi Gram: "Noi de mult vrem să facem «Rapsodia» lui Enescu. Băieții au făcut deja «Ciocârlia», au făcut mai multe încercări în trecut, dar acum, în fine, am reușit să o punem în practică pe scenă. Să vedem cum o să sune."  Concertul a marcat, printre altele, și începerea colaborării cu solistul vocal Bogdan Munteniță, invitat să cânte două piese în stil arhaic alături de Phoenix: "Colindul casei" și "Măi tătare!", a doua dintre ele reluată de formație, după ce a făcut parte din repertoriul acesteia în anii '70, fiind cenzurată de autoritățile vremii respective.

În seara în care Sinteza a fost prezentată pe scena Sălii Palatului, Volker Vaessen spunea: "E un concert deosebit de Ziua Națională. La mulți ani, România! Cred că e o idee foarte bună să mixăm binecunoscuta «Rapsodie română» care apaține unuia dintre cei mai mari compozitori români, George Enescu, cu o compoziție a lui Nicolae Covaci, la rândul său, un foarte bun compozitor al țării. Așa că va fi o seară specială."  Despre intențiile legate de acest eveniment propus de Phoenix, Nicu Covaci preciza că este vorba de "un gest patriotic": "Fiind Ziua României am încercat să ne legăm de acest nume de român, să ne aducem aminte cine ne-a dat nume, când, cum, și să fim mândri de acest nume."

Reluarea proiectului

Proiectul a fost reluat în 2018, odată cu demararea turneului național "Sinteza – Rapsodia", pe 10 februarie, la Iași. Formația a susținut spectacole pe tot parcursul anului, ajungând în mai multe orașe ale țării: Iași, Târgu Mureș, Cluj-Napoca, Alba Iulia, Sibiu, Brașov, Ploiești, Râmnicu Vâlcea, Drobeta-Turnu Severin, Constanța, Oradea, Timișoara, Reșița, Brăila, Focșani etc. Concertul de la București a avut loc pe 14 mai la Teatrul Național "Ion Luca Caragiale".

În spectacolul din 14 mai 2018, au urcat pe scenă, alături de formație, invitatul special Grigore Leșe, împreună cu colaboratorii din 2009, Nicușor Dumitru și Bogdan Munteniță. Turneul s-a încheiat pe 4 ianuarie 2019, cu un nou concert la București, de data aceasta într-un cadru mai restrâns, la Hard Rock Cafe. Formula Phoenix pentru acest turneu a fost: Nicu Covaci – chitară, voce, Costin Adam – solist vocal, Cristi Gram – chitară solo, voce, Vlady Săteanu – chitară bas, voce, Flavius Hosu – baterie, Lavinia Săteanu – vioară și, la o parte dintre concerte, Dzidek Marcinkiewicz – instrumente cu clape.

În aprilie 2019, în cadrul emisiunii Muzică și Radio realizată de Lenți Chiriac și difuzată de Radio România Actualități, Cristi Gram a anunțat că materialul proiectului Sinteza Rapsodia—Anotimpurile se află în curs de imprimare în studio, în vederea realizării unui album.

Note

Bibliografie
 Covaci, Nicolae. Phoenix: Giudecata înțelepților, Editura Integral, București, 2014. ISBN 978-973-8209-53-4
 Ionescu, Doru. "Integrala Phoenix", episodul 7 – "Știu că mă iubești și tu... Vlad Țepeș!", Televiziunea Română, 2017.

Vezi și
 Cei ce ne-au dat nume
 Rapsodia română

Proiecte Phoenix
2009 în muzică
2009 în România

Sinteza Rapsodia—Anotimpurile


La Estación Ferroviária de Pinhel, igualmente conocida como Estación de Pinhel, fue una antigua plataforma de la línea de Beira Alta, que servía al Ayuntamiento de Pinhel, en el distrito de Guarda, en Portugal.

Características

Descripción física
En enero de 2011, presentaba dos vías de circulación, ambas con 565 metros de longitud; las dos plataformas tenían 139 y 131 metros de extensión, y 30 y 40 centímetros de altura.

Historia
El tramo de la línea de Beira Alta entre las estaciones de Pampilhosa y Vilar Formoso, en el cual esta plataforma se inserta, entró en servicio, de forma provisional, el 1 de julio de 1882, siendo la línea totalmente inaugurada, entre Figueira da Foz y la frontera con España, el 3 de agosto del mismo año, por la Compañía de los Caminhos de Ferro Portugueses de Beira Alta.

En mayo de 1984, era utilizada por servicios Regionales y semidirectos de la operadora Caminhos de Ferro Portugueses.

Véase también
 Red Ferroviaria Nacional

Referencias

Enlaces externos

Pinhel
Pinhel
Pinhel

Estación de Pinhel


RFA Black Ranger (A163) was a British diesel-powered Ranger-class fleet support tanker of the Royal Fleet Auxiliary, built by Harland & Wolff at their yard in Govan.  On 27 February 1941, shortly after her commissioning, she was involved in a collision with the French destroyer Mistral which sustained minor damage and Black Ranger spent a short period under repair on the Clyde.

Black Ranger later served with the Arctic Convoys. In November 1960 she was involved in a collision with the submarine . She was retired from service in 1973 and put up for sale. Bought by Greek owners, she was renamed Petrola XIV in 1973 and then Petrola 14 in 1976. She was scrapped at Piraeus in May 1983.

References

Ranger-class tankers
Ships built in Govan
1940 ships
Ships built by Harland and Wolff

RFA Black Ranger


The Billboard Hot 100 is a chart that ranks the best-performing songs in the United States. The chart was first issued in the magazine issue of August 4, 1958. Prior to that, Billboard published four popular song charts; the Top 100, the first Billboard chart to feature a combined tabulation of sales, airplay and jukebox play; Best Sellers in Stores, ranking the best-selling singles in retail stores; Most Played by Jockeys, ranking the most played songs on US radio stations; and the leading song chart, Honor Roll of Hits, which ranks the most popular songs (not singles) in the country. With the foundation of the Hot 100, Top 100 and Most Played by Jockeys were discontinued. Best Sellers in Stores continued until October 13, 1958, while Honor Roll of Hits continued until 1963.
In 1958, twenty-five different songs were able to top one of the four charts. A majority of the songs which topped the Best Sellers in Stores, which Billboard considered the predecessor of the Hot 100, were able to also top the two other singles-tracking charts. The first song to top all three charts was Danny & the Juniors' "At the Hop".

On the Hot 100, eight acts hit the top, which were also their first. Those acts include Ricky Nelson, Domenico Modugno, The Elegants, Tommy Edwards, Conway Twitty, The Kingston Trio, The Teddy Bears, and The Chipmunks (even though David Seville went to number one earlier this year with "Witch Doctor", which hit prior to the creation of the Hot 100).

Pre-Hot 100
NOTE: The Hot 100 Era officially began on Monday, August 4, 1958, which would be the week ending August 10 (issue date August 4).  The Best Sellers in Stores list issued through October 13.

Hot 100

Number-one artists

See also
1958 in music
List of Billboard number-one singles

References

Further reading
Fred Bronson's Billboard Book of Number 1 Hits, 5th Edition ()

1958
1958 record charts

List of Billboard number-one singles of 1958


Republika Hrvatska i Savezna Republika Brazil održavaju diplomatske odnose od 23. prosinca 1992. Sjedište veleposlanstva je u Braziliji.

Veleposlanici
Veleposlanstvo Republike Hrvatske u Saveznoj Republici Brazil osnovano je odlukom predsjednika Republike od 28. listopada 1996.

Vidi još
Ministarstvo vanjskih i europskih poslova Republike Hrvatske

Vanjske poveznice
 Brazil na stranici MVEP-a

Izvori

Brazil

Popis hrvatskih veleposlanika u Brazilu


Die US-amerikanische Badmintonmeisterschaft 2010 fand vom 9. bis zum 11. April 2010 im Orange County Badminton Club in Orange, Kalifornien, statt.

Medaillengewinner

Weblinks
 http://www.tournamentsoftware.com/sport/tournament.aspx?id=FBBD9ED3-9E3C-4194-984E-CC1C5795F099

2010
Badminton 2010
Badmintonwettbewerb in Orange (Kalifornien)


Poujadismul a fost o mișcare politică și sindicală franceză apărută în 1953 în departamentul Lot și dispărută în 1958.

Ideologii politice
Mișcări sociale

Poujadism


Baron Kirkwood, of Bearsden in the County of Dunbarton, is a title in the Peerage of the United Kingdom. It was created in 1951 for the Scottish engineer, trade unionist, Independent Labour Party and later Labour politician David Kirkwood. The title is currently held by his grandson James, the fourth baron, who succeeded his brother David in 2023.

Baron Kirkwood (1951)
 David Kirkwood, 1st Baron Kirkwood (1872–1955)
 David Kirkwood, 2nd Baron Kirkwood (1903–1970)
 David Harvie Kirkwood, 3rd Baron Kirkwood (1931–2023)
 James Stuart Kirkwood, 4th Baron Kirkwood (born 1937)

The heir presumptive is the present holder's first cousin once removed, Douglas James Kirkwood (born 1974).

Male-line family tree

Line of succession

  David Kirkwood, 1st Baron Kirkwood (1872–1955)
  David Kirkwood, 2nd Baron Kirkwood (1903–1970)
  David Harvie Kirkwood, 3rd Baron Kirkwood (1931–2023)
  James Stuart Kirkwood, 4th Baron Kirkwood (born 1937)
 Hon. James Smith Kirkwood (1912–1983)
 Col. David Kirkwood (1945–2020)
 (1) Douglas James Kirkwood (born 1974)
 (2) David Angus Kirkwood (born 1978)
 (3) Robert Cameron Kirkwood (born 1981)

See also
Archibald Kirkwood, Baron Kirkwood of Kirkhope

Notes

References

Sources
 Kidd, Charles, Williamson, David (editors). Debrett's Peerage and Baronetage (1990 edition). New York: St Martin's Press, 1990,

Baronies in the Peerage of the United Kingdom
Noble titles created in 1951
Noble titles created for UK MPs

Baron Kirkwood


Miroslav Manolov ( ; ) este un fotbalist bulgar, care evoluează pe postul de atacant, fiind, în prezent, liber de contract. De-a lungul carierei a evoluat la cluburi precum ȚSKA Sofia, Cerno More Varna, Litex Loveci sau ASA Târgu Mureș.

Carieră

Începuturi
Născut în Sopot, Manolov și-a început cariera la clubul local, Metalik. Și-a făcut debutul la echipa din al treilea eșalon bulgar în anul 2000, la vârsta de doar 15 ani.

ȚSKA Sofia
Manolov și-a făcut debutul în sezonul 2003-2004, pe data de 28 octombrie 2003, în meciul de Cupa Bulgariei dimpotriva celor de la Pirin Blagoevgrad, înlocuindu-l pe Krasen Valkov.

În martie 2005 a fost împrumutat la Conegliano German, unde și-a arătat abilitatea de a marca. A fost golgheterul sezonului 2005-2006 al diviziei secunde bulgare, marcând 19 goluri în 25 de meciuri. S-a întors la ȚSKA după un sezon. Pe 27 august 2006, Manolov a marcat singurul său gol pentru ȚSKA în primul eșalon, într-o victorie cu 4-0 împotriva celor de la Spartak Varna.

Prima perioadă la Cerno More
Pe 8 ianuarie 2007, Daniel Morales a fost transferat de ȚSKA de la Cerno More Varna, Manolov fiind trimis la Varna alături de Daniel Georgiev, sub formă de schimb. Manolov a debutat pe 5 martie, împotriva fostei sale echipe, ȚSKA, într-un meci care s-a terminat la egalitate, 0-0.

Pe 14 iulie 2007 marchează primul său gol pentru Cerno More, într-o victorie cu 3-0 împotriva celor de la Makedonija Gjorče Petrov, într-un meci de Cupa Intertoto. Primul gol în ligă a fost marcat pe 1 decembrie, cu capul, fiind golul decisivr în derbiul cu rivalii de la Spartak Varna. Pe 5 aprilie 2008, Manolov marca primul său hattrick în prima divizie bulgară într-o victorie a echipei sale cu 4-1 împotriva celor de la Marek Dupnitsa.

Pe 15 iulie 2011, Manolov a revenit pentru Cerno More după o accidentare serioasă la genunchi, care l-a ținut pe bancă un an și jumătate. A jucat 18 minute într-un meci amical cu FC Bansko. În august 2011, Manolov primește numărul 10 purtat de Daniel Dimov. Primul său gol al sezonului a venit pe 5 noiembrie 2011, într-o victorie cu 2-0 împotriva celor de la Beroe Stara Zagora. În data de 22 martie 2012, Manolov a marcat încă un hattrick, împotriva Montanăi; primul gol a fost marcat în secunda șapte a partidei, stabilind un nou record al primei divizii bulgare pentru cel mai rapid gol marcat vreodată. Pe 23 septembrie 2012 a fost eliminat pentru prima oară de la transferul său la Cerno More, pentru un fault periculos. La finalul sezonului, Manolov se transferă la un alt club din primul eșalon bulgar.

Litex Loveci
Manolov se transferă la Litex Loveci pentru turul sezonului 2013-2014, unde marchează de 3 ori în 31 de meciuri. Apoi, acesta se întoarce la clubul din Varna.

A doua perioadă la Cerno More
După doar jumătate de sezon petrecut la Loveci, Manolov se întoarce la fostul său club, Cerno More Varna, unde marchează două goluri în 17 partide, înainte de a obține primul său transfer în străinătate.

Târgu Mureș
Pe 17 ianuarie 2015, Manolov semnează un contract pe doi ani cu ASA Târgu Mureș, primind numărul 9. Aici câștigă primul său trofeu din carieră, Supercupa României, în primele sale săptămâni la club. După un tur în care a marcat de 2 ori în 29 de partide, Manolov se desparte de clubul român.

Palmares
 ASA Târgu Mureș
 Supercupa României 2015

Referințe

Legături externe

Profil pe TransferMarkt

Nașteri în 1985
Nașteri pe 20 mai
Fotbaliști bulgari
Fotbaliști internaționali bulgari
Fotbaliști ai ASA Târgu Mureș
Bulgari în viață

Miroslav Manolov


Zeki Demirkubuz (d. 25 Temmuz 1964, Isparta), Türk film yönetmeni, senarist, yapımcı ve oyuncu.

Yaşam öyküsü
Zeki Demirkubuz 1964 yılında Isparta'da doğdu. Ortaokulu Isparta'da, Isparta Gönen Fen Lisesi Gönen Öğretmen Okulu'nda bitirdikten sonra İstanbul'a yerleşti. Liseye İstanbul'da başladıysa da ilk sömestrdan sonra okulu bırakarak fabrika ve atölyelerde çalışmaya başladı. 1980 darbesinden sonra tutuklanıp üç yıl hapis yattı, işkence gördü. Bu dönemde edebiyata ilgi duymaya başlayıp Dostoyevski'yi keşfetti. Özellikle Suç ve Ceza'nın, üzerindeki kalıcı etkileri o yıllarda oluştu. Tahliyesinden sonra Anadolu'nun çeşitli kentlerinde işportacılık yaptı. Askerliğini erteleyebilmek için okula dönmeye karar verdi ve liseyi dışarıdan bitirerek İstanbul Üniversitesi İletişim Fakültesi'ne girdi.

Sinemaya 1986 yılında Zeki Ökten'in asistanlığını yaparak başladı. İlk uzun filmi C Blok'u çekene kadar çeşitli yönetmenlerin asistanlığını yaptı. C Blok'tan sonra Demirkubuz, kendi senaryolarını yazan bağımsız bir yönetmen olarak çalışmaya devam etti. Uluslararası eleştirmenler ve izleyiciler, Demirkubuz'u Venedik Film Festivali'nde gösterilen ikinci filmi Masumiyet'le tanıdı. Demirkubuz'un üçüncü filmi olan Üçüncü Sayfa, Türkiye'deki film festivallerinin yanı sıra Locarno ve Rotterdam Film Festivalleri de dâhil olmak üzere Avrupa'da yapılan çok sayıda film festivalinde gösterildi. Bu dönemde Zeki Demirkubuz "Karanlık Üzerine Öyküler" adını verdiği üçlemesinin çalışmalarına başladı. Üçlemenin ilk iki filmi, Yazgı ve İtiraf, 2002 yılında Cannes Film Festivali'nin "Un Certain Regard" bölümünde gösterildi. Üçlemesini başrolünü de üstlendiği Bekleme Odası'yla (2003) tamamlayan Demirkubuz, daha sonra Masumiyet'in başlangıç öyküsünü anlatan Kader'i çekti (2006). 2009 yılında gösterime giren 'Kıskanmak' filminin ardından, 'Yeraltı' (2012) adlı filmi çekmiştir. Bulantı ve Kor filmlerini 2015 itibarıyla tamamlamıştır. Kemal Sunal'ın oynadığı Yoksul filminde oynamış ayrıca İşler Güçler dizisinin final bölümünde rol almıştır.

Beşiktaş JK taraftarı olan Demirkubuz'un en sevdiği futbolcu İlhan Mansız'dır. Bir röportajında Türk sinema tarihinde en sevdiği yönetmenin Yılmaz Güney olduğunu dile getirdi.

Filmleri

Kaynakça

Dış bağlantılar

Yaşayan insanlar
1964 doğumlular
Isparta doğumlu oyuncular
Zeki Demirkubuz
Türk film yönetmenleri
Türk senaristler
Türk erkek sinema oyuncuları
Türk kurgucular
Ankara Uluslararası Film Festivali Ödülü sahibi yönetmenler
İstanbul Üniversitesi İletişim Fakültesinde öğrenim görenler
Altın Portakal En İyi Film Ödülü kazanan yapımcılar

Zeki Demirkubuz


An Platanthera albomarginata in uska species han Liliopsida nga ginhulagway ni Friedrich Fritz Wilhelm Ludwig Kraenzlin. An Platanthera albomarginata in nahilalakip ha genus nga Platanthera, ngan familia nga Orchidaceae. Waray hini subspecies nga nakalista.

Mga kasarigan

Platanthera

Platanthera albomarginata


Chromaffin cells, also called pheochromocytes (or phaeochromocytes), are neuroendocrine cells found mostly in the medulla of the adrenal glands  in mammals. These cells serve a variety of functions such as serving as a response to stress, monitoring carbon dioxide and oxygen concentrations in the body, maintenance of respiration and the regulation of blood pressure.  They are in close proximity to pre-synaptic sympathetic ganglia of the sympathetic nervous system, with which they communicate, and structurally they are similar to post-synaptic sympathetic neurons. In order to activate chromaffin cells, the splanchnic nerve of the sympathetic nervous system releases acetylcholine, which then binds to nicotinic acetylcholine receptors on the adrenal medulla. This causes the release of catecholamines. The chromaffin cells release catecholamines: ~80% of adrenaline (epinephrine) and ~20%  of noradrenaline (norepinephrine) into systemic circulation for systemic effects on multiple organs (similarly to secretory neurones of the hypothalamus), and can also send paracrine signals. Hence they are called neuroendocrine cells.

Structure
There are two types of cells that originate from the neural crest and are related to the sympathetic nervous system (originate from a cell called sympathogonia):

1) Neuroblasts: These cells migrate, during the fourth to the fifth week of fetal development in humans, on both sides of the spinal cord toward the region just behind the dorsal aorta forming the two chains of sympathetic ganglia (Sympathetic chain). From these ganglia, the post synaptic sympathetic fibers will arise and extend toward their target organ. Some of these cells will migrate to the adrenal medulla to form sympathetic ganglia cells within the adrenal medulla (without postsynaptic sympathetic fibers). A tumor arising from these cells is called neuroblastoma.

2) Chromaffin cells (or pheochromocytes): These cells will migrate to the area adjacent to the sympathetic ganglia (hence the name paraganglia) and to the adrenal medulla where they will be the most abundant type of cells. The largest extra-adrenal cluster of chromaffin cells in mammals is the organ of Zuckerkandl. Tumors arising from these cell are called paragangliomas or pheochromocytomas. These terms can be used interchangeably but usually paraganglioma refer to a tumor originating from chromaffin cells outside the adrenal gland, which can also be called extra-adrenal pheochromocytoma, whereas pheochromocytoma typically refer to a tumor originating from the chromaffin cells within the adrenal gland.

Chromaffin cells also settle near the vagus nerve and carotid arteries. In lower concentrations, extra-adrenal chromaffin cells also reside in the bladder wall, prostate, and behind the liver.

In non-mammals, chromaffin cells are found in a variety of places, generally not organised as an individual organ, and may be without innervation, relying only on endocrine or paracrine signals for secretion.

Function

Chromaffin cells of the adrenal medulla are innervated by the splanchnic nerve and secrete adrenaline (epinephrine), noradrenaline (norepinephrine), some dopamine, enkephalin and enkephalin-containing peptides, and a few other hormones into the blood stream. The secreted adrenaline and noradrenaline play an important role in the sympathetic nervous system response, commonly called the fight-or-flight response. The enkephalins and enkephalin-containing peptides are related to, but distinct from endogenous peptides named endorphins (which are secreted from the pituitary); all of these peptides bind to opioid receptors and produce analgesic (and other) responses. The hormones are secreted from chromaffin granules; this is where the enzyme dopamine β-hydroxylase catalyses the conversion of dopamine to noradrenaline.  Distinct N and E cell forms exist (also Na and A cells in British nomenclature - noradrenaline and adrenaline); the former produce norepinephrine, the latter arise out of N cells through interaction with glucocorticoids, and convert norepinephrine into epinephrine.

Clinical significance
Neoplasms arising from these cells are pheochromocytomas (also called chromaffin or sympathetic paragangliomas, in contrast to non-chromaffin or parasympathetic paragangliomas of glomus cells). Sometimes only neoplasms of adrenal origin are named pheochromocytomas, while others are named extra-adrenal paragangliomas.

Heart failure
Following heart failure, the body increases sympathetic activity to the adrenal medulla as the compensatory mechanism to increase heart rate and cardiac output. This increased sympathetic activity leads to chronically increased synthesis and secretion of catecholamines from the adrenal chromaffin cells. This chronic increase of epinephrine and norepinephrine secretion causes desensitization of the chromaffin cells to catecholamines resulting in a decrease in production and presence of α2 adrenergic receptors on their cell membrane. This desensitization and downregulation of α2 adrenergic receptors is caused by the upregulation of the enzyme Adrenal G protein coupled receptor kinase 2 (GRK2) which effectively eliminates the normal autocrine-type negative feedback that normally prevents the cells from over producing the catecholamines and replaces it with a positive feedback loop in which increased secretion further elicits more secretion. This upregulation of GRK2 is also accompanied by upregulation and increased production of the enzyme tyrosine hydroxylase, which catalyzes the rate limiting step of catecholamine synthesis.

History
The word "chromaffin" comes from a portmanteau of chromium and affinity. They are named as such because they can be visualised by staining with chromium salts. Chromium salts oxidise and polymerise catecholamines to form a brown color, most strongly in the cells secreting noradrenaline. Chromaffin cells are also called pheochromocytes.

The enterochromaffin cells are so named because of their histological similarity to chromaffin cells (they also stain yellow when treated with chromium salts), but their function is quite different and they are not derivatives of the neural crest.

Paraganglia are clusters of either chromaffin cells or glomus cells near sympathetic ganglia.

See also
List of distinct cell types in the adult human body
List of human cell types derived from the germ layers

References

External links
  - "Endocrine System: adrenal gland, reticularis and medulla"
 Secretion Control in Adrenal Chromaffin Cells
 UC-San Diego Chromaffin Cell and Hypertension Research
 A Primer on Chromaffin Cells
 Rat Chromaffin cells primary cultures: Standardization and quality assessment for single-cell assays (a protocol)
 [https://pscientifics.com/adrenal-chromaffin-cell-stain-giemsa-staining-method/Adrenal Chromaffin Cell Stain (Giemsa Staining Method)
]

Neuroendocrine cells
Human cells
Adrenal gland

Chromaffin cell


Türkmenlioğlu, Sinop ilinin Gerze ilçesine bağlı bir köydür.

Tarihçe
Yerleşim, 1992 yılında Mahmuttırı köyünden ayrılarak köy statüsü kazandı.

Coğrafya
Köy, Sinop il merkezine 44 km, Gerze ilçe merkezine 6 km uzaklıktadır. Köy yakınlarındaki Yolüstü mevkiinde bir antik dönem yerleşim alanı bulunur.

Nüfus

Kaynakça

Dış bağlantılar

Gerze belde ve köyleri

Türkmenlioğlu


تصدر جمهورية الكونغو جواز السفر إلى المواطنين الكونغوليين للسفر إلى خارج جمهورية الكونغو، التي تعرف أيضا باسم الكونغو برازافيل.

السفر بدون تأشيرة

البلدان التالية تسمح تأشيرة مجانية أو تأشيرة دخول على أساس وصوله للسفر المواطنين الكونغوليين :

أفريقيا

الأمريكتين

آسيا

أوروبا

أوقيانوسيا

مراجع

وصلات خارجية

جمهورية كونغو
حكومة جمهورية الكونغو

جواز سفر جمهورية الكونغو


100077 Tertzakian este un asteroid din centura principală de asteroizi.

Descriere
100077 Tertzakian este un asteroid din centura principală de asteroizi. A fost descoperit pe  la Observatorul Palomar de Andrew Lowe. Asteroidul prezintă o orbită caracterizată de o semiaxă mare de 2,62 ua, o excentricitate de 0,21 și o înclinație de 14,1° în raport cu ecliptica.

Vezi și
 Lista planetelor minore: 100001-101000
 Centura de asteroizi

Referințe

Obiecte astronomice descoperite în 1992
Centura de asteroizi

100077 Tertzakian


Obi-Wan Kenobi (poznata i kao 'Star Wars: Obi-Wan Kenobi) američka je televizijska miniserija iz 2022. godine koju je producirao Lucasfilm studio za streaming platformu Disney+.

Miniserija usredotočuje se na istoimeni lik koji glumi Ewan McGregor, koji je prethodno glumio Jedija u prequel trilogiji, ovdje i kao izvršni producent. Serija, koja je u početku nastala kao antologijski spin-off filmova Rogue One i Solo, smještena je deset godina nakon događaja iz filma Epizoda III: Osveta Sitha, a ujedno označava povratak Haydena Christensena u ulozi Dartha Vadera.

Serija premijerno će bit prikazana 27. svibnja 2022. godine na Disney+-u a sastojat će se od šest epizoda.

Radnja
Deset godina nakon dramatičnih događaja iz Epizode III: Osveta Sitha, Obi-Wan Kenobi bdije nad Lukeom Skywalkerom na pustinjskom planetu Tatooineu, nakon što je pretrpio svoj najveći poraz, odnosno propast svog najboljeg prijatelja i šegrta Jedija Anakina Skywalkera, koji je postao zli i korumpirani sith Lord Darth Vader i koji je sada vođa inkvizitora, čiji je zadatak uništiti posljednje fragmente Jedi reda.

Glumačka postava

 Ewan McGregor kao Obi-Wan Kenobi
 Hayden Christensen kao Anakin Skywalker / Darth Vader
 Joel Edgerton kao Owen Lars
 Bonnie Piesse kao Beru Whitesun Lars
 Moses Ingram kao Reva / Third Sister
 Indira Varma kao Imperial officer
 Rupert Friend kao Grand Inquisitor
 Sung Kang kao Fifth Brother
 Kumail Nanjiani kao Haja Erstree
 Benny Safdie kao Nari
 Jimmy Smits kao Bail Organa
 Simone Kessell kao Breha Organa
 Vivien Lyra Blair kao Leia Organa

Uz to, O'Shea Jackson Jr., Maya Erskine i Rory Ross dobili su uloge u neobjavljenim ulogama.

Pojavit će se i mladi Luke Skywalker,  kojeg će glumiti Grant Feelyc

Produkcija

Snimanje
Snimanje je započelo u travnju 2021. u Los Angelesu, dok je McGregor potvrdio da je počeo snimati 4. svibnja, na Dan Ratova zvijezda. Za snimanje je korištena tehnologija videowall StageCraft, koja se prethodno koristila u Mandalorianu i The Book of Boba Fett. McGregor je radio kostimirane probe za Obi-Wan Kenobija na setu Mandaloriana i rekao da mu je StageCraft omogućio da se više zabavlja radeći na seriji nego u prequel trilogiji zbog manje upotrebe plavog i zelenog ekrana. McGregor je potvrdio kraj snimanja 19. rujna 2021. godine.

Glazba
Sredinom veljače 2022. godine John Williams snimio je glavnu temu serije s orkestrom u Los Angelesu. Williams je prethodno napisao temu za Obi-Wan Kenobi u prvom filmu sage, ali s vremenom je bio povezan s temom Force. Ovo je drugi put da je Williams napisao temu za film Zvjezdanih Ratova koji nije povezan s glavnom sagom, kao što je to učinio za Solo: Priča iz Ratova Zvijezda.

U travnju 2022. objavljeno je da je Natalie Holt skladala soundtrack za miniseriju, osim teme Obi-Wan, posuđujući svoj glas i nastupajući s vlastitom violinom. Holt je prva žena koja je ikada skladala glazbu za sagu.

Chow je otišla u London kako bi upoznala Holt i imala "dva dana intenzivnog ronjenja" pokazujući njezine nepotpune snimke serije. Holt je tada počela razvijati teme za nove likove i pisati soundtrack koji, kako je rekla, "ima korijena u tradicionalnim Ratovima zvijezda" više nego što je to učinila glazba Ludwiga Göranssona s Mandalorianom.

Holtina glazba snimljena je u Los Angelesu u Fox Studios Newman Scoring Stageu, s nekim dodatnim modernim zvukovima. Kao i kod prethodne glazbe Ratova zvijezda, Holt je bila pod utjecajem kulturne glazbe iz stvarnog svijeta da predstavlja različite planete u seriji, uključujući zapadnu i istočnjačku glazbu. Holt je koristila lovačke rogove i neke neobične udaraljke koje je proizveo Brian Kilgore kako bi stvorila temu inkvizitora. Holt je završila svoj rad za seriju krajem travnja 2022. godine.

Promocija
Prva službena slika serije zajedno s datumom izlaska objavljena je 9. veljače 2022. Mjesec dana kasnije, službeni trailer objavljen je na internetu.

Distribucija
Premijera serije prvotno je bilo zakazana za 25. svibnja 2022., točno 45 godina nakon osnutka sage, ali 31. ožujka 2022. objavljeno je da će serija biti objavljena na Disney+-u u petak, 27. svibnja 2022. s dvostrukom pizodom. Od treće epizode nadalje bit će objavljena tjedno srijedom.

Izvori

Vanjske poveznice

Zvjezdani ratovi
Američke serije
Televizijske serije koje su počele 2022.
Televizijske serije koje su završile 2022.

Obi-Wan Kenobi (televizijska serija)


Ruslands Grand Prix (, ) er et Formel 1-løb som bliver kørt på Sochi Autodrom i Sotji ved kysten af Sortehavet i Rusland. Det første løb blev kørt 12. oktober 2014, og var det første Formel 1-løb i Rusland nogensinde.

Vindere af Ruslands Grand Prix

Løb markeret med rosa baggrund var ikke en del af Formel 1-verdensmesterskabet.

Eksterne henvisninger

Ruslands Grand Prix


Arhiiatrosul era medicul personal al domnitorului, în epoca fanarioților; era în același timp medic al domnitorului și însărcinat cu supravegherea serviciilor sanitare și a farmaciilor. (Gáldi 153). Sec. XVIII.

Istoria medicinei

Arhiiatros


وديان في ليبيا

حرف أ
 وادي البرد بمدينة البيضاء .
 وادي الكوف بالجبل الأخضر .
 وادي أم العرائس .
 وادي أم الطلح .
 وادي ايراون .
 وادي ايسلان .
 وادي ابيتر .
 وادي الحي
 وادي المجينين
 وادي الآجال
 وادي الاثل الرياينه.
 وادي اطبيرق في طبرق .
وادى الحنيوة وادى النوفلية وادى اتلال وادى الزيد .

حرف ب
 وادي بي الكبير
 وادي بني وليد
 وادي برجوج
 وادي بو لشفه
 وادي بو مراس
 وادي بو شبيرم
 وادي بو شيبة
 وادي بطيحه
 وادي باب

حرف ت
 وادي تامت
 وادي تاناروت
 وادي تماسله
 وادي تينيناي
 وادي تمله
 وادي تناملو
وادي ترغت

حرف ج
 وادي جبيل
 وادي جرجير
 وادي جارف

حرف ح
 وادي حاد
 وادي حميم
 وادي حمام
 وادي حمامة
 وادي حجل
 وادي حليقيمة
 وادي حياة
 وادي حلق الريح

حرف خ
 وادي خليج
 وادي ختنه

حرف د
 وادي دويويرة

حرف ذ
 وادي ذمران

حرف ر
 وادي رمل
 وادي رمله
 وادي رباط

حرف ز
 وادي زغادنه
 وادي زلاف
 وادي زوزام
 وادي زمزم
 وادي زعتر
 وادي زرزر
 وادي زازمت

حرف س
 وادي سوف الجين
 وادي سيرات
 وادي سمالوس
 وادي سوس
 وادي سهل النار
 وادي ساريه
 وادي ساسو

حرف ش
 وادي شرشوف
 وادي شرشارة
 وادي شاطئ
 وادي شهوبيين
 وادي شعبة

حرف ص
 وادي صواخ

حرف ط
 وادي طلحية
 وادي طيبه

حرف ع
 وادي عدوان
 وادي عراض
 وادي عتبة
 وادي العودة في طبرق

حرف غ
 وادي غبي
 وادي غرارة
 وادي غان

حرف ف
 وادي فريش
 وادي فارغ
 وادي فخ
 وادي فيصل
 وادي فرس

حرف ق
 وادي قوز
 وادي قرزة
 وادي قطارة
 وادي قومان
 وادي قرضيب

حرف ك
 وادي كعام
 وادي الكوف

حرف م
 وادي ميمون دراج
 وادي مردوم
 وادي مجينين
 وادي محروقة
 وادي مسوس
 وادي مرا
 وادي مرتبة
 وادي معلق
 وادي ملغة
 وادي نشوع
 وادي نغارة
 وادي هيرة
 وادي هويد
 وادي هيشة

حرف و
 وادي واسق
 وادي وامس
 وادي وخيم

حرف ي
 وادي يار

الجبال في ليبيا

حرف أ
 جبل اركنو ( 1430 متر )
 جبال أكاكوس ( 1428 متر – سلسلة جبلية )
 الجبل الأخضر (ليبيا) ( 882 متر – سلسلة جبلية )
 الجبل الغربي

حرف ب
 جبل باكور ( 458 متر )
 جبل بن غنيمة ( 740 متر )

حرف ت
 جبل تارسو ( 2286 متر – سلسلة جبلية )
 جبل تادرارت ( 1357 متر – سلسلة جبلية )
 جبال تيبستي ( 3376 متر – سلسلة جبلية )

حرف ج
 جبل جردس الاحرار ( العبيد سابقا ) ( 676 متر )

حرف ف
 جبل فزان ( )

حرف س
 جبل السودا ( 840 متر )

حرف ع
 جبل العوينات ( 988 متر )

حرف غ
 الجبل الغربي

حرف ن
 جبل نفوسة ( 725 متر – سلسلة جبلية )
 جبل نقي ( 1650 متر – سلسلة جبلية )

حرف هـ
 الهروج ( 1200 متر – تجمع بركان هائل )
 جبل هوائش ( )

حرف و
 جبل واو الناموس ( 0000 متر – جبل بركاني )
 جبل ودان ( 671 متر )

جبال ليبيا
قوائم جبال حسب البلد
قوائم متعلقة بليبيا
قوائم متعلقة بجغرافيا ليبيا

قائمة وديان وجبال ليبيا


Anton Hieronymus Fritzsche Klubien (født 26. juli 1834 i Randers, død 5. december 1893 i København) var en dansk jurist.

Klubien blev student i 1852, cand. jur. i 1857, samme år volontær i Justitsministeriet, fuldmægtig sammesteds i 1863, Højesteretsadvokat i 1867.

Kilder

Jurister fra Danmark
Danskere i 1800-tallet
Personer fra Randers

Anton Hieronymus Fritzsche Klubien


Innan Glyvur er en lille bygd på Eysturoy, en af Færøerne. Stedet ligger i Sjóvar kommuna, lige nord for kommunecenteret Strendur. Innan Glyvur blev grundlagt i 1884. 1. januar 2009 havde Innan Glyvur 73 indbyggere, mod 38 i 1985.

Referencer

Eksterne henvisninger

Innan Glyvur på faroeislands.dk

Bygder på Færøerne
Eysturoy

Innan Glyvur


Vidros elétricos são vidros de automóveis que podem ser levantados e abaixados pressionando um botão ou interruptor, em vez de usar uma manivela.

O primeiro automóvel com vidros elétricos vendido no Brasil foi o Ford Del Rey, na sua versão de topo Ouro, em 1981.

Partes do automóvel
Tecnologias automotivas

Vidro elétrico


Gaj urni – Krematorij prvi je krematorij podignut u Hrvatskoj. Nalazi se na zagrebačkom groblju Mirogoju. Površina iznosi 20 hektara. Po podatcima od 1. siječnja 2017. godine na ovom je krematoriju pokopano 31.659 osoba, a prisutno je 15.895 grobnih mjesta.

Povijest
Krematorij je izgrađen prema projektu arhitekata Marijana Hržića, Davora Mancea i Zvonimira Krznarića. Prostorni i hortikulturni projekt groblja Gaj urni izradio je Miroslav Kollenz. Krematorij svečano je otvoren 11. studenoga 1985. godine. Prvi pokojnik kremiran je 30. siječnja 1986. godine, a prva osoba pokopana je 4. travnja iste godine.

Izvori

Vanjske poveznice
 Gradnja zagrebačkog krematorija. Intiman i dostojanstven ugođaj, pripremio: Branko Nadilo, Građevinar, 12/2013., str. 1133. – 1137., casopis-gradjevinar.hr

Groblja u Hrvatskoj
Građevine u Zagrebu

Gaj urni – Krematorij


NGC 5993 est une vaste galaxie spirale barrée relativement éloignée et située dans la constellation du Bouvier. Sa vitesse par rapport au fond diffus cosmologique est de (9635 ± 6 km/s), ce qui correspond à une distance de Hubble de . NGC 5993 a été découverte par l'astronome germano-britannique William Herschel en .

La classe de luminosité de NGC 5993 est II et elle présente une large raie HI. Elle renferme également des régions d'hydrogène ionisé. Selon la base de données Simbad, NGC 5993 est une galaxie active qui contient possiblement un quasar.

La vitesse de récession de NGC 5993 et de NGC 5992 sont presque les mêmes. Elles sont donc à la même distance de la Voie lactée. De plus, il existe un indice d'un flux stellaire entre les deux galaxies, un pâle pont stellaire que l'on perçoit sur l'image des deux galaxies obtenues des données du relevé SDSS. Il s'agit donc presque certainement d'une paire de galaxies en interaction gravitationnelle. De plus, selon Abraham Mahtessian, NGC 5992 et NGC 5993 forment une paire de galaxies.

Notes et références

Références

Voir aussi

Articles connexes
 Liste des objets du New General Catalogue

Liens externes

 NGC 5993 sur le site du professeur C. Seligman

5993
Constellation du Bouvier
Galaxie spirale
Galaxie spirale barrée
Galaxie active
Quasar
Galaxie en interaction
Galaxie découverte en 1787
Objet céleste découvert par William Herschel

NGC 5993