is required for morphine-induced itching. Deactivation As with other G protein-coupled receptors, signalling by the μ-opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis. The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2, and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2. Long-term or high-dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of MOR gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation. Tolerance and overdoses Fatal opioid overdose typically occurs due to bradypnea, hypoxemia, and decreased cardiac output (hypotension occurs due to vasodilation, and bradycardia further contributes to decreased cardiac output). A potentiation effect occurs when opioids are combined with ethanol, benzodiazepines, barbiturates, or other central depressants which can result in rapid loss of consciousness and an increased risk of fatal overdose. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However, tolerance to respiratory depression is quickly lost during withdrawal and may be completely reversed within a week. Many overdoses occur in people who return to their previous dose after having lost their tolerance following cessation of opioids. This puts addicts who receive medical treatment for opioid addiction at great risk of overdose when they are released, as they may be particularly vulnerable to relapse. Less commonly, massive overdoses have been known to cause circulatory collapse from vasodilation and bradycardia. Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example. Opioid antagonists work by binding competitively to µ-opioid receptors and displacing opioid agonists. Additional doses of naloxone may be necessary and supportive care should be given to prevent hypoxic brain injury by monitoring vital signs. Tramadol and tapentadol carry additional risks associated with their dual effects as SNRIs and can cause serotonin syndrome and seizures. Despite these risks, there is evidence to suggest that these drugs have a lower risk of respiratory depression compared to morphine. See also δ-opioid receptor