It’s long been known that opioid overdose deaths are caused by disrupted breathing, but the actual mechanism by which these drugs suppress respiration was not understood. Now, a new study by Salk scientists has identified a group of neurons in the brainstem that plays a key role in this process.
The findings, published June 8 in the journal Proceedings of the National Academy of Sciences, show how triggering specific receptors in these neurons causes opioid-induced respiratory depression, or OIRD, the disrupted breathing that causes overdose deaths. It also shows how blocking these receptors can cause OIRD to be reversed.
“The underlying mechanism of why opiates slow down and depress the breathing rhythm has not been fully characterized,” says senior investigator Sung Han, assistant professor in Salk’s Clayton Foundation Laboratories for Peptide Biology. “This knowledge can provide a stepping stone to better treatment options for OIRD.”
The U.S. saw more than 93,000 overdose deaths in 2020, of which an estimated 60 percent were attributed to opioids like fentanyl. Opioids work by binding to proteins on nerve cells (neurons) called opioid receptors and subsequently inhibiting their activity. Currently, naloxone is the only medication known to block the effects of opioids and reverse an overdose. But naloxone has limitations, including a short duration that requires it to be administered multiple times. It also works systemically, blocking opioid receptors throughout the entire body, including those that control pain.
To develop strategies to rescue OIRD with more specificity, Han’s team set out to search for the breathing neurons in the brain that also carry opioid receptors. In the new study, the researchers identified a group of neurons that express a certain type of opioid receptor (the mu opoid receptor) and are located in the brainstem breathing modulation center; they then characterized these neurons’ role in OIRD.
They found that mice that were genetically engineered to lack opioid receptors in these neurons didn’t have their breathing disrupted when exposed to morphine, as mice in the control group did. The researchers also found that, without introducing opioids, stimulating these receptors in control mice caused symptoms of OIRD.
The team then looked at ways to reverse the process by treating the overdosed mice with chemical compounds targeted to other receptors on the same neurons, which play an opposite role as the opioid receptor (activating rather than inhibiting them).
“We discovered four different chemical compounds that successfully activated these neurons and brought back the breathing rate during OIRD,” said first author Shijia Liu, a graduate student in the Han lab. Recovery in overdosed mice was close to 100 percent, which surprised the team.
The researchers next plan to look at whether other cell groups also play a role in OIRD. Further study would also examine the connection between breathing regulation and pain perception in the brain, potentially opening the door to developing more targeted treatments for OIRD.
“We hope to explain the pain-breathing segregation at the molecular or microcircuit level,” says Han, who holds the Pioneer Fund Development Chair. “By doing that, we can try to restore breathing without touching analgesic effects of opioids.”
Other authors on the study are Dong-Il Kim, Tae Gyu Oh, Gerald M. Pao, Jong-Hyun Kim, Kuo-Fen Lee and Ronald M. Evans of Salk; Richard Palmiter of the University of Washington; and Matthew R. Banghart of the University of California San Diego.
Shijia Liu et al, Neural basis of opioid-induced respiratory depression and its rescue, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2022134118
Scientists show how blocking opioid receptors in specific neurons can restore breathing during an overdose (2021, August 13)
retrieved 13 August 2021
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
Ni muda mrefu imekuwa inajulikana kwamba vifo vya overdose opioid ni unasababishwa na kuvurugika kupumua, lakini utaratibu halisi kwa ambayo dawa hizi kukandamiza kupumua haikueleweka. Utafiti wa hivi karibuni uliofanywa na wanasayansi wa Salk University umeonyesha kwamba kuna kikundi cha chembe za neva katika shina la ubongo ambazo huchangia sana utendaji wa ubongo. Utafiti huo, uliochapishwa Juni 8 katika jarida la Proceedings of the National Academy of Sciences, unaonyesha jinsi kuamsha vipokezi maalum katika neurons hizi husababisha opioid-induced kupumua kushuka, au OIRD, kupumua kuvurugika ambayo husababisha vifo vya overdose. Pia inaonyesha jinsi kuzuia receptors hizi inaweza kusababisha OIRD kuwa reversed. "Utaratibu wa msingi wa kwa nini dawa za kulevya hupunguza kasi na kupunguza mwendo wa kupumua haujafafanuliwa kikamilifu", anasema mtafiti mwandamizi Sung Han, profesa msaidizi katika Salk's Clayton Foundation Laboratories for Peptide Biology. "Ujuzi huu unaweza kutoa jiwe la hatua kwa chaguzi bora za matibabu ya OIRD, ""aliandika, ""Mashirika ya afya ya kimataifa yaliona vifo zaidi ya 93,000 vya overdose mnamo 2020, ambayo asilimia 60 ya takriban zilitokana na opioids kama fentanyl." Opioids hufanya kazi kwa kuunganisha na protini kwenye chembe za neva (neurons) zinazoitwa receptors za opioid na baadaye kuzuia shughuli zao. Kwa sasa, naloxone ndiyo dawa pekee inayojulikana kuzuia athari za dawa za kulevya na kurekebisha matumizi ya kupita kiasi. Lakini naloxone ina mapungufu, kutia ndani muda mfupi ambao unahitaji kutolewa mara nyingi. Pia hufanya kazi kwa mfumo, kuzuia vipokezi vya opioid katika mwili wote, ikiwa ni pamoja na zile zinazodhibiti maumivu. Ili kuendeleza mikakati ya kuokoa OIRD kwa usahihi zaidi, timu ya Han ilianza kutafuta neuroni za kupumua katika ubongo ambazo pia hubeba vipokezi vya opioid. Katika utafiti huu, watafiti waligundua kikundi cha neuroni ambazo zinaonyesha aina fulani ya kipokezi cha opioid (mu-o-o-o-o-o) na ziko katika kituo cha kupumua cha brain stem, kisha walielezea jukumu la neuroni hizi katika OIRD. Waligundua kwamba panya ambao walikuwa genetically engineered kukosa opioid receptors katika neurons hizi hakuwa na kupumua yao kuvurugwa wakati wa kuambukizwa morphine, kama panya katika kundi la kudhibiti alifanya. Watafiti pia waligundua kwamba, bila kuanzisha opioids, kuchochea receptors hizi katika panya kudhibiti kusababisha dalili za OIRD. Timu hiyo ilitafuta njia za kugeuza mchakato huo kwa kutibu panya waliopatikana na dawa za kulevya kwa kutumia kemikali zinazolenga receptors nyingine kwenye neurons hizo, ambazo zina jukumu tofauti na opioid receptor (kufanya kazi badala ya kuzizuia). "Tuligundua misombo minne tofauti ya kemikali ambayo ilifaulu kuamsha neuroni hizi na kurudisha kiwango cha kupumua wakati wa OIRD", alisema mwandishi wa kwanza Shijia Liu, mwanafunzi wa kuhitimu katika maabara ya Han. Ugonjwa huo ulisababisha kupotea kwa asilimia 100 ya panya waliopatikana na dawa hiyo, jambo ambalo lilishangaza wataalamu. Watafiti wa sasa wana mpango wa kuangalia ikiwa makundi mengine ya seli pia yana jukumu katika OIRD. Utafiti zaidi pia utachunguza uhusiano kati ya udhibiti wa kupumua na utambuzi wa maumivu katika ubongo, uwezekano wa kufungua mlango kwa maendeleo ya matibabu zaidi ya lengo kwa OIRD. "Tunatumaini kuelezea kutenganishwa kwa maumivu ya kupumua katika ngazi ya molekuli au microcircuit", anasema Han, ambaye anashikilia Mwenyekiti wa Maendeleo ya Mfuko wa Pioneer. "Kwa kufanya hivyo, tunaweza kujaribu kurudisha kupumua bila kugusa athari za analgesic za opioids. ""Wanafunzi wengine wa utafiti huo ni Dong-Il Kim, Tae Gyu Oh, Gerald M. Pao, Jong-Hyun Kim, Kuo-Feng Lee na Ronald M. Evans wa Salk; Richard Palmiter wa Chuo Kikuu cha Washington; na Matthew R. Bangart wa Chuo Kikuu cha California San Diego." Shigeru M. na wenzake, Neural msingi wa opioid-induced kupumua unyogovu na uokoaji wake, Proceedings of National Academy of Sciences (2021). "Kama ilivyoelezwa katika ""Makumbusho ya Ugonjwa wa Ugonjwa"" (D.O.I. 10.1073.pn.2023.1383) wanasayansi wanaonyesha jinsi kuzuia opioid receptors katika neurons maalum inaweza kurudisha kupumua wakati wa overdose (Mwezi wa 2021 Agosti 13) ""Kumbukumbu hii ni chini ya haki za uchapaji.""" Isipokuwa kwa ajili ya utafiti wa kibinafsi au utafiti, hakuna sehemu yoyote inaweza kuzalishwa bila ruhusa ya maandishi. Yaliyomo hutolewa kwa madhumuni ya habari tu.