{"title":"Opioid tolerance and dependence","authors":"Marian E. Fundytus , Terence J. Coderre","doi":"10.1016/S1082-3174(99)70013-9","DOIUrl":null,"url":null,"abstract":"<div><p>Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca<sup>2+</sup>). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.</p></div>","PeriodicalId":101001,"journal":{"name":"Pain Forum","volume":"8 1","pages":"Pages 3-13"},"PeriodicalIF":0.0000,"publicationDate":"1999-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S1082-3174(99)70013-9","citationCount":"48","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pain Forum","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1082317499700139","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 48
Abstract
Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca2+). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.
虽然阿片类药物是最常用的镇痛药,但其治疗效果受到长期使用的耐受性和依赖性的限制。许多研究已经检查了阿片类药物耐受性和依赖性发展的可能机制。最近,一些研究小组关注兴奋性氨基酸受体,特别是n -甲基- d -天冬氨酸(NMDA)受体,以及相关的细胞内第二信使系统作为阿片耐受性和依赖性的可能介质。本文提出的假设是这些阿片耐受性和依赖性模型的延伸,表明代谢性谷氨酸受体(mGluRs)在阿片耐受性和依赖性的发展中起关键作用。我们提出,与磷脂酰肌醇(PI)水解正偶联的I组mGluRs(也可能是δ-阿片受体)的活性在慢性吗啡给药期间增加。这最终导致蛋白激酶C的激活增加,伴随着μ-阿片受体的磷酸化(使其脱敏),以及与NMDA受体相关的离子通道(允许增加Ca2+的流入)。我们还认为,II组和III组mGluRs存在异源脱敏,它们与环磷酸腺苷(cAMP)的产生负偶联,导致阿片类药物依赖和戒断期间cAMP的产生增加。因此,尽管我们同意先前研究者关于NMDA受体重要性的观点,但我们假设mGluRs在兴奋性氨基酸对阿片耐受性和依赖性的贡献中也起着关键作用。