Recent advances on the δ opioid receptor: from trafficking to function

Abstract

Within the opioid family of receptors, δ (DOPrs) and μ opioid receptors (MOPrs) are typical GPCRs that activate canonical second-messenger signalling cascades to influence diverse cellular functions in neuronal and non-neuronal cell types. These receptors activate well-known pathways to influence ion channel function and pathways such as the map kinase cascade, AC and PI3K. In addition new information regarding opioid receptor-interacting proteins, downstream signalling pathways and resultant functional effects has recently come to light. In this review, we will examine these novel findings focusing on the DOPr and, in doing so, will contrast and compare DOPrs with MOPrs in terms of differences and similarities in function, signalling pathways, distribution and interactions. We will also discuss and clarify issues that have recently surfaced regarding the expression and function of DOPrs in different cell types and analgesia. 1 Please note that drug or target nomenclature is not only in accordance with BJPs Concise Guide to Pharmacology (Alexander et al., 2013) but also with the recent review of the opioid receptor nomenclature (Cox et al., 2015). LINKED ARTICLESThis IntroductionOf the opioid family of receptors, the μ opioid receptor (MOPr) is the most well known. In binding with morphine and other semi-synthetic opioids, MOPrs are a well-studied clinical target. Unfortunately, MOPr agonists also induce a number of unwanted effects such as constipation, respiratory depression, analgesic tolerance, dependence and euphoria, which limit medical use and may lead to non-medical abuse.Another member of the opioid receptor family, the δ opioid receptor (DOPr), has high sequence similarity to the MOPr, yet has different physiological and pharmacological properties and is not selectively targeted by an approved pharmaceutical product. Our knowledge of how this receptor functions in different cell types and under different pathological conditions is rapidly evolving. We will present recent evidence of the roles that this receptor may play under different conditions and in different cell types, and discuss how trafficking of this receptor influences DOPr function.The concept that the location of a GPCR such as the DOPr, either intracellular or in different cell types, plays an important role in how the receptor functions is not novel. However, the location, and hence the function, of the DOPr has recently been the subject of some debate. This has resulted in some confusion as to the role of the DOPr under normal or physiological conditions. We will discuss these issues and describe recent findings of where DOPrs are localized and how this receptor functions. Novel interactions, pathways and physiological effects of DOPr activation will also be described suggestive of possible clinical roles of this receptor. Part I. An overview of DOPr localization, trafficking and functionIn the following section, we will first explore the anatomical and cellular localization of DOPrs. This will be followed by an assessment of our curre...

Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum

“…This finding has since been replicated in numerous studies using both pharmacological techniques and immunogold electron microscopy [1,2], and provided the first indication that, unlike most GPCRs, DOPr's are not constitutively trafficked to the cell membrane. Indeed, DOPr's appear to undergo cell membrane-directed trafficking on an 'as-needed' basis via the regulated secretory pathway [2], and this stimulusdriven trafficking has recently been the subject of considerable study.…”

“…This finding has since been replicated in numerous studies using both pharmacological techniques and immunogold electron microscopy [1,2], and provided the first indication that, unlike most GPCRs, DOPr's are not constitutively trafficked to the cell membrane. Indeed, DOPr's appear to undergo cell membrane-directed trafficking on an 'as-needed' basis via the regulated secretory pathway [2], and this stimulusdriven trafficking has recently been the subject of considerable study. Membrane trafficking and functional up-regulation of DOPr's has been observed both in vivo and in vitro following diverse pathological and pharmacological challenges, including chronic inflammatory pain [5], capsaicin treatment [1], chronic ethanol consumption, hypoxia and cancer [2].…”

“…This is of interest because GPCR trafficking and localisation has important functional and hence therapeutic implications [1]. This is particularly true of the δ-opioid receptor (DOPr) [1,2].…”

“…They are Gi/ocoupled receptors which upon agonist binding and activation mediate antinociceptive, anxiolytic and euphoric effects [2,3]. While no DOPr-selective agonists are currently approved for clinical use, these effects make them an important class of potential novel therapeutics, particularly given that DOPr-selective agonists appear to exert fewer side effects than MOPr-active drugs [2].…”

“…Indeed, DOPr's appear to undergo cell membrane-directed trafficking on an 'as-needed' basis via the regulated secretory pathway [2], and this stimulusdriven trafficking has recently been the subject of considerable study. Membrane trafficking and functional up-regulation of DOPr's has been observed both in vivo and in vitro following diverse pathological and pharmacological challenges, including chronic inflammatory pain [5], capsaicin treatment [1], chronic ethanol consumption, hypoxia and cancer [2]. The most extensively studied of these challenges, however, is chronic opioid exposure.…”