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.

Linked articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Keywords: pain; primary afferent neurons; receptor trafficking; β-arrestin; δ opioid receptor; μ opioid receptor.

Figure 1

A schematic model of ROCK-LIMK–β-arrestin 1 dependent regulation of DOPr function. (A) The DOPr agonist, SNC80, binds with DOPrs to activate RhoA-ROCK. As β-arrestin 1 is associated with LIMK and one of the phosphatases, possibly slingshot (SSL), within the trans-Golgi network, cofilin is activated to increase actin filament severing and turnover. This allows a regulated release of DOPrs to the cell membrane to influence the functional effect of the DOPr agonist, SNC80. (B) In the absence of β-arrestin 1, LIMK phosphorylates and inactivates cofilin. This leaves stable actin ‘tracks’ in place to enhance DOPr release to the plasma membrane and increases SNC80-induced locomotion and the pain-relieving effects of SNC80 following a mechanical stimulus (C). Preventing ROCK phosphorylation of LIMK prevents DOPr activation of the pathway and agonist-induced DOPr release to the cell membrane blocking the locomotor and analgesic effects of SNC80 (modified from Mittal et al., 2013).