Opioid receptor trafficking and interaction in nociceptors

Abstract

Opiate analgesics such as morphine are often used for pain therapy. However, antinociceptive tolerance and dependence may develop with long-term use of these drugs. It was found that μ-opioid receptors can interact with δ-opioid receptors, and morphine antinociceptive tolerance can be reduced by blocking δ-opioid receptors. Recent studies have shown that μ-and δ-opioid receptors are co-expressed in a considerable number of small neurons in the dorsal root ganglion. The interaction of μ-opioid receptors with δ-opioid receptors in the nociceptive afferents is facilitated by the stimulus-induced cell-surface expression of δ-opioid receptors, and contributes to morphine tolerance. Further analysis of the molecular, cellular and neural circuit mechanisms that regulate the trafficking and interaction of opioid receptors and related signalling molecules in the pain pathway would help to elucidate the mechanism of opiate analgesia and improve pain therapy. LINKED ARTICLESThis 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 Abbreviations CGRP, calcitonin gene-related peptide; DOPr-eGFP, δ-opioid receptors inserted with the enhanced green fluorescent protein at the C-terminus; DAMGO, Tyr-D-Ala-Gly-MePhe-Gly-ol; DRG, dorsal root ganglion; HA, haemagglutinin; IB4, isolectin B4; LDCV, large dense-core vesicle; PC12 cell, phaeochromocytoma cell; PM, plasma membrane BackgroundMorphine is widely used for pain therapy. However, its clinical applications are often limited by the development of antinociceptive tolerance. That is, when a dose of morphine is given repeatedly and selectively for a single condition, it gradually loses its antinociceptive potency (Fields, 2004;Manchikanti and Singh, 2008). Studies over the past few decades have demonstrated the presence of many types of opioid receptor in the nociceptive sensory neurons and their Aδ-and C-fibre terminals in the superficial dorsal horn of the spinal cord (Fields et al., 1980; Moskowitz and Goodman, 1984;Gouarderes et al., 1991;Besse et al., 1992;Mennicken et al., 2003). The μ-and δ-opioid receptors are predominantly found to be expressed in small-diameter neurons of the dorsal root ganglion (DRG). These small DRG neurons convey the signals from peripheral nociceptors, thermoreceptors and sensitive mechanoreceptors to the superficial dorsal horn of spinal cord, and cause the release of the excitatory neurotransmitter glutamate, as well as the neuropeptides substance P and calcitonin gene-related peptide (CGRP), from the afferent terminals. This excitatory neurotransmission can be presynaptically inhibited by activating μ-or δ-opioid receptors (Ueda et al., 1995;Zachariou and Goldstein, 1996;Beaudry et al., 2011). Therefore, it is of interest to explore the molecular and cellular mechanisms that regulate opioid analgesia and tolerance. The present review discusses the expression, intracellular trafficking and interaction of opioid recept...

A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors

“…It is possible that these differences reflect cell-type-dependent differences in receptor behavior. The intracellular localization is reduced upon tagging the receptors on the C-terminal tail with GFP (Scherrer et al, 2009;Wang et al, 2010) but is retained in HA and Myc-tagged ␦Rs in small-diameter DRG neurons (Wang et al, 2008(Wang et al, , 2010Zhang et al, 2015). This differential subcellular localization seen with different tags suggests that intracellular retention of ␦R is an actively regulated process, dependent on sequences along the cytoplasmic surface of the receptor, which is shared across multiple neuronal types.…”

Co‐expression of μ and δ opioid receptors by mouse colonic nociceptors

“…DRG neurons express δ, μ and κ opioid receptors, GPCRs that inhibit neuronal excitability and release of inflammatory neuropeptides (Stein, ). However, the functional expression of these receptors on specific subsets of DRG neurons has been an area of ongoing controversy (Scherrer et al ., ; Woolf, ; Beaudry et al ., ; Bardoni et al ., ; Zhang et al ., ). In the somatosensory system, recent studies (Bardoni et al ., ) suggest a divergence of μ and δ receptor expression, with δ receptors being mainly expressed on myelinated A‐type fibres and μ and δ receptor co‐expression in less than 10% of DRG neurons.…”

The delta opioid receptor tool box

“…They are also an excellent tool to study the in vivo trafficking of the delta opioid receptor (Scherrer et al, 2006; Pradhan et al, 2009, 2010; Faget et al, 2012; Bertran-Gonzalez et al, 2013). However, there has been much debate about whether the addition of the eGFP tag alters the cellular distribution and subcellular compartmentalization of delta opioid receptors compared to the endogenous form (Gendron et al, 2014; Zhang et al, 2015). Controversy in this regard is due to the differences in the localization of delta opioid receptors found using DOR-eGFP mice versus delta opioid receptor antibodies.…”