Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

Abstract

SUMMARY Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity.

Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen

“…It is, however, still unclear whether DORs are differentially expressed in mechanical vs. heat sensitive primary afferent fibres terminating in the superficial layers I and II of the spinal dorsal horn. Depending on the experimental approach, DOR receptors have been found largely in peptidergic fibres [3;21;48], in a small subset of non-peptidergic C-fibres and myelinated A-fibres [4;42], or not at all at DRG neuron membranes of naïve animals [6;9]. Our functional approach now revealed that none of the investigated fibre types was considerably inhibited by saturating concentrations of the DOR agonist SNC80.…”

“…They seem to express the TRPM8 channel [13] and could be muscle afferents (R. P. Seal, unpublished observations) or epidermal free nerve endings [30]. Interestingly, TH + DRG neurons have recently been shown not to express MORs [4]. Considering the lack of inhibition by DAMGO observed in most VGluT3 + C-fibres innervating lamina II neurons (present study), this suggests that the population of VGluT3 + C-fibres innervating lamina II neurons could be C-LTMRs.…”

“…Functional DORs have recently been found on mechanosensitive Aβ fibres innervating Merkel cells and terminating in lamina III/IV of the spinal dorsal horn [4], which might transiently express VGluT3 during development [30]. It is, however, still unclear whether DORs are differentially expressed in mechanical vs. heat sensitive primary afferent fibres terminating in the superficial layers I and II of the spinal dorsal horn.…”

Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes

“…*p Ͻ 0.05; **p Ͻ 0.01; ***p Ͻ 0.001. Scale bar, 100 m. We next examined the neurotrophin receptor TrkC, as it is expressed by SAIs and other DRG neurons, including proprioceptors (Airaksinen et al, 1996). Before touch dome innervation at E13.5 and shortly after innervation at E16.5, the percentages of TrkC ϩ and TrkB ϩ TrkC ϩ DRG neurons were equivalent in K14; Atoh1 CKO mice and control littermates ( Fig.…”

“…This is an important consideration because the cell-autonomous and non-cellautonomous mechanisms that control SAI molecular phenotype, peripheral projection morphology, and electrophysiological function are unknown. Importantly, multiple lines of evidence suggest that SAI neurons respond to BDNF and NT3 signaling, presumably through the expression of TrkB and TrkC (Airaksinen et al, 1996;Albers et al, 1996;Fundin et al, 1997;Carroll et al, 1998;LeMaster et al, 1999;Cronk et al, 2002;Szeder et al, 2003;Krimm et al, 2004). These observations raise the possibility that Merkel cell-derived neurotrophins might play a role in directing SAI neuron maturation.…”