Editors' ChoiceNeuroscience

Resolving a Painful Controversy

Science Signaling  25 Mar 2014:
Vol. 7, Issue 318, pp. ec81
DOI: 10.1126/scisignal.2005298

The role of δ opioid receptors (DORs) in sensory neurons and the presence of neurons containing both DORs and μ opioid receptors (MORs) are controversial (see Imlach and Christie). To identify DOR-positive sensory neurons, Bardoni et al. primarily used knockin mice expressing DOR tagged with green fluorescent protein (GFP). The pattern of fluorescence in these mice was similar to dorsal root ganglia (DRG) neurons that were positive for the DOR transcript or to the binding of a DOR-specific ligand in the central nervous system of wild-type mice. Marker analysis for specific classes of myelinated sensory (NF200-positive) neurons indicated that DORs were present in several distinct sets of neurons with characteristics of low-threshold mechanoreceptive neurons (LTMRs) and nociceptive neurons. Retrograde tracer analysis showed that the LTMRs positive for DOR-GFP were not positive for MOR. Instead, in situ immunochemistry revealed that the DOR-GFP and MOR were colocalized at the plasma membrane of a subset of the large-diameter CGRP (a peptide neurotransmitter)– and MOR-positive nociceptive neurons. Morphological and anatomical analysis of whole-mount skin preparations showed that DOR-GRP–positive nerves were associated with (i) the Merkel cells in the touch domes of guard hair cells as the slowly adapting β-amyloid (Aβ) LTMRs that respond to skin indentation; (ii) Meissner corpuscles as rapidly adapting Aβ LTMRs; (iii) a previously undefined type of neuron organized with circumferentially located nerve endings around the hair follicles; and (iv) free nerve endings that terminate in the skin, which is typical of nociceptors. Electrophysiological analysis of a somatosensory system preparation indicated that all of the randomly tested DOR-GFP–positive cells responded to mechanical stimulation and that one population exhibited conduction properties similar to nociceptive neurons (myelinated, high-threshold mechanoreceptive, intermediate-velocity Aδ fibers) and a second population exhibited properties of low-threshold mechanoreceptive Aδ fibers that may mediate both pain and touch sensation. The Aβ DOR-GFP–positive cells could not be assayed in this preparation. Electrophysiological analysis of spinal cord slice preparations from wild-type mice showed that the DOR agonist deltorphin II increased the paired-pulse ratio, consistent with a reduction in the presynaptic activity of Aβ fibers. Analysis of cultured DRGs from DOR-GFP mice showed that deltorphin II inhibited voltage-gated calcium channels in DOR-GFP–positive cells and neurons that responded to both the DOR agonist and a MOR agonist were rarely detected, consistent with the low frequency of detection of these double-positive neurons in vivo. Thus, this extensive analysis suggests that DOR sensory neurons play an important role in both the response to innocuous touch and harmful mechanical stimulation, which has implications for the development of DOR-selective antagonists to treat peripheral neuropathic pain.

R. Bardoni, V. L. Tawfik, D. Wang, A. François, C. Solorzano, S. A. Shuster, P. Choudhury, C. Betelli, C. Cassidy, K. Smith, J. C. de Nooij, F. Mennicken, D. O’Donnell, B. L. Kieffer, C. J. Woodbury, A. I. Basbaum, A. B. MacDermott, G. Scherrer, Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 81, 1312–1327 (2014). [PubMed]

W. Imlach, M. J. Christie, The light touch of delta opioid receptors. Neuron 81, 1220–1222 (2014). [Online Journal]