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

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. •Opioid receptors regulate cutaneous mechanosensation•DOR is expressed by myelinated low-threshold mechanoreceptors that encode touch•DOR depresses neurotransmitter release at the central terminals of mechanoreceptors•DOR and MOR coexist at the surface of peptidergic myelinated nociceptors Bardoni et al. report that the opioid system not only controls pain but broadly regulates cutaneous mechanosensation, including touch. They demonstrate that the delta opioid receptor inhibits voltage-gated calcium channels to depress myelinated mechanosensory neuron input to the spinal cord.