title: Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.
abstract: 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.
authors.affiliation: Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Bardoni
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Vivianne L
authors.initials: VL
authors.lastname: Tawfik
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Amaury
authors.initials: A
authors.lastname: François
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shuster
authors.affiliation: Department of Physiology and Cellular Biophysics, Department of Neuroscience, Columbia University, New York, NY 10032, USA.
authors.forename: Papiya
authors.initials: P
authors.lastname: Choudhury
authors.affiliation: Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Betelli
authors.affiliation: Graduate Program in Neuroscience, University of Wyoming, Laramie, WY 82071, USA; Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Cassidy
authors.affiliation: Graduate Program in Neuroscience, University of Wyoming, Laramie, WY 82071, USA; Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Smith
authors.affiliation: Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Joriene C
authors.initials: JC
authors.lastname: de Nooij
authors.affiliation: AstraZeneca R&D Montreal, Department of Translational Science, Montreal, QC H4S 1Z9, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Mennicken
authors.affiliation: AstraZeneca R&D Montreal, Department of Translational Science, Montreal, QC H4S 1Z9, Canada.
authors.forename: Dajan
authors.initials: D
authors.lastname: O'Donnell
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR7104 CNRS/Université de Strasbourg, U964 INSERM, 67400 Illkirch, France.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Woodbury
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
authors.affiliation: Department of Physiology and Cellular Biophysics, Department of Neuroscience, Columbia University, New York, NY 10032, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: MacDermott
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA. Electronic address: gs25@stanford.edu.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D015220:Calcium Channels; D017465:Receptors, Opioid, delta