title: Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia.
abstract: Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models.
authors.affiliation: IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire, Neurobiology and Genetic Department, Illkirch F-67400, France INSERM, U964, Illkirch F-67400, France CNRS, UMR7104, Illkirch F-67400, France UdS Université de Strasbourg, Strasbourg F-67000, France Laboratori de Neurofarmacologica, Facultat de Ciencies de la Salut i de la vida, Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, 08003 Barcelona, Spain Molecular Nociception, Wolfson Institute for Biomedical research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Gaveriaux-Ruff
authors.forename: Chihiro
authors.initials: C
authors.lastname: Nozaki
authors.forename: Xavier
authors.initials: X
authors.lastname: Nadal
authors.forename: Xavier C
authors.initials: XC
authors.lastname: Hever
authors.forename: Raphael
authors.initials: R
authors.lastname: Weibel
authors.forename: Audrey
authors.initials: A
authors.lastname: Matifas
authors.forename: David
authors.initials: D
authors.lastname: Reiss
authors.forename: Dominique
authors.initials: D
authors.lastname: Filliol
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nassar
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000473:pathology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D010879:Piperazines / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000172:deficiency*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010879:Piperazines; D017465:Receptors, Opioid, delta; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D013460:Sulfur Isotopes; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005620:Freund's Adjuvant