title: μ-Opioid receptor inhibition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain.
abstract: Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in μ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the μ-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund's adjuvant and in naïve rats. This loss of inhibition was not due to μ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by μ-opioid receptors, probably by hindering their signaling mechanisms.
authors.affiliation: Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States; Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, United States.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States; Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, United States.
authors.forename: J A
authors.initials: JA
authors.lastname: McRoberts
authors.affiliation: Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States; Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, United States. Electronic address: marvizon@ucla.edu.
authors.forename: J C G
authors.initials: JC
authors.lastname: Marvizón
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000209:etiology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects; D012585:Sciatica / Q000188:drug therapy* / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013373:Substance P / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013373:Substance P
keywords: inflammation; internalization; neurokinin 1 receptor; neuropathic pain; opioid receptor; substance P