title: Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance.
abstract: The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
authors.affiliation: Departments of Pharmacology and Anesthesiology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: L R
authors.initials: LR
authors.lastname: Gardell
authors.forename: S E
authors.initials: SE
authors.lastname: Burgess
authors.forename: M
authors.initials: M
authors.lastname: Ibrahim
authors.forename: A
authors.initials: A
authors.lastname: Dogrul
authors.forename: C M
authors.initials: CM
authors.lastname: Zhong
authors.forename: E T
authors.initials: ET
authors.lastname: Zhang
authors.forename: T P
authors.initials: TP
authors.lastname: Malan
authors.forename: M H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: F
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004361:Drug Tolerance; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage; D006614:Hindlimb; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007106:Immune Sera / Q000008:administration & dosage; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage; D010147:Pain Measurement / Q000187:drug effects; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D012684:Sensory Thresholds / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014110:Touch
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D007106:Immune Sera; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004399:Dynorphins; D009020:Morphine