title: Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers.
abstract: Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin. Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7. The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRP. Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin antiserum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Gardell
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Wang
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Burgess
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: T Philip
authors.initials: TP
authors.lastname: Malan
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004343:Drug Implants; D004361:Drug Tolerance; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D007106:Immune Sera / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009409:Nerve Crush; D009412:Nerve Fibers / Q000187:drug effects* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D004343:Drug Implants; D007106:Immune Sera; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D004399:Dynorphins; D009020:Morphine; C036730:dynorphin A, desTyr(1)-desTrp(14)-desAsp(15)-desAsn(16)-desGlu(17)-; D015740:Calcitonin Gene-Related Peptide