Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery.
Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (-)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction.
Gardell
Luis R
LR
Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
King
Tamara
T
Ossipov
Michael H
MH
Rice
Kenner C
KC
Lai
Josephine
J
Vanderah
Todd W
TW
Porreca
Frank
F
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology; D004399:Dynorphins / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007536:Isomerism; D008297:Male; D009294:Narcotics / Q000009:adverse effects*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010111:Oxymorphone / Q000009:adverse effects; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D009294:Narcotics; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D004399:Dynorphins; D010111:Oxymorphone