Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery

• Published in: Neuroscience letters 2006-03, Vol.396 (1), p.44-49
• Main Authors: Gardell, Luis R., King, Tamara, Ossipov, Michael H., Rice, Kenner C., Lai, Josephine, Vanderah, Todd W., Porreca, Frank
• Format: Article
• Language: English
• Subjects: Afferent Pathways - drug effects; Afferent Pathways - metabolism; Afferent Pathways - physiopathology; Animals; Antinociceptive tolerance; Biological and medical sciences; Central Nervous System - drug effects; Central Nervous System - metabolism; Central Nervous System - physiopathology; Disease Models, Animal; Drug Administration Schedule; Drug Tolerance - physiology; Dynorphin; Dynorphins - drug effects; Dynorphins - metabolism; Fundamental and applied biological sciences. Psychology; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Isomerism; Male; Medical sciences; Narcotics - adverse effects; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Nociceptors - drug effects; Nociceptors - metabolism; Nociceptors - physiopathology; Opioid; Oxymorphone - adverse effects; Pain - chemically induced; Pain - metabolism; Pain - physiopathology; Pain Measurement - drug effects; Pain Threshold - drug effects; Pain Threshold - physiology; Rats; Rats, Sprague-Dawley; Receptors, Opioid - agonists; Receptors, Opioid - metabolism; Receptors, Opioid, mu - drug effects; Receptors, Opioid, mu - metabolism; Spinal Nerve Roots - drug effects; Spinal Nerve Roots - metabolism; Spinal Nerve Roots - physiopathology; Tactile hyperesthesia; Up-Regulation - drug effects; Up-Regulation - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2005.11.009

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.