Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance

The nonopioid actions of spinal dynorphin may promote aspects of abnormal p ain after nerve injury. Mechanistic similarities have been suggested betwee n opioid tolerance and neuropathic pain. Here, the hypothesis that spinal d ynorphin might mediate effects of sustained spinal opioids was explored. Po ssible abnormal pain and spinal antinociceptive tolerance were evaluated af ter intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkepha lin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (d uring the DAMGO infusion) and a decrease in antinociceptive potency and eff icacy of spinal opioids (tolerance), signs also characteristic of nerve inj ury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a de crease in the m receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dyno rphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hype ralgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive p otency and efficacy of spinal morphine. Neither dynorphin antiserum nor con trol serum administration altered baseline non-noxious or noxious threshold s or affected the intrathecal morphine antinociceptive response in saline-i nfused rats. These data suggest that spinal dynorphin promotes abnormal pai n and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unex plained clinical observations and offer a novel approach for the developmen t of strategies that could improve the long-term use of opioids for pain.