Clonidine, administered intracerebroventricularly in mice, produces an anti-analgesic effect which may be mediated spinally by dynorphin a (1–17)

Abstract

Clonidine, administered intracerebroventricularly, was shown to have two actions in the tail-flick test in mice: an overt anti-analgesic and a latent analgesic effect. The antianalgesic effect was demonstrated by antagonism of the antinociceptive response to morphine, administered intrathecally. This anti-analgesic effect was attentuated by naloxone and nor-binaltorphimine, given intrathecally. Given intracerebroventricularly by itself, clonidine had no antinociceptive effect; however, the administration of naloxone and nor-binaltorphimine intrathecally uncovered the latent antinociceptive action of clonidine given intracerebroventricularly. This sensitivity to the opioid antagonists, given intrathecally, indicated that an endogenous anti-analgesic opioid might mediate the actions of clonidine at the spinal level. The putative opioid was postulated to be dynorphin A (1–17). Analgesia induced by intrathecally administered morphine was attentuated by the intrathecal administration of dynorphin A (1–17) at doses of less than 10 pg (5 fmol). This action of dynorphin was blocked by naloxone (5 fg, 0.014fmol) and nor-binaltorphimine (10 ng, 12.3 pmol) at doses which did not block mu and kappa receptors in the spinal cord. The authors propose that clonidine, given intracerebroventricularly, activates an anti-analgesic system which descends spinally and is mediated by dynorphin A (1–17) in the spinal cord. This antianalgesic effect of dynorphin A (1–17) appears to be a new function for dynorphin A (1–17).