SUPRASPINAL FLUMAZENIL INHIBITS THE ANTIANALGESIC ACTION OF SPINAL DYNORPHIN-A-(1-17)

DynorphinA (Dyn) administered intrathecally or released spinally in mi ce produces antianalgesia, that is, antagonizes morphine analgesia (ta il-flick test). Spinal transection eliminates this Dyn antianalgesia. Present results in mice show that intracerebroventricular administrati on of flumazenil, a benzodiazepine receptor antagonist, also eliminate d the antianalgesic action of Dyn; flumazenil in the brain eliminated the suppressant effect of intrathecal Dyn on intrathecal and intracere broventricular morphine-induced antinociception. Intracerebroventricul ar clonidine, naloxone, and norbinaltorphimine release spinal Dyn. The latent antinociceptive actions of these compounds were uncovered by i ntracerebroventricular flumazenil. Thus, Dyn, given intrathecally or r eleased spinally, activates a pathway that is inhibited by intracerebr oventricular flumazenil. Dyn antianalgesia is not significantly altere d by intracerebroventricular administration of bicuculline and picroto xin, suggesting that activation of the gamma-aminobutyric acid recepto r has little if any involvement in the antianalgesic action of Dyn. Th e antagonistic effect of Dyn seems to be mimicked by benzodiazepine ag onists. Furthermore, administration of a benzodiazepine receptor inver se agonist ,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) inhibite d Dyn antianalgesia as did flumazenil. Thus, flumazenil, through a ben zodiazepine antagonist or inverse agonist action, interrupts, as does spinal transection, the neuronal circuit (cord/brain/cord) necessary f or the antianalgesic action of spinal Dyn. Because Dyn antianalgesia i s an indirect action, activation of the neuronal circuit must lead to the release of a direct-acting antianalgesic mediator in the spinal co rd. (C) 1998 Elsevier Science Inc.