Supraspinal flumazenil inhibits the antianalgesic action of spinal dynorphin A (1-17).
DynorphinA (Dyn) administered intrathecally or released spinally in mice produces antianalgesia, that is, antagonizes morphine analgesia (tail-flick test). Spinal transection eliminates this Dyn antianalgesia. Present results in mice show that intracerebroventricular administration of flumazenil, a benzodiazepine receptor antagonist, also eliminated the antianalgesic action of Dyn; flumazenil in the brain eliminated the suppressant effect of intrathecal Dyn on intrathecal and intracerebroventricular morphine-induced antinociception. Intracerebroventricular clonidine, naloxone, and norbinaltorphimine release spinal Dyn. The latent antinociceptive actions of these compounds were uncovered by intracerebroventricular flumazenil. Thus, Dyn, given intrathecally or released spinally, activates a pathway that is inhibited by intracerebroventricular flumazenil. Dyn antianalgesia is not significantly altered by intracerebroventricular administration of bicuculline and picrotoxin, suggesting that activation of the gamma-aminobutyric acid receptor has little if any involvement in the antianalgesic action of Dyn. The antagonistic effect of Dyn seems to be mimicked by benzodiazepine agonists. Furthermore, administration of a benzodiazepine receptor inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) inhibited Dyn antianalgesia as did flumazenil. Thus, flumazenil, through a benzodiazepine antagonist or inverse agonist action, interrupts, as does spinal transection, the neuronal circuit (cord/brain/cord) necessary for the antianalgesic action of spinal Dyn. Because Dyn antianalgesia is an indirect action, activation of the neuronal circuit must lead to the release of a direct-acting antianalgesic mediator in the spinal cord.
Rady
J J
JJ
Research Service and Department of Pharmacology and Toxicology, Veterans Affairs Medical Center, Milwaukee, WI 53295, USA.
Holmes
B B
BB
Fujimoto
J M
JM
D000698:Analgesia; D000700:Analgesics / Q000037:antagonists & inhibitors*; D000818:Animals; D003000:Clonidine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004399:Dynorphins / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D005442:Flumazenil / Q000008:administration & dosage*; D018755:GABA Agonists / Q000008:administration & dosage; D058785:GABA-A Receptor Agonists; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000008:administration & dosage; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D010830:Physostigmine / Q000008:administration & dosage
D000700:Analgesics; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D009270:Naloxone; C051844:norbinaltorphimine; D005442:Flumazenil; D009271:Naltrexone; D004399:Dynorphins; D009020:Morphine; D010830:Physostigmine; D003000:Clonidine