Naloxone and norbinaltorphimine administered intracerebroventricularly antagonize spinal morphine-induced antinociception in mice through the antianalgesic action of spinal dynorphin A (1-17).
Previously, a number of analgesic agonists, when administered i.c.v. to mice, were shown putatively to activate the release of dynorphin A (1-17) (Dyn A) in the spinal cord. Whether released endogenously or administered i.t., Dyn A produces an antianalgesic action against i.t. administered morphine. In the present study, the opioid antagonists, naloxone and norbinaltorphimine (N-BNI), were shown to activate the Dyn A system. Intracerebro-ventricular administration of both naloxone and N-BNI antagonized the antinociceptive effect of i.t. morphine in the mouse tail-flick test, an effect designated as an antianalgesic action. This antianalgesic action was demonstrated to be mediated by spinal Dyn A in the following ways: 1) the antagonistic effect of i.c.v. naloxone and N-BNI was eliminated by administration of small doses of i.t. naloxone and N-BNI, a unique situation where administration of the opioid antagonists at a second (i.t.) site reversed the antagonistic effect of opioid antagonists administered at the other (i.c.v.) site; 2) i.t. pretreatment with dynorphin antiserum prevented the antianalgesic effect; 3) morphine pretreatment (s.c., 10 mg/kg), which produces desensitization to the effect of spinal Dyn A, eliminated the antianalgesic effect; and 4) pretreatment with i.c.v. naloxone (3 hours) and N-BNI (24 hours) which presumably releases Dyn A produced desensitization to the antagonistic effect of i.c.v. naloxone and N-BNI as well as to the antianalgesic action of i.t. Dyn A. Taken together, the results indicate that both i.c.v. naloxone and N-BNI produced indirect antagonistic actions which were mediated at the spinal cord by the antianalgesic action of Dyn A.(ABSTRACT TRUNCATED AT 250 WORDS)
Holmes
B B
BB
Research Service, Medical College of Wisconsin, VA Medical Center, Milwaukee.
Fujimoto
J M
JM
D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D004399:Dynorphins; D009020:Morphine