In mononeuropathic rats, the enhancement of morphine antinociception by L-365,260, a selective CCK(B) receptor antagonist, depends on the dose of systemic morphine and stimulus characteristics.
The ability of the selective cholecystokinin(B) (CCK(B)) receptor antagonist L-365,260 (0.2 mg/kg s.c.) to modulate the antinociceptive action of relatively low doses of systemic morphine (0.1, 0.3 and 1.0 mg/kg i.v.) was evaluated using a well established rat model of peripheral unilateral mononeuropathy. Behavioural tests based on both mechanical (vocalization threshold to paw pressure) and thermal (struggle latency after immersion of the paw into a cold (10 degrees C), warm (44 degrees C) or hot (46 degrees C) water bath) stimuli were used. Experiments were performed 2 weeks after the surgery when the pain-related behaviour has fully developed. We demonstrated a differential effect of L-365,260 depending both on the dose of morphine and the test used. Pretreatment with the CCK(B) receptor antagonist (0.2 mg/kg) inverted the ineffectiveness of the lowest dose (0.1 mg/kg i.v.) of morphine against the noxious (46 degrees C) thermal stimulus, and the effect of the combination was equal to that seen after the dose 0.3 mg/kg of morphine alone. Likewise, in the mechanical test, the already enhanced effect of this dose (0.1 mg/kg) of morphine on the nerve-injured paw was further increased (by 4-fold) after L-365,260 pretreatment. These effects were abolished by naloxone (0.01 mg/kg i.v.). However, the effects of the higher doses (0.3 and 1.0 mg/kg i.v.) of morphine against the mechanical or noxious thermal stimuli were not significantly enhanced by pretreatment with the CCK(B) receptor antagonist. Further, L-365,260 was found to be completely ineffective in modulating the responses to morphine at 10 degrees C and at 44 degrees C.
Idänpään-Heikkilä
J J
JJ
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Perrot
S
S
Guilbaud
G
G
Kayser
V
V
D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage*; D003080:Cold Temperature; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D013314:Stress, Mechanical; D014828:Vocalization, Animal / Q000187:drug effects
D000700:Analgesics; D001570:Benzodiazepinones; D009292:Narcotic Antagonists; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D009270:Naloxone; C058121:L 365260; D009020:Morphine