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

• Published in: European journal of pharmacology 1997-05, Vol.325 (2-3), p.155
• Main Authors: Idänpään-Heikkilä, J J, Perrot, S, Guilbaud, G, Kayser, V
• Format: Article
• Language: English
• Subjects: Analgesics - administration & dosage; Animals; Benzodiazepinones - administration & dosage; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Male; Morphine - administration & dosage; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Pain - drug therapy; Pain - etiology; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - antagonists & inhibitors; Sciatic Nerve - drug effects; Sciatic Nerve - injuries; Sciatic Nerve - physiopathology; Stress, Mechanical; Vocalization, Animal - drug effects
• ISSN: 0014-2999
• DOI: 10.1016/S0014-2999(97)00123-4

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.