title: Cholecystokinin receptor mechanism(s) and morphine tolerance in mice.
abstract: In a previous work, the effects of cholecystokinin receptor agonists on tolerance to morphine antinociception were evaluated. In the present study, the influence of cholecystokinin antagonists on the inhibition of tolerance to morphine antinociception by cholecystokinin agonists has been investigated. Maximum tolerance to morphine antinociception was obtained by morphine administration (50 mg/kg) to mice once daily for 4 days. The cholecystokinin receptor agonists caerulein (0.005 mg/kg) or cholecystokinin-8 (0.01 mg/kg) but not unsulfated cholecystokinin-8 (0.01 mg/kg) decreased the development of tolerance to morphine (9 mg/kg). The cholecystokininA receptor antagonist MK-329 (1 mg/kg) or the cholecystokininB receptor antagonist L-365,260 (0.25, 0.5 and 1 mg/kg) also diminished the tolerance to morphine antinociception. When animals were challenged with different doses of MK-329 (0.25, 0.5 and 1 mg/kg) against cholecystokinin-8 (0.01 mg/kg), caerulein (0.005 mg/kg) or unsulfated cholecystokinin-8 (0.01 mg/kg) on day 4 in tolerant mice, different response were obtained. Higher doses of MK-329 (1 mg/kg) caused a small decrease in attenuation of the morphine tolerance induced by cholecystokinin-8 and caerulein. Low doses of L-365, 260 diminished the effect of cholecystokinin-8 on morphine tolerance. Conversely high doses of the drug potentiated the response of caerulein (0.005 mg/kg). When animals were treated with MK-329 or L-365,260 before unsulfated cholecystokinin-8, reduction of the tolerance to morphine antinociception was obtained. These data indicate that both cholecystokinin receptors may modulate morphine tolerance.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran.
authors.forename: M R
authors.initials: MR
authors.lastname: Zarrindast
authors.forename: S
authors.initials: S
authors.lastname: Nikfar
authors.forename: M
authors.initials: M
authors.lastname: Rezayat
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002108:Ceruletide / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D020109:Devazepide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011897:Random Allocation; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013997:Time Factors