Role of L-type Ca2+ channels in attenuated morphine antinociception in streptozotocin-diabetic rats.
The role of L-type Ca2+ channels in morphine antinociception was studied in streptozotocin-induced diabetic and control rats, using [3H]PN200-110 [isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycabonylpyridine-3-caboxylate] binding (0.005-1.0 nmol/l) and rat whole brain membranes, to determine if the attenuation of morphine antinociception was related to alterations in dihydropyridine-sensitive Ca2+ channel binding characteristics. The tail-flick antinociceptive effect of morphine (4 mg/kg, i.p.) was significantly reduced in diabetic rats in comparison to that in controls. Nimodipine (0.1-3 mg/kg, i.p.) did not produce antinociception but significantly potentiated the morphine response in control rats. Nimodipine (0.3-3 mg/kg, i.p.) reversed the attenuation of morphine antinociception in a dose-dependent manner in diabetic rats. Moreover, insulin (2 U/kg, s.c.) [correction of mu/kg] reversed the attenuated morphine antinociception in streptozotocin-diabetic rats. A significant increase in the Bmax (+41%) of [3H]PN200-110 binding was observed in diabetic rat brain membranes compared to that in control rats. However, there was no change in affinity (Kd) value of [3H]PN200-110. The reduced morphine response in diabetic rats, in accordance with up-regulation of dihydropyridine sites, may be due to an increased Ca2+ influx through L-type channels. These results suggest a functional role of L-type Ca2+ channels in morphine antinociception and the diabetic state may lead to alterations in their density.
Gullapalli
Srinivas
S
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, Phase-X, S.A.S. Nagar-160 062, Punjab, India.
Gurumoorthy
Krishnamoorthy
K
Kaul
Chaman Lal
CL
Ramarao
Poduri
P
D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D017275:Isradipine / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009553:Nimodipine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014316:Tritium
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007004:Hypoglycemic Agents; D007328:Insulin; D014316:Tritium; D009553:Nimodipine; D013311:Streptozocin; D009020:Morphine; D017275:Isradipine