L-type Ca2+ channel modulation by dihydropyridines potentiates kappa-opioid receptor agonist induced acute analgesia and inhibits development of tolerance in rats.
The effect of 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs), nimodipine (NIM) and lercanidipine (LDP) on the analgesic response of selective kappa-opioid receptor agonists, U50,488H, PD117,302 and U69,593 was determined in male Sprague-Dawley rats using the tail-flick test. The effect of NIM on development of tolerance to U50,488H-induced analgesia and the status of brain DHP-sensitive Ca(2+) channel (L-type) binding sites in both U50,488H-naive and tolerant rats was determined using the highly selective DHP radioligand, [(3)H]PN200-110. Tolerance was induced by injecting U50,488H (25 mg/kg, i.p.) twice daily for 4 days. Intraperitoneal (i.p.) injection of kappa-opioid receptor agonists produced a dose-dependent acute analgesic response. NIM (1 mg/kg; i.p.) and LDP (0.3 mg/kg; i.p.) used in the study produced no tail-flick analgesia. Administration of NIM and LDP (15 min prior) significantly potentiated the analgesia produced by three kappa-opioid receptor agonists. Tolerance developed completely to the analgesic effect induced by U50,488H (25 mg/kg, i.p.) administered on the 5th day. NIM (1 mg/kg, i.p.) twice daily for 4 days not only completely inhibited the development of tolerance to analgesic response but also significantly potentiated it (supersensitivity). There was a significant up-regulation of DHP binding sites (B(max): +41%) in whole brain membranes of tolerant rats when compared to vehicle treated naive rats, implicating increased influx of Ca(2+) through L-type channels in kappa-opioid tolerance. U50,488H (25 mg/kg, i.p.) and NIM (1 mg/kg, i.p.) twice daily for 4 days also resulted in an equivalent up-regulation of DHP binding sites (+36%) as that of U50,488H alone. These results strongly suggest a functional role of L-type Ca(2+) channels in the regulation of pain sensitivity, mechanism of kappa-opioid analgesia and expression of tolerance.
Gullapalli
S
S
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Phase - X, Sector 67, S.A.S.Nagar (Mohali) - 160 062, Punjab, India.
Ramarao
P
P
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000698:Analgesia / Q000379:methods / Q000706:statistics & numerical data*; D000818:Animals; D044482:Benzeneacetamides; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D002186:Cannabinoids; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology
D044482:Benzeneacetamides; D020746:Calcium Channels, L-Type; D002186:Cannabinoids; D004095:Dihydropyridines; D011758:Pyrroles; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013876:Thiophenes; C054718:PD 117302; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C045444:U 69593