Role of L-type Ca(2+) channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia.
Previous studies have shown that the kappa-opioid effects are sensitive to pertussis toxin (PTX) and affected by Ca(2+) fluxes. However, the possible involvement of Ca(2+) channels in PTX-induced inhibition of kappa-opioid effects has not been reported. The effect of intracerebroventricular (i.c.v.) treatment of pertussis toxin (1 microg/rat, PTX) or saline on the kappa-opioid agonist, U-50,488H (U5H) induced tail-flick analgesia and hypothermia in rats was determined. The effect of nimodipine (NIM), a dihydropyridine (DHP)-sensitive Ca(2+) channel blocker (CCB), on PTX-induced modulation of U5H effects was examined. The DHP ligand, [3H]PN200-110 binding was also determined in both PTX and saline treated rats to study the possible involvement of L-type Ca(2+) channels in PTX modulation of kappa-opioid agonist effects. The analgesia and change in colonic temperature were determined using tail-flick analgesiometer and telethermometer, respectively. U5H (40 mg/kg, i.p.) produced significant analgesic and hypothermic responses. PTX treatment significantly (P<0.01) antagonized the analgesic and hypothermic effects of U5H. Acute pretreatment of NIM (1 mg/kg, i.p.) 15 min prior significantly (P<0.01) reversed the PTX-induced antagonism of U5H effects. In the binding study, PTX treatment (72 h before) resulted in a significant (P<0.005) upregulation (+45% vs. saline control) of DHP binding (B(max)) with no change in affinity (K(d)). The results showed significant upregulation of DHP binding in accordance with PTX-induced antagonism of U5H effects and this blockade was reversed by NIM. Thus, present results suggest that U5H-induced analgesia and hypothermia may be mediated through PTX-sensitive transducer G-proteins (G(i/o)) coupled to L-type Ca(2+) channels.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, Phase -X, S.A.S. Nagar (Mohali)-160 062, Punjab, India.
Srinivas
S
Gullapalli
Poduri
P
Ramarao
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000037:antagonists & inhibitors*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D017275:Isradipine / Q000493:pharmacokinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists
D018712:Analgesics, Non-Narcotic; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017473:Receptors, Opioid, kappa; D009553:Nimodipine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D037342:Pertussis Toxin; D017275:Isradipine