Role of L-type Ca2+ channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia

Previous studies have shown that the K-opioid effects are sensitive to pertussis toxin (PTX) and affected by Ca2+ fluxes. However, the possible involvement of Ca2+ channels in PTX-induced inhibition Of K-opioid effects has not been reported. The effect of intracerebroventricular (i.c.v.) treatment of pertussis toxin (I mug/rat, PTX) or saline on the K-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 Ca2+ channel blocker (CCB), on PTX-induced modulation of U5H effects was examined. The DHP ligand, [H-3]PN200-110 binding was also determined in both PTX and saline treated rats to study the possible involvement of L-type Ca2+ channels in PTX modulation of K-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 (I 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 Ca2+ channels. (C) 2002 Elsevier Science B.V. All rights reserved.