Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions

Publisher Website
Google Scholar
Abstract
The study was aimed at elucidating the possible participation of l-type Ca2+ channel in the acute analgesic effect of an opiate and the development of tolerance to this action. Sufentanil, a selective p agonist, and two dihydropyridines, the Ca2+ antagonist nimodipine and the Ca2+ agonist Bay K 8644, were selected. The tail-flick test was used to assess the nociceptive threshold. In naive rats, nimodipine (200 μg/kg) potentiated the analgesic effect of sufentanil reducing the ED50 from 0.26 to 0.08 μg/kg. Similar results were observed with its (−)-enantiomer Bay N 5248, while the (+) enantiomer Bay N 5247 was ineffective. Tolerance to the opiate was induced by chronic subcutaneous administration of sufentanil with minipumps (2 μg/h, 7 days). In these conditions the dose-response curve to sufentanil was displaced to the right and the ED50 was increased to 1.49 μg/kg. In tolerant rats, nimodipine preserved its potentiating ability and prevented the displacement to the right of the sufentanil dose response-curve (ED50 = 0.48 μg/kg). When nimodipine was pumped (1 μg/h, 7 days) concurrently with sufentanil, the development of tolerance to the opioid was not disturbed. However, the expression of tolerance was abolished and even the effect of acutely administered sufentanil was markedly potentiated (ED50 = 0.03 μg/kg). Similar experiments were performed with Bay K 8644. In naive rats, Bay K 8644 at a low dose (20 μg/kg) that behaves as a calcium agonist, antagonized the analgesic effect of sufentanil (ED50 = 0.58 μg/kg), whereas at a high dose (200 μg/kg) it potentiated this action (ED50 = 0.15 μg/kg). In tolerant rats, Bay K 8644 (20 μg/kg) preserved its antagonizing ability inducing a displacement to the right of the sufentanildose-response curve (ED50 = 4.2 μg/kg). When Bay K 8644 was pumped (1 μg/h, 7 days) concurrently with sufentanil, it enhanced the expression of tolerance to the opiate (ED50 = 3.8 μg/kg). These results suggest that the calcium fluxes through the l-type channel in neurones are functionally linked to the activation of the μ opiate receptor: the blockade of the channel increased the potency of sufentanil, whereas its activation reduced the potency of the opiate. In chronic experiments, DHPs concurrently administered with sufentanil did not affect the development of tolerance to the opiate. However, nimodipine prevented the expression of this phenomenon. Even more, the animals became hypersensitive to the opiate suggesting that the adaptative mechanisms induced by chronic opiate could be affected by chronic nimodipine.