Involvement of hypothalamic pituitary adrenal axis on the effects of nifedipine in the development of morphine tolerance in rats

It has been shown that nifedipine, as a calcium channel blocker, can attenuate the development of tolerance to the antinociceptive effect of morphine; however, the role of HPA axis on this action has not been elucidated. We examined the effect of nifedipine on morphine analgesic tolerance in intact and adrenalectomized (ADX) rats and on HPA activity induced by morphine. Adult male rats were rendered tolerant to morphine by daily injection of morphine (15 mg/kg i.p.) for 8 days. To determine the effect of nifedipine on the development of morphine tolerance, nifedipine (1, 2 and 5 mg/kg i.p.) was injected concomitant with morphine. The tail-flick test was used to assess the nociceptive threshold, before and 30 min after morphine administration in days 1, 3, 5 and 8. Our results showed that despite the demonstration of tolerance in both ADX and sham operated rats, nifedipine in ADX rats prevented morphine tolerance development at a lower dose (2 mg/kg) than in sham operated rats, however corticosterone replacement prevented nifedipine effect in ADX rats. Acute administration of morphine produced significant increase in plasma corticosterone level, and with repeated injection, a tolerance to this neurosecretory effect was developed. Nifedipine (5 mg/kg) attenuated the acute effect of morphine, but could not block its neurosecretory tolerance.