Intrathecal morphine and clonidine: antinociceptive tolerance and cross-tolerance and effects on blood pressure

Abstract

The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. Chronic treatment with morphine (32.0 micrograms/day for 7 days) produced tolerance to the antinociceptive effects of morphine in conscious rats, and chronic morphine or chronic clonidine (32.0 micrograms/day for 7 days) reduced the antinociceptive potency of morphine in lightly anesthetized rats. The pressor effects of morphine were attenuated by chronic morphine and were converted to marked, dose-dependent depressor effects by chronic clonidine. Clonidine dose dependently inhibited the tail-flick reflex in lightly anesthetized rats (ED50 = 1.7 micrograms) and produced biphasic effects on blood pressure; lesser doses (0.1-3.2 micrograms) produced depressor effects whereas a greater dose (10.0 micrograms) produced a pressor response. Yohimbine, but not naloxone, antagonized the antinociceptive effects of clonidine, whereas both yohimbine and naloxone altered the dose-response function for the effects of clonidine on blood pressure. Tolerance developed to the antinociceptive effects of clonidine in the hot-plate, but not in the tail-flick, test in conscious rats. In lightly anesthetized rats, the antinociceptive potency of clonidine was reduced by chronic clonidine or chronic morphine, whereas chronic clonidine, but not chronic morphine, shifted the dose-response function for effects of clonidine on blood pressure to the right. These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.