Experimental study of selective muscarinic receptor antagonists on attenuation of morphine tolerance and dependence in rats

Objective: To characterize the role of muscarinic receptor subtype in the process of the morphine tolerance and dependence.

Methods: The morphine (Antinociception) tolerance was assessed by using hot-plate latency, and morphine dependence was characterized by naloxone-precipitated withdrawal. Intraperitoneal (i.p.) or intrathecal (i.t.) injection of muscarinic M1 selective antagonist pirenzepine or M2 selective antagonist methoctramine was carried out.

Results: Methoctramine (i.p.) for 6 days restored the sensitivity to morphine in male Sprague Dawley rats that are tolerant as a result of 6 days of b.i.d. morphine injection, in contrast, saline and pirenzepine (i.p.) did not increase the mean HP latency of morphine tolerant rats. Both methoctramine and pirenzepine in doses did not alter the baseline HP latency. Concurrent treatment with pirenzepine (i.t.) significantly attenuated the development of morphine tolerance produced by twice daily injection of morphine in a dose-dependent manner, however, methoctramine (i.t.) also decreased without dose-relation. In addition, the withdrawal symptoms precipitated by naloxone in morphine dependent rats were blocked by methoctramine (i.p.) or pirenzepine (i.t.) at single dose injection in a dose-dependent manner. Methoctramine (i.t.) at 200 micrograms/kg could partially inhibit the withdrawal symptoms.

Conclusions: The data suggested that the muscarinic receptor subtype predominating M2 receptor at the peripheral and M11 in the spinal cord mediate the process of morphine tolerance and dependence in rat.