Possible Nonopioid-Mediated Analgesia Produced by Methotrimeprazine in Rats

Abstract

BACKGROUND: Several reports in the 1960s demonstrated that methotrimeprazine (MTMZ), a phenothiazine derivative, is effective for treating acute and chronic pain. Although MTMZ has received little attention in recent decades, the fact that it derives from a class of drugs usually associated with cognitive and emotional processes, rather than the traditional analgesics, makes it interesting as a potential source of information about the mechanisms of analgesia.OBJECTIVE: To explore the analgesic properties of MTMZ in a dose-related design in the formalin test, and to examine whether the lowest dose of MTMZ that produces analgesia will activate endogenous opioid systems.METHODS: The analgesic properties of three doses of MTMZ, compared with a saline control, were explored in male Sprague-Dawley rats using the formalin test. Sedative effects were studied by using the line-crossing test concomitantly with the formalin test.RESULTS: MTMZ had no effect during the first phase of formalin responding. During the second phase of the formalin test, MTMZ doses of 5.0 and 10.0 mg/kg produced a significant decrease in formalin responses. Sedative effects were observed at all doses, even though the dose of 2.5 mg/kg did not significantly decrease formalin responses compared with controls. Statistical analyses revealed no significant correlation between the degree of sedation and the degree of analgesia at any dose of MTMZ. The nonspecific opioid antagonist naloxone did not alter the analgesic effect of 5.0 mg/kg MTMZ, indicating that the mechanism of action is independent of endogenous opioid systems.CONCLUSION: MTMZ decreased responses in the formalin pain test in rats. Although the drug's sedative effects were apparent in the line crossing test, they were not significantly correlated with pain responses. These results suggest that the decrease in formalin responses might be due, in part at least, to the analgesic properties of MTMZ. The fact that MTMZ belongs to a class of drugs that is relatively unexplored in relation to pain and analgesia indicates a potential source for the development of new pharmacological agents for treating persistent pain. Furthermore, the nonopioid mechanism of action suggests that this agent may be useful when opioid medications are contraindicated.