Agmatine potentiates the analgesic effect of morphine by an alpha(2)-adrenoceptor-mediated mechanism in mice.

The effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and a combination of agmatine and morphine on tail-flick test have been investigated in mice. Adult male Swiss-Webster mice were used in the study. Agmatine (10, 20 and 40 mg/kg), clonidine (0.15 mg/kg), yohimbine (0.625 and 1.25 mg/kg), or saline were injected into mice intraperitoneally. Morphine (1 and 2 mg/kg) was given subcutaneously. Agmatine alone did not produce any significant change on radiant tail-flick latencies, but it potentiated significantly and dose-dependently morphine-induced (1 mg/kg) analgesia. The potentiating effect of agmatine (40 mg/kg) on morphine-induced analgesia was blocked completely by yohimbine (0.625 mg/kg), a selective alpha(2)-adrenoceptor antagonist, pretreatment. Clonidine (0.15 mg/kg), an alpha(2-)adrenergic receptor agonist, caused a significant increase of the tail-flick latencies of the mice. Yohimbine (0.625 mg/kg) also blocked clonidine-induced analgesia. In addition, yohimbine (0.625 mg/kg) was ineffective on the tail-flick test and did not produce any significant change on the morphine-induced analgesia. Our results indicate that cotreatment of agmatine with morphine produces antinociceptive enhancement via an alpha(2-)adrenergic receptor-mediated mechanism and agmatine-morphine combination may be an effective therapeutic strategy for medical treatment of pain.