Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats

Although tricyclic antidepressant are especially useful in the treatment of chronic pain conditions, most of the work about its mechanism of action has been made on acute pain tests. The present study was aimed at studying the role played by noradrenergic and opioidergic influences on the antinociceptive activity of subchronically administered clomipramine in the formalin test (a tonic pain model) in rats. Clomipramine produced antinociception after 7 days, administration (2.5 mg/kg/day), an effect equivalent to that obtained by acute morphine (5 mg/kg). The antinociceptive effect of clomipramine was inhibited by the following: nonspecific blocking of alpha₁-and alpha₂-adrenoceptors by phentolamine, specific blocking of alpha₁-adrenoceptors by prazosin; stimulation of alpha₂ receptors by clonidine; and blocking of the opioid receptors by naloxone. Blocking the alpha₂-receptors with yohimbine did not antagonize the effect of clomipramine. These results suggest that clomipramine produces antinociception in this test, partly via the participation of the endogenous opioid system and partly by further activating or potentiating previously activated noradrenergic pathways which are involved in the control of pain information.