Antiallodynic and antihyperalgesic effect of milnacipran in mice with spinal nerve ligation

BACKGROUND: The antidepressant, milnacipran, has been reported to have antinociceptive, antiallodynic, and antihyperalgesic effects. In this study, we examined the mechanisms of the, antiallodynic and antihyperalgesic effects of milnacipran in a model of neuropathic pain induced by spinal nerve ligation in mice. METHODS: The fifth left lumbar nerve of male C57BL6 mice was tightly ligated. Withdrawal threshold to tactile stimulation and withdrawal latency to heat stimulation in the injured or contralateral paw was tested by using von Frey filaments and radiant heat, respectively. RESULTS: Milnacipran was administered either orally (7.5-120 mg/kg), intrathecally, intracerebroventricularly, or locally (210 ng-21 mu g). Both systemic, intrathecal and intracerebroventricular milnacipran increased withdrawal threshold and withdrawal latency in nerve-ligated mice whereas local injection had no effect. Depletion of spinal serotonergic or noradrenergic neurons was achieved by use of the specific neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine, applied intrathecally 3 days before evaluation of the analgesic effect of milnacipran. Spinal serotonergic and noradrenergic denervation attenuated the effect of milnacipran in sham-operated mice. In nerve-ligated mice, however, the effect of milnacipran was lost after noradrenergic denervation but not after serotonergic denervation. CONCLUSIONS: We concluded that the antiallodynic and antihyperalgesic effects of milnacipran on neuropathic pain induced by spinal nerve ligation are principally mediated through action at supraspinal and spinal sites via activation of the spinal noradrenergic system.