Differential Blockade of Nerve Injury-Induced Shift in Weight Bearing and Thermal and Tactile Hypersensitivity by Milnacipran

Antidepressants such as tricyclic antidepressants have become used to treat a variety of chronic pain conditions. However, the side effects are dose-limiting in the treatment of chronic pain. Milnacipran is a norepinephrine/serotonin reuptake inhibitor that does not have the severe side effects associated with traditional tricyclic antidepressants. The effects of intrathecal and systemic administration of milnacipran on spinal nerve ligation (SNL)-induced thermal and mechanical hypersensitivity and shift in weight bearing were determined. Intrathecal administration of milnacipran was found to reverse both SNL-induced thermal and tactile (to von Frey filaments) hypersensitivity, as well as shift in weight bearing. Acute systemic administration of milnacipran also reversed nerve injury-induced thermal hypersensitivity for up to 5 hours but failed to reverse tactile hypersensitivity or shift in weight bearing. Of note, both intrathecal and subcutaneous administration of milnacipran induced thermal antinociception in both SNL and sham rats. Chronic (daily) systemic administration of milnacipran alleviated both thermal hypersensitivity and shift in weight bearing, with both acute and chronic effects observed on thermal hypersensitivity. However, chronic systemic milnacipran administration failed to alleviate tactile hypersensitivity to von Frey filaments. These results indicate that different mechanisms underlie shift in weight bearing, thermal hypersensitivity, and tactile hypersensitivity. Perspective: These results indicate that the ability of milnacipran to relieve nerve injury-induced allodynia, hyperalgesia, and shift in weight bearing depends on the route of administration and the duration of treatment, with alleviation of SNL-induced tactile hypersensitivity and shift in weight bearing as a result of activity within the central-rather than the peripheral-nervous system.