The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.

Abstract

Antidepressants are often used for the treatment of neuropathic pain, and their analgesic effects rely on increased noradrenaline and serotonin levels in the spinal cord. Clinical studies have also shown that bupropion, a dopamine and noradrenaline reuptake inhibitor, has strong efficacy in neuropathic pain; however, the role of spinal cord dopamine in neuropathic pain is unknown. We hypothesized that bupropion inhibits neuropathic pain by increasing noradrenaline and dopamine in the spinal cord. In the present study, we determined the efficacy and underlying mechanisms of intrathecal administration of bupropion in a rat model of neuropathic pain. Male Sprague-Dawley rats were anesthetized, and right L5 spinal nerve ligation (SNL) was performed to produce mechanical hyperalgesia of the hindpaw. Withdrawal threshold to a paw pressure test was measured before and after intrathecal administration of bupropion, without or with intrathecal antagonists for α2-adrenoceptors and dopamine D2 receptors. In vivo microdialysis was performed in the dorsal horn of the lumbar spinal cord to measure noradrenaline and dopamine concentrations after intrathecal injection of bupropion. We also measured the noradrenaline and dopamine contents in the ipsilateral dorsal lumbar spinal cord in normal rats and in rats 2, 3, and 4 weeks after SNL. Intrathecal injection of bupropion produced a dose-dependent antihyperalgesic effect (3, 10, 30, and 100 μg, P < 0.001). The effect (30 μg) was dose-dependently reversed by intrathecal pretreatment (15 minutes before bupropion injection) with the α2-adrenoceptor antagonist idazoxan (3, 10, and 30 μg, P < 0.001) and D2 receptor antagonist sulpiride (3, 10, and 30 μg, P < 0.001). Microdialysis revealed that noradrenaline and dopamine concentrations in the spinal dorsal horn were increased after intrathecal injection of bupropion (30 μg, P < 0.001 and P = 0.001, respectively). Furthermore, the noradrenaline and dopamine contents in the spinal dorsal horn were increased 2 weeks after SNL (P < 0.001 and P = 0.044, respectively) and then decreased gradually. These findings suggest that plasticity of descending inhibitory pathways such as the noradrenaline and dopamine systems contributes to the maintenance of neuropathic pain and that spinal cord noradrenaline and dopamine both play an inhibitory role in neuropathic pain.