Antinociceptive Effect of Riluzole in Rats with Neuropathic Spinal Cord Injury Pain

Abstract

Symptoms of neuropathic spinal cord injury (SCI) pain include cutaneous hypersensitivity and spontaneous pain below the level of the injury. Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, has been demonstrated to attenuate neural excitotoxicity by blocking the effects of the excitatory amino acid glutamate on glutamate receptors and by inhibiting voltage-gated Na(+) and Ca(2+) channels. Neuropathic pain in rat models of SCI is thought to be mediated by dysfunctional ion channels and glutamate receptors expressed on CNS neurons. Thus riluzole's mechanism of action could be relevant in treating neuropathic SCI pain. The current study evaluated the antinociceptive potential of riluzole in rats following a SCI. Four weeks after a brief compressive injury to the mid-thoracic spinal cord, rats displayed significantly decreased hind paw withdrawal thresholds, suggestive of below-level cutaneous hypersensitivity. A single systemic dose of riluzole (8 mg/kg) injected intraperitoneally (i.p.) reversed cutaneous hypersensitivity in SCI rats. To identify riluzole's CNS site of action, riluzole was injected intrathecally (i.t.) and intracerebroventricularly (i.c.v.) in SCI rats. Significant antinociceptive effects were obtained following i.c.v., but not i.t., injection. Systemic riluzole was also antinociceptive in uninjured rats, increasing the latency to respond to an acute noxious thermal stimulus in the tail flick test. Unlike in SCI rats, however, riluzole was not effective when administered directly into the CNS, indicating a peripherally mediated antinociceptive mechanism. Although riluzole appears to have a general antinociceptive effect, the site of action may be model dependent. In total, these data indicate that riluzole may be an effective clinical analgesic for the treatment of below-level neuropathic SCI pain. Although the exact mechanism of action is not clear, there is a predominant supraspinal component of riluzole-induced antinociception in SCI rats.