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Spinal cord injury (SCI) pain exhibits many symptoms associated with peripheral neuropathic pain, including increased tactile hypersensitivity. One novel approach to ameliorate SCI pain is the use of cannabinoid (CB) ligands. The current study evaluated the efficacy of the nonselective CB receptor agonist WIN 55,212-2 on tactile hypersensitivity in rats following a brief compression to the thoracic spinal cord. The withdrawal thresholds of the hind paws following SCI were significantly decreased, indicating tactile hypersensitivity. Systemic injection of WIN 55,212-2 increased withdrawal thresholds in a dose-dependent manner. Pretreatment with the CB 1 receptor subtype-selective antagonist AM 251 completely abolished the antinociceptive effect of WIN 55,212-2 whereas pretreatment with the CB 2 receptor subtype-selective antagonist AM 630 did not alter the antinociceptive effect of WIN 55,212-2. These data indicate that a CB 1 selective agonist may be novel therapeutic treatment for clinical SCI pain. KeywordsAM 251; AM 630; allodynia; chronic pain; CB 1 receptor; neuropathic pain Trauma or disease to either the peripheral or central nervous system leads to persistent pain. There are few effective treatments for patients with chronic neuropathic pain. The cannabinoids show promise in alleviating peripheral neuropathic pain, which in turn, may have efficacy on central neuropathic pain states.Studies in rats indicate that the cannabinoid receptors (subtypes CB 1 and CB 2 ) have key roles in modulating pain, especially neuropathic pain. The CB 1 receptor has been identified in the rat dorsal root ganglia, spinal cord, and brain areas relevant to the processing of pain-related information (Farquhar-Smith et al., 2000;Hohmann et al., 1999;Tsou et al., 1998). There are numerous studies in rat models of peripheral neuropathic pain that demonstrate significant suppression of thermal and mechanical hypersensitivity with a non-selective CB receptor agonist, which is attenuated with a selective CB 1 receptor antagonist (Bridges et al., 2001;Fox et al., 2001;Herzberg et al., 1997;Pascual et al., 2005;Ulugol et al., 2004). However, a role for the CB 1 receptor in rats with central neuropathic pain caused by a spinal cord injury (SCI) has not been examined. The current study evaluated the effect of the non-selective CB receptor agonist WIN 55,212-2 in a rat model of neuropathic pain induced by compression of the spinal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Gatley et al., 1996;Pertwee et al., 1995). NIH Public AccessSurgical and behavioral testing procedures were revi...

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.

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