Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Spinal reflexive responses to noxious stimuli are inhibited by cannabinoids in spinally transected dogs (Gilbert 1981). Support for spinal mechanisms of cannabinoid analgesic action is also derived from the ability of intrathecally administered cannabinoids to produce antinociception (Smith and Martin 1992; Welch et al. 1995; Yaksh 1981). The behavioral data are consistent with the ability of spinally administered cannabinoids to suppress noxious heat-evoked and after-discharge firing (Hohmann et al. 1998) and noxious stimulus-evoked Fos protein expression in the spinal dorsal horn neurons (Hohmann et al. 1999c). Spinal administration of a CB1R-selective agonist also inhibits C fiber and A6 fiber-evoked responses of wide dynamic range (WDR) neurons through a CB1R mechanism with only minor effects on A-3 fiber-evoked responses (Kelly and Chapman 2001). Systemic and intrathecally administered cannabinoids retain a weak but long-lasting antinociceptive effect in spinally transected rats (Lichtman and Martin 1991b; Smith and Martin 1992), providing compelling evidence for spinal mechanisms of cannabi-noid antinociception.
Spinal administration of a cannabinoid (HU210) also suppresses C fibermediated post-discharge responses, a measure of neuronal hyperexcitability, in carrageenan-inflamed and noninflamed rats (Drew et al. 2000); these effects were blocked by a CB1R antagonist. Spinal administration of anandamide produced CB1R-mediated effects in carrageenan-inflamed rats that were similar to that reported for HU210, but only inconsistent effects were observed in noninflamed rats (Harris et al. 2000). Upregulation of CB1Rs is also observed in the spinal cord following nerve injury, suggesting that regulation of spinal CB1Rs may contribute to the therapeutic efficacy of cannabinoids in neuropathic pain states (Lim et al. 2003). These data implicate involvement of spinal CB1Rs in both acute and persistent pain states.
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