Alpha2-adrenergic receptor subtype specificity of intrathecally administered tizanidine used for analgesia for neuropathic pain.

Abstract

Intrathecally administered alpha2-adrenergic receptor subtype-specific antagonists were used to determine which alpha2-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine in a chronic constriction injury (CCI) rat model of neuropathic pain. Seven days after CCI and intrathecal catheter surgeries had been performed in Sprague-Dawley rats, baseline neuropathic pain tests including cold-floor ambulation and paw pinch were performed. Either the dimethyl sulfoxide vehicle (seven rats) or one of the antagonists--5, 23, or 46 microg yohimbine (22 rats); 5, 25, 50, or 100 microg prazosin (25 rats); or 5, 45, or 90 microg WB4101 (11 rats)--were intrathecally administered to the animals, followed in 30 minutes by 50 microg intrathecally administered tizanidine. The neuropathic pain tests were repeated 30 minutes later. The resulting profile showed a descending order of antagonist efficacy for yohimbine, prazosin, and WB4101 for the cold-floor ambulation test and for the paw-pinch test of the affected paw. As expected given tizanidine's lack of analgesic effect on the contralateral, normal paw, there were no effects of antagonists on contralateral paw responses. The results of the paw-pinch test on the affected side were compared with binding data cited in the existing literature for the three different alpha2-adrenergic receptor subtypes (alpha2A, alpha2B, and alpha2C) with yohimbine, prazosin, and WB4101. The antagonist response profile for the paw-pinch test of the affected paw most closely approximated the alpha2B receptor binding profile. The antagonist profile from the current study is most consistent with the theory that the alpha2B-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine on CCI-associated neuropathic pain.