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

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Object. Intrathecally administered α2-adrenergic receptor subtype—specific antagonists were used to determine which α2-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine in a chronic constriction injury (CCI) rat model of neuropathic pain.

Methods. 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 µg yohimbine (22 rats); 5, 25, 50, or 100 µg prazosin (25 rats); or 5, 45, or 90 µg WB4101 (11 rats)—were intrathecally administered to the animals, followed in 30 minutes by 50 µg 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 α2-adrenergic receptor subtypes (α2A, α2B, and α2C) with yohimbine, prazosin, and WB4101. The antagonist response profile for the paw-pinch test of the affected paw most closely approximated the α2B receptor binding profile.

Conclusions. The antagonist profile from the current study is most consistent with the theory that the α2B-adrenergic receptor subtype mediates the analgesic effect of intrathecally administered tizanidine on CCI-associated neuropathic pain.

Article Information

Address reprint requests to: James W. Leiphart, M.D., Ph.D., Department of Neurosurgery, George Washington University, 2150 Pennsylvania Avenue, NW, Suite 7–420, Washington, DC 20037. email: jleiphart@mfa.gwu.edu.

© AANS, except where prohibited by US copyright law.

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    Graph showing antagonist's inhibition of the analgesic effect of tizanidine on cold-related allodynia. Values show the mean percentage of reduction (< SEM, compared with baseline testing) in the time animals raised their paws from the cold floor. Tizanidine was intrathecally administered after the intrathecal administration of the antagonist yohimbine (squares), prazosin (circles), or WB4101 (triangles). There was no statistically significant difference among the effects of the three antagonists according to ANOVA. Each point represents between five and seven rats.

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    Graphs showing antagonist's inhibition of the analgesic effect of tizanidine on affected paw pinch. Values show the mean maximum percentage of effectiveness (MPE) on affected paw pinch (± SEM) of tizanidine, which was intrathecally administered after the intrathecal administration of the antagonist yohimbine, prazosin, or WB4101. There was a statistically significant difference between the effects of the three antagonists. *p < 0.05, ***p < 0.005 compared with the nearest antagonist according to the post hoc t-test. Each point represents between five and nine rats.

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    Graph demonstrating antagonist's inhibition of the analgesic effect of tizanidine on contralateral paw pinch. Values show the mean maximum percentage of effectiveness (± SEM) on contralateral paw pinch of tizanidine, which was intrathecally administered after the intrathecal administration of the antagonist yohimbine, prazosin, or WB4101. There was no statistically significant difference among the three antagonists according to ANOVA. Each point represents between five and nine rats.

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    Graph depicting antagonist's inhibition of the analgesic effect of tizanidine on affected paw pinch, best-fit logarithmic curves. Values show the mean maximal percentage of effectiveness on affected paw pinch of tizanidine, which was intrathecally administered tizanidine after the intrathecal administration of the antagonist yohimbine, prazosin, or WB4101. Each point represents between five and nine rats.

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    Comparison of antagonist ratios from the paw-pinch test and ratios from binding data. The labels 2A, 2B, 2C, 1A, and 1B all refer to the means for the binding ratios of α-adrenergic receptor subtypes based on receptor preparations described in the existing literature. Labels 2A, 2B, and 2C are presented with their SEMs. Pawpinch data were obtained from the current study. Data from tail-flick and hotplate tests (asterisks) were obtained from another study in which these antagonists were intrathecally administered and their effects on normal nociception was determined.

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