Spinal pharmacology of alpha2-adrenergic analgesia in neuropathic pain

Neuropathic pain has demonstrated significant resistance to traditional pain therapies. Recent development of the chronic constriction injury model (CCI), a rat model of neuropathic pain developed by Bennett and Me (1988), has made more extensive research into the physiology of neuropathic pain and potential therapies possible. The experiments performed for this dissertation assessed both acute and chronic intrathecally administered morphine and tizanidine, an alpha2-adrenergic agonist, as potential analgesics for CCI neuropathic pain. The experiments also explored spinal alpha2-adrenergic receptor subtype expression and activity in CCI rats. Both acute and chronic intrathecally administered morphine and tizanidine were analgesic in various tests of neuropathic pain, with tizanidine being analgesic only for neuropathic pain signs, not for normal nociceptive pain. The rats became tolerant to the analgesic effects of intrathecally administered morphine and tizanidine within a few days, but there was no significant cross tolerance between the two drugs. An antagonist study demonstrated that the analgesia produced by intrathecally administered tizanidine was mediated through the alpha2B-adrenergic receptor subtype. Spinal alpha2-adrenergic receptor mRNA levels were decreased, but the quantity of alpha2-adrenergic receptors in the dorsal horn was increased in CCI rats. The predominant alpha 2-adrenergic receptor subtype in the spinal cord dorsal horn was alpha 2A, with no significant amount of alpha2B, and no change in receptor subtype expression induced by the CCI model. The results of this dissertation suggested that CCI rats had an increase in alpha2-adrenergic receptors expressed on the spinal cord projections of the affected primary sensory afferents, and a decrease in alpha2-adrenergic receptors expressed on the other neurons of the spinal cord. The findings of this dissertation also suggested a possible role for the dorsal root ganglion in neuropathic pain analgesia produced by intrathecally administered tizanidine.