The alpha(2A) adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice

We have addressed the role of the sympathetic nervous system in the develop ment and maintenance of neuropathic pain. Using a new neuropathic mouse mod el, we examined the development of hyperalgesia in transgenic mice lacking functional alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if sympathetic-sensory coupling generates hyperalgesia. The de velopment of neuropathic hear hyperalgesia required the presence of both th e alpha(2A) adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the a lpha(2A) adrenoceptor or the SPGN, indicating different mechanisms of sensi tization. These results suggest that the development of neuropathic heat hy peralgesia, but not mechanical hyperalgesia, requires sympathetic-sensory c oupling in the peripheral nervous system. Nerve injury enhanced the analges ic efficacy of the alpha(2) adrenoceptor agonist dexmedetomidine, and parad oxically also induced an analgesic response to alpha(2) adrenoceptor antago nists. The alpha(2) agonist-evoked analgesia to mechanical stimuli was medi ated by activating central alpha(2A) adrenoceptors, possibly at the spinal level. The peripherally restricted alpha(2) antagonist L659,066 evoked anal gesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral alpha(2) adrenoceptor plays a role in both t he development and the maintenance of neuropathic heat hyperalgesia. The al pha(2) antagonist-evoked analgesia for heat stimuli was mediated by blockin g peripheral and probably central alpha(2) adrenoceptors, while the analges ia for mechanical stimuli was mediated by blocking central alpha(2A) adreno ceptors. Intradermal injections with an alpha(2) agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic-sensory co upling at the level of the cutaneous nociceptor did not contribute to the m aintenance of neuropathic hyperalgesia. Published for the International Ass ociation for the Study of Pain by Elsevier Science B.V.