Injury or lesions of the spinal cord can result in neuropathic pain. Dorsal rootlets are commonly involved, but often not all rootlets of a ganglion are injured. However little is known of the changes that occur in the dorsal root ganglion (DRG) after nerve root injury that might lead to abnormal afferent input to the spinal cord and contribute to neuropathic pain. We will produce a partial rhizotomy in the adult rat as a model of dorsal root injury in humans; the caudal half of the rootlets of L5 will be severed (and ligated), and the rostral half will be left uninjured. Preliminary results indicate that partial rhizotomy produces neuropathic activity, characterized by abnormal ectopic discharges (ED) and adrenergic responses in DRG neurons, and cutaneous hyperalgesia. Two hypotheses about causes of neuropathic activity are tested. 1. To determine if neuropathic activity and hyperalgesia after partial rhizotomy are caused by an abnormal coupling between sympathetic efferent and primary afferent neurons, we will test whether a) electrical stimulation of the sympathetic trunk increases ED recorded extracellularly from dorsal root fibers and whether hyperalgesia and the incidence of ED are reduced after sympathectomy; b) adrenergic receptor antagonists reduce the hyperalgesia; c) there is an increased or novel expression of the appropriate adrenergic receptors in the DRG after partial rhizotomy; d) topical applications to the DRG of specific agonists for that receptor selectively increase (and selective antagonists decrease) ED recorded extracellularly in vivo or intracellularly in vitro; e) whether the incidence of electrophysiologically determined adrenergic sensitivity in neurons agrees with the anatomically determined incidence of tyrosine hydroxylase immunopositive basket formations around neurons functionally characterized as adrenergically sensitive and then labeled by neurobiotin injection. 2. To determine if neuropathic activity after partial rhizotomy is caused by an increase in the intrinsic excitability of the somal membrane in DRG neurons after partial rhizotomy, we will obtain patch-clamp electrophysiological recordings from acutely dissociated DRG neurons, fluorescently labeled as cutaneous and injured or intact, and test for an increase in membrane excitability as evidenced, a) under current clamp, by an increased incidence of ED, a more negative action potential (AP) threshold and other indices of hyperexcitability and/or b) under voltage clamp, by an increase in peak total sodium current.
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