MECHANISMS OF CAUSALGIA

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The long term goal of this proposal is to uncover the mechanism of the disabling painful neuropathic disease, such as causalgia, TO investigate the mechanisms of neuropathic pain, an animal model is developed by ligating the L5 and L6 spinal nerves of the rat unilaterally, This results in various behavioral signs of neuropathic pain that can be sen in human patients with sympathetically maintained pain (SMP), a particular type of neuropathic pain that is poorly understood. A series of hypotheses concerning the mechanisms that underlie SMP is formulated. To test the hypotheses, 6 specific aims are proposed. 1) To test whether SMP critically depends on ectopic discharges arising from the injured afferents, behavioral tests for neuropathic pain will be performed during conduction block of the activity of injured afferents. 2) To test whether the ectopic discharge are die to the development of abnormal adrenergic sensitivity by injured afferents, single unit activity will be recorded from dorsal root filaments of the injured segments and the effects of systemically applied adrenergic agonists and antagonist will be determined. 3) To test whether the ectopic discharges are due to sprouting of sympathetic postganglionic fibers and their newly formed synapses on sensory neurons, the noradrenergic fiber and putative synapses in the injured afferents will be examined using light and electron microscopic immunocytochemical labeling for antibody against tyrosine hydroxylase. 4) T test whether the ectopic discharges are due to the development of abnormal sympathetic activity, single unit activity will be recorded form postganglionic sympathetic fibers innervating the ligated spinal nerves. 5) To test whether evoke d pain (allodynia and hyperalgesia) is produced by inputs carried by intact (uninjured) afferents, behavioural tests for neuropathic pain will be performed during conduction block of the activity of intact afferents. 6) To test whether SMP is much more readily developed when the peripheral nerve is injured proximally as compared to a distal injury due to a more pronounced abnormality of the adrenergic system, adrenergic activity will be examined as proposed in Specific Aims 2-4 on two previously developed models which are produced by a distal injury. Accomplishing the specific aims will result in a better understanding of and an improved treatment for disabling neuropathic pain.