The sympathetic nervous plays a key role in neuropathic pain, but there are many inconsistencies in published studies, and the precise mechanisms underlying the sympathetic-sensory interactions are not completely known. The present study is to show that some of the difficulties arise from the fact that transected axons up-regulate not only alpha-adrenergic receptors (alpha-ARs), but also P2X-purinoceptors (P2X-Rs) and neuropeptide Y-receptors (NPY-Rs), that all of these receptors are tonically stimulated after segmental nerve lesions, that inflaming axons (neuritis) up-regulates these receptors on appropriate dorsal root ganglion (DRG) cell bodies, that the act of transection in the segmental nerve lesion inflames near-by axons, that these inflamed un- transected axons also up-regulate these receptors, and that the source of some of the confusion in the literature is that these events are not clearly separated. To test these hypotheses:
Specific Aim 1 is to show that P2X-Rs and NPY-Rs as well as alpha-ARs are up-regulated on sensory cells whose axons are transfected in the segmental nerve injury model, and that the cells are tonically stimulated by sympathetic ligands (norepinephrine, ATP, and NPY) released presumably from sprouted sympathetic axons.
Specific Aim 2 is to show that inflammation of a nerve (neuritis) leads to up-regulation of alpha-ARs, P2X-Rs and NPY-Rs on the sensory neurons whose axons travel in that nerve.
Specific Aim 3 will combine the above the above aims by showing that transection of axons in the segmental nerve lesion inflames the sensory axons in neighboring nerves, which leads to up-regulation of alpha-ARs, P2X-Rs and NPY-Rs on both transected and un-transected neurons. To achieve these aims, a multi-disciplinary approach will be used and successful completion of the project will provide further insights into the role of the sympathetic nervous system in neuropathic pain and help resole many of the confusing contractions in the literature.
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