An experimental inflammation of the rat's sciatic nerve (a neuritis) has been produced by applying Complete Freunds Adjuvant to the surface of the nerve at the mid-thigh level. The neuritis produces heat- and mechano-hyperalgesia and cold- and mechano-allodynia in the ipsilateral hind paw that last for up to 5-6 days. At the time of peak symptom severity, there is an endoneurial immune cell infiltrate and evidence for plasma extravasation at the site of treatment, but little or no structural damage to axons or glia. The absence of degeneration and regeneration in the nerve, and the brief duration of the syndrome, are uniquely different than all present models of neuropathic pain. The mechanisms producing neuropathic pain in the territory of the inflamed nerve are likely to be distinctly different than those producing pain after cutaneous injury because the latter involves changes in receptor terminal transduction and impulse generation properties that are not present at """"""""mid-axon"""""""" level. Our results suggest two novel concepts: (1) a focal, strictly inflammatory process in a nerve may give rise to neuropathic pain sensations in a distant region, and (2) such pain may be due to a neuroimmune interaction that generates ectopic discharge in uninjured nociceptor axons. The objectives of this proposal are to discover the causative factors involved in the genesis of the pain. Histological and immunocytochemical techniques will be used to determine the spatial and temporal extent of the inflammation, to identify the immune cell types that infiltrate the nerve, to determine whether pro-inflammatory cytokines and NGF are present, and to confirm the presence of plasma extravasation. To test whether a neuroimmune factor is involved, inhibitors of immune function will be given to see if they prevent the neuropathic pain. Electrophysiological recordings from identified sensory axons will determine if abnormal discharge arises at the site of inflammation and if there is peripheral sensitization due to an antidromically-conducted ectopic discharge.
