Focal neurological lesions are known to dramatically attenuate the later development of rheumatoid arthritis (RA) in humans and experimental arthritis (EA) in animals. in preliminary experiments we have found that joints at higher risk of developing EA are more densely innervated by small-diameter substance P-containing nociceptive afferent neurons. In addition, we found that prior treatment of the nerves in one extremity with capsaicin, which selectively depletes substance P and other transmitters in small-diameter primary afferents, results in unilateral arthritis. A pathogenetic role for substance P (SP) in the development of arthritis is suggested by the fact that SP can be released into the peripheral tissues, where it exerts a pro-inflammatory effect. We propose to confirm these observations and to test the hypothesis that the modulation of the development of arthritis in the rat is mediated by neural influences on the blood flow and vascular permeability of the synovial membrane. There is no pathognomonic laboratory test for RA. Its diagnosis is based on the presence of a constellation of signs and symptoms. The bilateral symmetry of RA, an important diagnostic clinical feature which also appears in all forms of experimental arthritis in animals, is not explained by any hypothesized pathogenetic mechanism. We propose to test the hypothesis that production of bilaterally symmetric disease requires activity of somato-sympathetic nociceptive reflexes. In preliminary experiments we have found that contralateral swelling, induced by the injection of a noxious stimulus into the paw; can be blocked by pretreating nerves in the injected paw with capsaicin. We propose to extend our studies of the neural mechanisms of this contralateral swelling reflect (CSR) and to test the hypothesis that establishment of bilateral symmetry in EA requires activity in such a somatosympathetic nociceptive reflex. There are many important gaps in our knowledge of the neurobiology of the joint. The proposed experiments will employ recent advances in peptide neurobiology to study the role of the peripheral nervous system in the pathogenesis of experimentally-induced arthritis in the rat.