Arthritis, inflammation of a joint, is a painful and often debilitating condition. Blood borne or local factors have been considered to be primarily responsible for the inflammation. An unexpected recent finding in our studies using a knee joint arthritis model strongly suggests another possibility. Peripheral inflammation, as well as the thermal and behavioral manifestations characteristic of the arthritis model, are significantly blocked by spinal cord infusion of specific non-N-methyl-D- aspartate (non-NMDA) or gamma aminobutyric acid (GABAA) receptor antagonists through a microdialysis fiber. Direct spinal infusion of either a non-NMDA or NMDA excitatory amino acid receptor antagonist prevents the increases in dorsal horn release of the excitatory amino acids, glutamate and aspartate, and immunoreactivity for glutamate. The substance P increases in the dorsal horn that occur in response to induction of knee joint inflammation do not occur with pretreatment with a non-NMDA antagonist. The present proposal outlines specific questions to address the following novel hypothesis that central processing of afferent input to the spinal dorsal horn plays a critical role in the control of both peripheral inflammation and the perception of pain. The studies outlined will (1 )determine if administering receptor blockers or other pharmacological agents into the cord modifies either the inflammation or the accompanying pain, (2)determine the specific role of the sympathetic nervous system, descending pathways, and primary afferents in this process, (3)determine the specific events responsible for the central processing resulting in inflammation and pain, and (4)begin to determine the dorsal horn circuitry responsible for the central control of inflammation. These studies will derive key information utilizing microdialysis, high performance liquid chromatography (HPLC), immunohistochemistry, computer-assisted quantitation, electrophysiology, electron microscopy, behavioral assessment, and thermography. The long term aims of these studies are to understand the role that spinal processing plays in painful peripheral events such as inflammation and to determine the dorsal horn circuitry responsible for processing nociceptive information with the goal of alleviating arthritic and other inflammatory pain.