Joint manipulation is a non-pharmacological treatment approach that has been utilized for many years, for the treatment of musculoskeletal disorders. Although there is increasing evidence to support the use of manipulative therapy in the management of painful musculoskeletal conditions, the neurophysiological mechanisms of the analgesia remain largely unknown. The current proposal is designed to establish an animal model of manipulation-induced analgesia that can be utilized to test the hypothesis that central inhibitory mechanisms are involved in mediating manipulation-induced analgesia. Specific Aim #1 will establish and characterize the analgesic effects of joint manipulation in animal models of articular pain. Specific Aim #2 will establish the spinal pharmacological receptors involved in the analgesic effects of joint manipulation. Specific Aim #3 will establish the effects of joint manipulation on hyperalgesia and pain in human subjects with clinical disorders that parallel the animal models utilized in Specific Aim #1 The current proposal is designed to gain preliminary data that can form the basis for more extensive studies using a variety of neuroanatomical, pharmacological and physiological approaches. These results are significant because they are expected to demonstrate involvement of central inhibitory mechanisms in the pain relief produced by joint manipulation and thus, provide a scientific rationale for its use. This information will further assist the clinician in determining the treatment of choice for a particular patient and potentially guide future clinical research.