Pain is a uniquely individual experience that is powerfully shaped by the action of descending control mechanisms. These systems may play crucial roles in the moment-to-moment tuning of the sensitivity, spatial, and temporal response characteristics of nociceptive processing mechanisms during both acute and pathological pain states. However, these systems remain poorly understood in human subjects. The proposed research will use psychophysics and multiparametric MRI to (i) delineate the brain mechanisms that subserve and regulate endogenous analgesia (EA) in the healthy state and (ii) to identify alterations in mechanisms supporting EA in chronic pain and their therapeutic relevance. In both healthy subjects and chronic pain patients, EA will be probed using the DNIC (diffuse noxious inhibitory controls) and offset analgesia paradigms. Functional MRI will examine activation of brainstem mechanisms important in EA, while both functional and structural connectivity analyses will assess the regulation of these brainstem mechanisms by cerebral cortical regions involved in attention and affect. One pathological painful condition, migraine, will be examined since it allows changes in EA associated with chronic pain to be investigated between episodes of pain. Finally, EA and EA associated structural and functional parameters will be used to predict the efficacy of one compound, amitriptyline, to treat migraine in individual patients. Taken together, the proposed research will provide substantial insights into basic mechanisms supporting and regulating EA and can provide a foundation for mechanism-based individualized choice of therapy that may benefit all chronic pain patients.
