PROJECT SUMMARY Chronic pain is ubiquitous, costly, and burdensome. Individuals with chronic pain suffer daily—the pain impairs their ability to work, move, and live freely. On a societal level, chronic pain stresses both the healthcare system and the economy. Despite its impact, there is no cure for chronic pain. The inability to properly treat chronic pain has led to the current opioid epidemic. Although we are now beginning to understand the mechanisms underlying chronic pain, we have few ways of assessing and probing these mechanisms. A chronic pain biomarker mechanistically coupled to the circuitry responsible for inducing and maintaining chronic pain would help researchers study and clinicians treat chronic pain. Offset analgesia is a psychophysical phenomenon characterized by a transient, disproportionately large decrease in pain following a slight reduction in noxious stimulus intensity. This phenomenon is both mechanistically and clinically interesting. Mechanistically, it uncouples a noxious stimulus from pain qualia—two often-conflated constructs. Clinically, it is blunted in patients with chronic pain, making it a biomarker for chronic pain. Yet, we do not understand how offset analgesia occurs. By elucidating offset analgesia's mechanisms, we will gain a greater understanding of the nociceptive-pain circuitry. Moreover, it would transmute offset analgesia from a psychophysical correlate of chronic pain to a biomarker that provides neurophysiological insight. This proposal aims to assess the dopamine dependence of offset analgesia. Although we do not know offset analgesia's mechanisms, several lines of evidence suggest it may be dopaminergic. If the dopamine hypothesis holds, then the core mechanisms responsible for chronic pain may also be responsible for mediating offset analgesia. Aim 1 will attempt to generalize offset analgesia to other noxious stimuli since previous work has only tested noxious heat stimuli. We will compare the offset analgesic response and dynamics between hot and cold noxious stimuli. Establishing cold offset analgesia enables us to investigate its broader mechanisms by ensuring our results are not specific to a single modality. Aim 2 will investigate the correlative role of nucleus accumbens in offset analgesia. If the mesolimbic system is responsible for offset analgesia, its dynamics should capture the temporal dissociation between the noxious stimulus (temperature) and pain ratings. Finally, in Aim 3, I will gain experience in a clinical trial led by Dr. Apkarian that uses methylphenidate to perturb dopamine levels. An increase in the offset analgesic response with methylphenidate relative to placebo would indicate dopamine dependence. Understanding the dopamine dependence of offset analgesia is crucial to understanding its underlying mechanisms and its use as a chronic pain biomarker.