Chronic pain is a disabling disease that affects a large proportion of the U.S. population. An intriguing pain syndrome that results from trauma, often with associated peripheral nerve injury, is sympathetically maintained pain (SMP). SMP is characterized by pain and hyperalgesia to mechanical and thermal stimuli that are dependent on sympathetic innervation of the painful region. Based on advances made during the last granting period, a model has been developed to explain the pathophysiology and pharmacology of SMP. The proposed studies will test a tenet of the model that a1 adrenoceptors develop in peripheral tissues such that the release of norepinephrine from the sympathetic terminals activates nociceptors and leads to pain. Parallel studies will be done in patients and in a recently developed nerve injury paradigm for SMP in rats. The proposed clinical and behavioral studies will address two questions: (1) Is a peripheral a-adrenergic receptor the culprit in SMP? To answer this question, the pain and hyperalgesia produced by intradermally administered alpha1-, alpha2- and beta-adrenergic agonists and a adrenergic blockers will be compared in normal subjects and in patients with SMP or with sympathetically independent pain (SIP). The adrenergic pharmacology of SMP will be further characterized with behavioral studies in rat using a partial sciatic nerve injury paradigm. Earlier studies have indicated that the pain behavior in this rat paradigm is sympathetically maintained. The proposed behavioral studies will also provide information about the site of interaction between the sympathetic efferents and the somatic afferent fibers. (2) Can alpha-adrenergic drugs be used in the diagnosis of SMP? During the past granting period, a diagnostic test for SMP was developed based on the pain relief obtained during intravenous administration of phentolamine. In the proposed studies, the relief of pain and hyperalgesia in SMP following topical administration of clonidine will be investigated as a less invasive diagnostic tool. The proposed studies will lead to a better understanding of the pathophysiology and pharmacology of SMP and to the development of more specific diagnostic tests and pharmacological therapies for alleviating the pain and hyperalgesia in this debilitating pain state.