Inflammatory pain forms a major symptom in many diseases and often complicates the disease and disturbs its treatment. The major causes of inflammatory responses are peripheral tissue injuries where a variety of endogenous chemical agents are released from damaged cells, immune cells and injured nerve terminals. Inflammation is suggested to be initiated by the neurogenic component, which involves the effector function of small myelinated and unmyelinated nociceptive primary afferent fibers. Release of vasoactive peptides from these terminals due to injury to peripheral tissue helps develop neurogenic inflammation. An increasing number of studies demonstrate that the effector action of primary afferent fibers is centrally mediated by way of dorsal root reflexes (DRRs). On the other hand, sympathetic efferents have been shown to modulate inflammatory pain possibly by interaction with primary afferent terminals. We hypothesize that neurogenic inflammation resulting from the generation of DRRs depends in part on a sympathetic- sensory interaction. The proposed studies will examine if DRR-mediated cutaneous neurogenic inflammation and DRRs are modulated by sympathetic efferents and where the sympathetic modulation takes place. Acute cutaneous inflammation will be evoked by intradermal injection of capsaicin (CAP). Multi- or single-unit recordings of afferent and efferent activity of primary afferent fibers and cutaneous blood flow measurements in anesthetized rats will be used to test the hypotheses: 1. Intact sympathetic efferents are essential for the sensitization of nociceptors following intradermal injection of CAP. The increased afferent barrage due to sensitization of nociceptors would then trigger DRRs through spinal circuits (Specific Aims 1, 2 and 3); 2. Generation of DRRs following CAP injection is, at least, partially dependent on the enhanced sympathetic postganglionic efferent activity that would sensitize nociceptors by releasing norepinephrine, neuropeptide Y (NPY) or adenosine 5'-triphosphate to activate peripheral alpha- adrenergic, NPY, or purinergic receptors. (Specific Aim 4). The long-term goal of these studies is to learn how sympathetic- sensory interactions affect the generation of DRRs and, in turn, modulate neurogenic inflammation. Therefore, this project will provide important new information on inflammatory pain mechanisms that will doubtless help us understand inflammation-related pain better. Obviously, this information will also provide valuable insight into the potential therapeutic value of drugs in management of neurogenic inflammatory pain.
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