This application is for a Mentored Research Scientist Development Award (K01). Recently, agmatine (decarboxylated arginine) has been isolated from mammalian brain and spinal cord. Agmatine both antagonizes the NMDA receptor and inhibits nitric oxide synthase (NOS). Because glutamate is thought to drive synaptic plasticity by activating both NMDA receptors and NOS in series, it is conceivable that agmatine participates in control of synaptic plasticity and related behavioral phenomena (e.g. learning and memory, opioid tolerance, chronic pain) as a neuromodulator of glutamate. Exogenously administered agmatine has been shown to be neuroprotective in a model of cerebral ischemia and to prevent development of opioid-induced tolerance, both thought to be processes requiring plasticity. Preliminary data presented here demonstrates that exogenous agmatine reverses nerve injury- and inflammation-induced allodynia and hyperalgesia. The primary goal of the proposed study is whether endogenous agmatine participates in the control of spinally derived pain. The proposed studies will address that goal through pursuit of the following specific aims. 1). Determine the effect of endogenous agmatine in the spinal cord on nerve injury- and inflammation-induced hyperalgesia. The induction of behaviorally assessed allodynia and hyperalgesia will be compared across strains and conditions with differing agmatine concentration in spinal cord extracts. 2). Determine whether endogenous agmatine can be released from the spinal cord. Agmatine concentration in spinal cord dialysate will be compared prior to and following exposure to K+ and other depolarizing substances. 3). Determine how localization of agmatine in spinal cord and dorsal root ganglia (DRG) is related to that of other neurochemical markers. Antisera directed against agmatine will be used in laser confocal and electron microscopy studies to determine its regional, cellular, and ultrastructural localization in the spinal cord and DRG as well as its relationship to the localization of pain-related signaling molecules and proteins. 4.) Determine the relationship between agmatine and glutamate-mediated excitation in the spinal cord. Electrophysiological experiments will explore whether previously observed NMDA receptor channel blockade or other action accounts for agmatine's block of neuronal excitation and behavioral plasticity in spinal cord. The results of these studies will clarify the role of endogenous agmatine in nociception, its localization in relation to neurochemical markers of nociception, and its relationship to the excitatory nociceptive transmitter glutamate. The studies will also explore its participation as a novel neuromodulator of central sensitization. Elucidation of the role of the endogenous agmatine during hyperalgesia and allodynia may lead to the development of a novel class of analgesic drugs or the identification of therapeutic targets.
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