This proposal is for an Exploratory/Developmental Grant Application (R21), specifically addressing RFA # PAR-01-047, the Cuffing Edge Basic Research Award (CEBRA) program. Recently, agmatine (decarboxylated arginine) has been isolated from mammalian brain & spinal cord and found to antagonize NMDA receptors and inhibit nitric oxide synthase (NOS). Because glutamate is thought to drive synaptic plasticity by activating both NMDA receptors and NOS in series, agmatine may participate in control of synaptic plasticity and related behavioral phenomena (e.g. learning, memory, chronic pain, opioid tolerance and self-administration) as a neuromodulator of glutamate. Exogenously administered agmatine is neuroprotective in models of cerebral ischemia (Gilad, 1996) and spinal cord injury (Yu et. al., 2000) and prevents development of opioid analgesic tolerance (Kolesnikov 1996; Fairbanks, 1997), all considered to be processes requiring plasticity. In addition to these published reports, preliminary data presented here demonstrates that exogenous agmatine prevents fentanyl self-administration. The primary goal of the proposed study is to determine whether endogenous agmatine modulates opioid-induced analgesic tolerance and self-administration. That objective will be addressed by determining the relationship of agmatine levels to opioid tolerance and self-administration. First, agmatine concentration will be systematically measured in brain and spinal cord regions thought to be involved in opioid addiction and analgesic tolerance. These measurements will be compared across multiple strains of mouse known to have differential sensitivities to induction of opioid analgesic tolerance and self-administration. If, as exogenous agmatine findings predict, endogenous agmatine protects against induction of opioid analgesic tolerance and self -administration, then mouse strains with relatively low concentrations of central nervous system agmatine will be more sensitive to induction than those with high concentrations of CNS agmatine, an inverse correlation. The second component of the project will determine whether manipulating levels of CNS agmatine changes analgesic tolerance and self-administration also through an inverse relationship. The results of these proposed Phase I CEBRA R21 studies will determine whether or not there exists a modulatory relationship between endogenous agmatine and the glutamatergic mechanisms underlying opioid tolerance and self-administration. Such a finding would provide a rationale for pursuing in depth mechanistic clarification of the role of endogenous agmatine in opioid analgesic tolerance and self-administration, a strategy that would comprise the subsequent PHASE 11 CEBRA R01 application. Elucidation of a role for endogenous agmatine in modulation of the development of opioid tolerance and self-administration may lead to the development of a novel class of drugs or alternative methods to treat addiction, or to the identification of new therapeutic targets.
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