Spinal Galanin and its Receptors in Pain Processing

描述(申请人提供)：脊髓甘丙素系统在 导致组织后疼痛行为的传入加工的调节 和神经损伤。脊髓的调制似乎是通过激活 三个克隆和表达的甘丙肽受体(Ga1R1、2、3)中的一个或多个 它们存在于脊髓中。这项提案的重点是， 甘丙肽活性和药理的这几个方面由以下几个方面强调 五个具体目标。具体目标1：系统定义抗伤害感受性药物 大鼠鞘内甘丙素及其同系物在急性脑缺血模型中的变化 伤害性处理(热逃逸)，组织损伤后疼痛状态 (福尔马林和卡拉胶痛敏)，以及神经损伤后的疼痛状态 (长春新碱诱发触觉异常痛)。具体目标2： 通过检查确定介导甘丙肽脊髓作用的脊髓受体 鞘内甘丙素、同系物和片段的剂量依赖性活性 鞘内注射Gal-1反义/错义治疗大鼠， 2和3受体。具体目标3：由于甘丙素在 几个系统和可以阻断钙通道的开放，确定是否，在 与其抗伤害性感受性特征一致，这些激动剂调制被诱发的 体内释放脊髓谷氨酸和前列腺素。具体目标4检查 鞘内注射甘丙素的行为特征和反应 小鼠体内准备过度表达甘丙肽的激动剂和拮抗剂。 具体目标5系统地表征和比较I125的位移 Gal-r特异性表达细胞系中甘丙素结合的抑制 鞘内给药后腺苷环化酶与抗伤害性反应 人工合成的候选多肽家族(Galp片段)和 已知与Ga1R结合的非肽(半乳糖)分子。 因此，这些研究将系统地定义脊髓的活动 甘丙素能系统在调节脊髓伤害性感受功能中的作用我们相信 这些研究的结果将提供直接证据证明 这种脊髓肽能系统在疼痛中的作用，并指向新的发展方向 抗过敏性药物。

DESCRIPTION (provided by applicant): Spinal galanin systems play a role in the regulation of afferent processing that results in pain behavior after tissue and nerve injury. The spinal modulation appears to be mediated by activation of one or more of three cloned and expressed galanin receptors (Ga1R1,2,3) some of which are present in spinal cord. The focus of this proposal, characterizing these several aspects of galanin activity and pharmacology is underscored by five specific aims. Specific Aim 1: Systematically define the antinociceptive profile of intrathecal galanin and homologues in rats on models of acute nociceptive processing (thermal escape), post tissue injury pain states (formalin and carrageenan hyperalgesia), and in post nerve injury pain states (Chung tactile allodynia Vincristine evoked tactile allodynia). Specific Aim 2: Define the spinal receptor mediating the spinal action of galanin by examining the dose dependent activity of intrathecal galanin, homologues and fragments in rats treated with intrathecally delivered antisenses/mis-senses for the Gal 1, 2 and 3 receptors. Specific Aim 3: As galanin has a presynaptic locus in several systems and can block opening of calcium channels, determine if, in accord with its antinociceptive profile, these agonists modulate the evoked release of spinal glutamate and prostaglandin in vivo. Specific Aim 4 examine the behavioral characteristics and response to intrathecally delivered galanin agonists and antagonists in mice prepared to be over expressors of galanin. Specific aim 5 systematically characterize and compare displacement of I125 galanin binding in Gal-r specific expressing cell lines, suppression of adenylate cyclase and antinociceptive actions after intrathecal delivery of combrnatorially synthesized candidate families of peptidic (Galp fragments) and non-peptidic (galnon) molecules which are known to bind at the Ga1R sites. These studies will thus systematically define the actions of spinal galanin-ergic systems in regulating spinal nociceptive function. We believe the outcome of these studies will provide direct evidence for the role played by this spinal peptidergic system in pain and point to the development of novel anti-hyperpathic agents.