Spinal Galanin and its Receptors in Pain Processing

描述（由申请人提供）：脊髓甘丙肽系统在 调节传入处理，导致疼痛行为后，组织 和神经损伤。脊髓调制似乎是通过激活 一种或多种三种克隆和表达的甘丙肽受体（Ga 1 R1，2，3）， 存在于脊髓中。该提案的重点是， 甘丙肽活性和药理学的这几个方面被强调为 五个具体目标。具体目标1：系统地定义抗伤害感受 急性脑梗死模型大鼠鞘内甘丙肽及其同系物的分布 伤害性处理（热逃逸），组织损伤后疼痛状态 （福尔马林和角叉菜胶痛觉过敏），并在神经损伤后疼痛状态 （Chung触觉异常性疼痛，依那普利汀诱发触觉异常性疼痛）。具体目标二： 通过检查确定介导甘丙肽脊髓作用的脊髓受体 鞘内甘丙肽、同源物和片段的剂量依赖性活性 用鞘内递送的Gal 1反义/错义处理的大鼠， 2和3受体。具体目标3：由于甘丙肽在突触前位点， 几个系统，可以阻止钙通道的开放，确定是否，在 雅阁受体激动剂与其抗伤害感受特性一致， 脊髓谷氨酸和前列腺素在体内的释放。具体目标4检查 行为学特征和对鞘内注射甘丙肽的反应 激动剂和拮抗剂在制备为甘丙肽过表达者的小鼠中的应用。 具体目标5系统表征和比较I125的置换 Gal-r特异性表达细胞系中甘丙肽结合， 腺苷酸环化酶和鞘内注射后的抗伤害作用 组合合成的候选肽家族（Galp片段）和 已知在Ga 1 R位点结合的非肽（galnon）分子。 因此，这些研究将系统地定义脊髓的作用。 甘丙肽能系统在调节脊髓伤害感受功能中的作用。我们相信 这些研究的结果将提供直接的证据， 这种脊髓肽能系统在疼痛和点发展的新 抗过敏剂。

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.