Nicotinic Acetylcholine Receptors in Neuropathic Pain

神经性疼痛中的烟碱乙酰胆碱受体

• 批准号: 6918393
• 负责人: MICHELLE A VINCLER
• 金额: $ 18.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918393
• 关键词: acetylcholine; analgesia; behavior test; gamma aminobutyrate; glutamates; immunocytochemistry; laboratory rat; nerve injury; neural transmission; neuropharmacology; neurotransmitter biosynthesis; nicotinic receptors; pain; polymerase chain reaction; receptor expression; spinal cord injury; western blottings

DESCRIPTION (provided by applicant): The objectives of this proposal center around an improved understanding of the spinal nicotinic acetylcholine receptors in the spinal cord of normal and nerve-injured rats. A further understanding of spinal nicotinic systems will result in novel, specific pharmacological targets for the treatment of neuropathic pain. The spinal nicotinic system has been largely ignored because the intrathecal administration of nicotinic agonists generally produces more pronociception than antinociception. Recently, data from our laboratory and others, has shown that the pharmacology of nicotinic agonists in the presence of chronic, neuropathic pain is altered. In nerve-injured mice and rats, intrathecal nicotinic agonists produce only antinociception. Data from our laboratory has shown that several nicotinic acetylcholine receptor subunits are upregulated following spinal nerve ligation. Spinal interneurons upregulate their expression of the alpha3 and the alpha7 subunits while primary afferents increase their expression of the alpha5 subunit. Previously, we have also found that the alpha5 subunit contributes to mechanical allodynia in neuropathic rats. However, the contributions of the alpha3 and alpha7 subunits are still unknown. This proposal outlines both anatomical and functional experiments to determine the contribution of these upregulated subunits to the maintenance of mechanical allodynia following nerve injury. We will use immunocytochemistry to identify the spinal structures that upregulate these two nicotinic subunits. We will use the anatomical data obtained from these studies to further investigate the function of these upregulated subunits in the spinal cord of neuropathic rats. The functionality of these subunits will be investigated using in vitro release experiments. Selective nicotinic agonists and antagonists will be used to elicit the release of GABA in the isolated spinal cord slice and in synaptosomes. Finally, the behavioral implications of nicotinic subunit upregulation will be determined with the intrathecal administration of selective nicotinic agonists and antagonists in normal and spinal nerve-ligated rats. The results of these studies will further define spinal nicotinic anatomy and functioning in the nerve-injured animal thereby, providing unique potential targets for the pharmacological treatment of neuropathic pain.

描述（由申请人提供）：该提案的目标围绕正常和神经损伤大鼠的脊髓中对脊柱烟碱乙酰胆碱受体的深入了解。对脊柱烟碱系统的进一步了解将导致新颖的，特定的药理靶标，用于治疗神经性疼痛。脊柱烟碱系统已被大大忽略，因为烟碱激动剂的鞘内给药通常比抗伤害感受更多。最近，我们实验室和其他人的数据表明，在存在慢性神经性疼痛的情况下，烟碱激动剂的药理学已改变。在神经损害的小鼠和大鼠中，鞘内烟碱激动剂仅产生抗伤害感受。 我们实验室的数据表明，脊柱神经结扎术后几个烟碱乙酰胆碱受体亚基被上调。脊柱中间神经元上调其对α3和α7亚基的表达，而初级传入则增加了其对α5亚基的表达。以前，我们还发现α5亚基有助于神经性大鼠的机械性异常性疾病。但是，alpha3和alpha7亚基的贡献仍然未知。该建议概述了解剖学和功能实验，以确定这些上调亚基对神经损伤后机械异常性疾病的贡献。我们将使用免疫细胞化学来确定上调这两个烟碱亚基的脊柱结构。我们将使用从这些研究获得的解剖学数据进一步研究这些上调的亚基在神经性大鼠的脊髓中的功能。这些亚基的功能将使用体外释放实验研究。选择性的烟碱激动剂和拮抗剂将用于引起在分离的脊髓切片和突触体中释放GABA。最后，烟碱亚基上调的行为意义将由正常和脊柱神经粘合大鼠的选择性烟碱激动剂和拮抗剂的固定性施用确定。这些研究的结果将进一步定义脊柱烟碱解剖结构，并在神经受损的动物中起作用，从而为神经性疼痛的药理治疗提供了独特的潜在靶标。