NO mechanisms in N2O antinociception in inbred mice

描述(由申请人提供)：缺乏对神经元型一氧化氮合酶(NNOS)和一氧化氮合酶(NO)的作用的了解，这是一个问题，因为如果没有它，研究人员可能会忽视可能在疼痛控制中利用的替代靶点。我们的长期目标是提高疼痛临床治疗的有效性。这项应用的目的是确定诱导的抗伤害感觉在小鼠中的作用。我们的中心假设是DBA/2菌株对N2O的低反应性可能是由于参与N2O诱导的抗伤害感受的酶、辅因子、启动子强度/反应或翻译后修饰的异常所致。通过利用两个近交系(C5BL/6和DBA/2)对N2O的不同反应，本研究将获得对TO N2O作用的更多知识。这项研究的具体目的包括：1)确定脊髓和脊髓上N2O诱导的抗伤害感受在NOS基因敲除和敲除小鼠中的作用；2)建立增加C57BL/6和DBA/2小鼠脑源性抗伤害感受的药物之间的剂量-反应关系；以及3)测量和比较N2O暴露对小鼠的影响。这些目标将通过药理学、神经化学和分子生物学方法实现。这一贡献将是重大的，因为预计将确定新的治疗干预目标，并将刺激能够优化疼痛管理的新药的开发。我们的长期目标是提高疼痛临床治疗的有效性。这项拟议研究的基本原理是确定并本地化开发可用于优化疼痛管理的药物(可能还有非药物)手段的新靶点。

DESCRIPTION (provided by applicant): Lack of understanding of the role of neuronal nitric oxide synthase (nNOS) and nitric oxide ( problem because, without it, researchers may be overlooking alternative targets that might be exploited in pain management. Our long-term goal is to increase the efficacy of clinical management of pain. The objective in this application is to identify the role of induced antinociception in mice. Our central hypothesis is that the poor responsiveness of the DBA/2 strain to N2O might be due to an anomaly in the enzyme, cofactor, promoter strength/response or post-translational modification) that is involved in N2O-induced antinociception. By taking advantage of the differential responsiveness of two inbred strains (C5BL/6 and DBA/2) to N2O, this research will garner increased knowledge of the role of to N2O. The Specific Aims of the proposed research include the following: 1) determination of the role of spinal and supraspinal N2O-induced antinociception in NOS knockout and knockdown mice; 2) establishing the dose-response relationship between drugs that increase brain induced antinociception in C57BL/6 and DBA/2 mice; and 3) measurement and comparison of the effects of N2O exposure on mice. These goals will be attained by pharmacological, neurochemical and molecular biology methods. This contribution will be significant because it is expected that new targets for therapeutic intervention will be identified and development of new drugs that can optimize pain management will be stimulated. Our long-term goal is to increase the effectiveness of clinical management of pain. The rationale for the proposed research is to identify and localize new targets for development of drugs (and possibly non-drug) means that can be used to optimize pain management.