NO mechanisms in N2O antinociception in inbred mice

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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.