Behavioral Pharmacology of Injury Restricted Fentanyl Analogues.

项目摘要 μ-阿片受体（莫尔）激动剂（例如，芬太尼、羟考酮）对于治疗疼痛是非常有效的。 然而，它们的治疗益处伴随着不必要的副作用，如耐受性，呼吸抑制， 和成瘾，这表明需要改进治疗方案。最近，氟化芬太尼类似物 已经产生了相对于芬太尼具有降低的pKa的FFA。此属性允许这些 新的莫尔激动剂被与损伤相关的低pH微环境选择性激活 组织，同时保持相对惰性的全身性。因此，它们应该产生有效的抗伤害感受 同时避免了传统莫尔激动剂（成瘾、呼吸道感染）的不良反应 抑郁症。）然而，关于这些pH值的滥用倾向和呼吸抑制作用的文献- 限制性配体是有限的。该奖学金建议在模型中严格比较FFA和芬太尼， 大鼠的抗伤害感受、滥用潜力和呼吸抑制。具体而言，目标1将确定抗- 测试配体在高度变化的疼痛形式中的伤害感受效力和功效。目标2将评估 测试配体在自我给药中产生滥用相关效应的效力和功效。最后，Aim 3将 测量测试配体产生呼吸抑制的效力和功效 体积描记法。还将研究性别影响。最终，拟议的研究将提供关键的 关于一类新的候选阿片类药物治疗的安全范围的信息。的结果 研究将大大有助于寻找更安全，非强化，疼痛治疗。该研究金基金 培训计划将包括科学培训和专业发展。为确保做好准备， 作为一个医生，科学家的职业生涯，将特别注意学术研究与持续的整合 接触临床医学。这项奖学金的所有方面将在杰克逊校园进行， 密西西比大学医学中心。申请人将接受科学培训和专业 从申办者和共同申办者，他们的合作者，在神经科学计划，和 健康科学研究生院。

PROJECT SUMMARY Mu-opioid receptor (MOR) agonists (e.g., fentanyl, oxycodone) are highly efficacious for the treatment of pain. However, their therapeutic benefits are coupled with unwanted side effects like tolerance, respiratory depression, and addiction, indicating the need for improved therapeutic options. Recently, fluorinated fentanyl analogues (FFAs) have been produced which possessed a decreased pKa relative to fentanyl. This property allows these novel MOR agonists to become selectively activated by the low pH microenvironment associated with injured tissues while remining relatively inert systemically. Therefore, they should produce antinociception with efficacy and potency like fentanyl while avoiding the unwanted effects of traditional MOR agonists (addiction, respiratory depression.) However, literature regarding the abuse liability and respiratory depressing effects of these pH- restricted ligands is limited. This fellowship proposes to rigorously compare FFAs to fentanyl in models of antinociception, abuse potential, and respiratory depression in rats. Specifically, Aim 1 will determine the anti- nociceptive potency and efficacy of the test ligands across highly varied pain modalities. Aim 2 will evaluate the potency and efficacy of the test ligands to produce abuse-related effects in self-administration. Finally, Aim 3 will measure the potency and efficacy of the test ligands to produce respiratory depression using whole-body plethysmography. Sex effects will also be investigated. Ultimately, the proposed research will provide critical information regarding the safety margins of a new class of candidate opioid therapeutics. The results of this investigation will contribute greatly to the search for safer, non-reinforcing, treatments for pain. This fellowship training plan will encompass scientific training and professional development. To ensure proper preparation for a career as a physician-scientist, special attention will be paid to integration of academic research with continued exposure to clinical medicine. All aspects of this fellowship will be carried out at the Jackson campus of the University of Mississippi Medical Center. The applicant will receive scientific training and professional development from the Sponsor and Co-Sponsor, their collaborators, the Program In Neuroscience, and the School of Graduate Studies in the Health Sciences.