Behavioral Pharmacology of Injury Restricted Fentanyl Analogues.

项目总结 MU-阿片受体(MOR)激动剂(如芬太尼、羟考酮)对疼痛的治疗非常有效。 然而，它们的治疗益处伴随着不想要的副作用，如耐受性、呼吸抑制、 和成瘾，这表明需要改进治疗选择。最近，氟化芬太尼类似物 与芬太尼相比，已产生的(FFA)具有更低的pKA。此属性允许这些 新型MOR激动剂将被与损伤相关的低pH微环境选择性激活 同时系统地重新开采相对惰性的组织。因此，它们应该产生有效的抗伤害作用。 和芬太尼一样的效力，同时避免了传统的MOR激动剂(成瘾、呼吸)的不良影响 抑郁。)然而，有关这些酸碱度的滥用倾向和呼吸抑制作用的文献- 限制性配体是有限的。这项研究建议严格比较FFA和芬太尼在模型中的作用。 大鼠的抗伤害性、滥用潜能和呼吸抑制。具体地说，目标一号将确定反- 测试配体在高度不同的疼痛方式中的伤害性效力和有效性。目标2将评估 测试配体在自我管理中产生与滥用有关的影响的效力和效力。最后，《目标3》将 使用全身测量测试配体产生呼吸抑制的效力和效果 体积描记术。性行为的影响也将被调查。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安全边际的信息。这样做的结果 研究将极大地有助于寻找更安全、非强化的疼痛治疗方法。这一团契 培训计划将包括科学培训和专业发展。确保为…做好准备 作为一名内科科学家的职业生涯，将特别注意学术研究与继续 接触临床药物。这项奖学金的所有方面都将在 密西西比大学医学中心。申请者将接受科学培训和专业培训 发起人和共同发起人、他们的合作者、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.