Comparison of the reinforcing, antinociceptive, and respiratory depressant effects of prototypical and G-protein biased mu-opioid receptor agonists in male and female Sprague-Dawley rats.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2024-12-01 Epub Date: 2024-09-27 DOI:10.1007/s00213-024-06690-x

C Austin Zamarripa, Tanya Pareek, Loc M Pham, Bruce E Blough, Hayley M Schrock, Eric J Vallender, Kenneth J Sufka, Kevin B Freeman

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引用次数: 0

Abstract

Rationale: G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints.

Objectives: The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats.

Methods: In the self-administration study, four separate groups of Sprague-Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography.

Results: All MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner.

Conclusion: The present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics.

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比较雌雄 Sprague-Dawley 大鼠体内原型μ-阿片受体激动剂和偏向 G 蛋白的μ-阿片受体激动剂的强化、抗痛觉和呼吸抑制作用。

理由：据报道，与原型缪阿片受体（MOR）激动剂相比，G 蛋白偏向缪阿片受体（MOR）激动剂在抗痛觉和呼吸抑制方面表现出更优越的治疗窗口期。然而，关于偏 G 蛋白的 MOR 激动剂与其他行为终点相关的滥用潜力的研究相对较少：本研究旨在定量比较原型 MOR 激动剂芬太尼和羟考酮与 G 蛋白偏向型 MOR 激动剂 SR14968 和 SR17018 对雄性和雌性大鼠的强化、抗痛觉和呼吸抑制作用：在自我给药研究中，四组独立的Sprague-Dawley（SD）大鼠在渐进比例强化计划下自我静脉注射芬太尼、羟考酮、SR14968和SR17018。采用受试者内设计，使用热板试验、神经病理性和炎症性抗痛觉试验以及全身褶皱成像技术，对不同组别的 SD 大鼠分别进行了静脉注射芬太尼、羟考酮、SR14968 和 SR17018 的测试：结果：所有MOR激动剂都具有强化作用，但SR14968和SR17018的药效低于羟考酮和芬太尼。此外，所有 MOR 激动剂在所有痛觉模式下都能产生剂量依赖性和完全有效的抗痛觉作用。羟考酮和芬太尼，而不是 SR14968 或 SR17018，会以剂量依赖的方式产生呼吸抑制：本研究结果表明，本研究中测试的 G 蛋白偏向 MOR 激动剂可产生 MOR 典型的抗痛觉作用，显示出较低但明显的滥用潜力，并且在剂量高于抗痛觉范围时不会产生呼吸效应。应进一步研究 SR 系列中的非典型 MOR 激动剂，将其作为开发更安全镇痛药的基础分子。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.