Antinociceptive and adverse effects of morphine:ketamine mixtures in rats

IF 1.6 4区心理学 Q3 BEHAVIORAL SCIENCES

Behavioural Pharmacology Pub Date : 2023-11-16 DOI:10.1097/fbp.0000000000000761

Conor D. Strumberger, Evangeline J. D’Epagnier, Kevin H. Nguyen, John D. Rogers, Matthew P. Meyer, Yashmita Malhotra, Jillian E. Hinman, Elisabeth L. Jansen, Vanessa Minervini

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引用次数: 0

Abstract

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague–Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

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吗啡：氯胺酮混合物对大鼠的抗镇痛作用和不良反应

处方阿片类药物是治疗中度至重度疼痛的黄金标准，尽管其不良反应有据可查。在所有处方药中，阿片类药物的滥用最为普遍，致命的过量用药已达到流行病的程度。提高阿片类药物安全系数的一种策略是将阿片类药物与非阿片类药物联合使用，以减少缓解疼痛所需的阿片类药物剂量，从而减少大剂量时出现的不良反应。N-甲基-D-天冬氨酸受体拮抗剂氯胺酮已被安全地用作镇痛药，但仅在非常有限的条件下使用。目前的研究以 24 只成年雄性 Sprague-Dawley 大鼠为对象（每种试验 8 只），对吗啡和氯胺酮单独使用和混合使用时的抗痛觉、行为抑制和胃肠道效应进行了鉴定，以确定它们之间的相互作用。单独给药时，吗啡和氯胺酮都会产生抗痛觉作用，降低对食物的反应，并减少胃肠道转运（即产生便秘）。吗啡：氯胺酮混合物的效应一般具有相加性，但 1:1 混合物的抗镇痛效应除外，其观察效应与预测效应之间的斜率差异（即非平行移动）表明，在较小剂量时具有协同作用，而在较大剂量时具有相加性。吗啡与氯胺酮的混合物具有抗痛觉作用，但吗啡产生便秘的效力并没有增强。吗啡和氯胺酮在产生依赖性、戒断、滥用或呼吸抑制等不良反应方面的相互作用性质尚不清楚，但也可能与混合物中每种药物的比例有关。重要的是要确定在人类身上产生最大潜在治疗窗口的条件。

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来源期刊

Behavioural Pharmacology 医学-行为科学

CiteScore

3.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Behavioural Pharmacology accepts original full and short research reports in diverse areas ranging from ethopharmacology to the pharmacology of schedule-controlled operant behaviour, provided that their primary focus is behavioural. Suitable topics include drug, chemical and hormonal effects on behaviour, the neurochemical mechanisms under-lying behaviour, and behavioural methods for the study of drug action. Both animal and human studies are welcome; however, studies reporting neurochemical data should have a predominantly behavioural focus, and human studies should not consist exclusively of clinical trials or case reports. Preference is given to studies that demonstrate and develop the potential of behavioural methods, and to papers reporting findings of direct relevance to clinical problems. Papers making a significant theoretical contribution are particularly welcome and, where possible and merited, space is made available for authors to explore fully the theoretical implications of their findings. Reviews of an area of the literature or at an appropriate stage in the development of an author’s own work are welcome. Commentaries in areas of current interest are also considered for publication, as are Reviews and Commentaries in areas outside behavioural pharmacology, but of importance and interest to behavioural pharmacologists. Behavioural Pharmacology publishes frequent Special Issues on current hot topics. The editors welcome correspondence about whether a paper in preparation might be suitable for inclusion in a Special Issue.