Cannabinoid CB1 allosteric ligands suppress inflammatory pain in male mice without tolerance, motor impairment, memory deficits or respiratory depression

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2026-09-11 Epub Date: 2026-07-23 DOI:10.1111/bph.70572

Ifeoluwa D. Solomon, Sumanta Garai, Ganesh A. Thakur, Andrea G. Hohmann

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引用次数: 0

Abstract

Background and Purpose

Positive allosteric modulators (PAMs) engage sites distinct from the orthosteric CB₁ cannabinoid receptor binding site. GAT211, a racemic ligand, contains GAT228 (R) and GAT229 (S) enantiomers. Whether enantiomer-mediated differences in allosteric activation or positive allosteric modulation translate into differences in therapeutic efficacy or unwanted cannabimimetic effects remain unknown.

Experimental Approach

We evaluated therapeutic efficacy of the pure CB₁ allosteric agonist, GAT228 (R), and the PAM, GAT229 (S), in inflammatory pain induced by complete Freund's adjuvant (CFA) in male mice. We assessed whether these allosteric ligands would spare tolerance, memory deficits, motor impairment and respiratory depression associated with the orthosteric CB₁/CB₂ agonist CP55,940.

Key Results

GAT228 and GAT229 attenuated CFA-induced mechanical hypersensitivity in a CB₁-dependent manner without producing tolerance or hypothermia associated with the orthosteric CB₁/CB₂ agonist CP55,940. CP55,940 also produced memory deficits, motor impairment, and robust respiratory depression. GAT228 and GAT229 failed to do so. Unlike CP55,940, allosteric ligands did not produce motor impairment or notable respiratory depression in the presence or absence of CFA-induced inflammation. Allosteric ligands increased novel object recognition memory, whereas CP55,940 decreased time spent exploring the novel object. Intraplantar CFA increased immobility time in the tail suspension test, indicative of pain-related behavioural despair, which was normalized by allosteric ligands and exacerbated by CP55,940.

Conclusion and Implication

CB₁ allosteric ligands represent promising, safer therapeutic strategies for pain management compared to direct CB₁ orthosteric agonists. Overall, this work contributes to offering a novel pathway for pain management that minimizes the risk of adverse effects.

查看原文本刊更多论文

大麻素CB1变构配体抑制雄性小鼠炎症性疼痛，无耐受性、运动损伤、记忆缺陷或呼吸抑制。

背景和目的：正变构调节剂（PAMs）参与不同于正构CB1大麻素受体结合位点的位点。GAT211是一种外消旋配体，包含GAT228 (R)和GAT229 (S)对映体。对映体介导的变构激活或正变构调节的差异是否转化为治疗效果的差异或不想要的大麻模拟效应仍然未知。实验方法：我们评估了纯CB1变构激动剂GAT228 (R)和PAM GAT229 (S)对完全弗氏佐剂（CFA）诱导的雄性小鼠炎症性疼痛的治疗效果。我们评估了这些变构配体是否会避免与正位CB1/CB2激动剂CP55,940相关的耐受性、记忆缺陷、运动障碍和呼吸抑制。关键结果：GAT228和GAT229以CB1依赖的方式减弱cfa诱导的机械超敏反应，而不会产生与正位CB1/CB2激动剂CP55,940相关的耐受性或低温。CP55,940还产生记忆缺陷、运动障碍和强烈的呼吸抑制。GAT228和GAT229未能做到这一点。与CP55,940不同，在存在或不存在cfa诱导的炎症时，变构配体不会产生运动障碍或明显的呼吸抑制。变构配体增加了新物体识别记忆，而CP55,940减少了探索新物体的时间。足底CFA增加了尾巴悬吊试验中的不动时间，表明疼痛相关的行为绝望，这种行为被变张力配体正常化，并被CP55,940加剧。结论和意义：与直接CB1矫形受体激动剂相比，CB1变构配体是一种有希望的、更安全的疼痛治疗策略。总的来说，这项工作有助于提供疼痛管理的新途径，最大限度地减少不良反应的风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.