Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA; Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA.
Neuropharmacology. 2023 Apr 1;227:109424. doi: 10.1016/j.neuropharm.2023.109424. Epub 2023 Jan 28.
Recent evidence suggests that inhibition of the M muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use disorder (OUD). Previous studies from our group and others have demonstrated that acute administration of the long-acting M negative allosteric modulator (NAM) ML375 attenuates established self-administration of cocaine, ethanol, oxycodone, and remifentanil in rats. In the present study, we characterized the effects of acute and repeated administration of the novel, short-acting M NAM VU6008667 on the reinforcing effects of oxycodone and reinstatement of oxycodone-seeking behaviors in male Sprague-Dawley rats, as well as on physiological withdrawal from oxycodone. Acute VU6008667 decreased oxycodone self-administration under both fixed ratio 3 (FR3) and progressive ratio (PR) schedules of reinforcement and attenuated cue-induced reinstatement of lever pressing following extinction from oxycodone self-administration, a commonly used relapse model. When administered daily to opioid-naïve rats, VU6008667 prevented acquisition of oxycodone self-administration behavior. VU6008667 had minimal effects on naloxone-precipitated withdrawal. After acute administration, VU6008667 did not inhibit sucrose self-administration and, when given chronically, delayed but did not prevent acquisition of sucrose maintained self-administration. VU6008667 also did not impact oxycodone induced anti-nociception or motor coordination, but mildly decreased novelty exploration. Finally, acute or daily VU6008667 administration did not impair cued fear conditioning. Overall, these results suggest that inhibition of the M mAChR may provide a novel, non-opioid based treatment for distinct aspects of OUD by inhibiting opioid intake in established OUD, reducing relapse during abstinence, and by reducing the risk of developing OUD.
最近的证据表明，抑制 M 毒蕈碱乙酰胆碱受体（mAChR）可能为治疗阿片类药物使用障碍（OUD）提供一种新的非阿片类机制。我们小组和其他小组的先前研究表明，长效 M 负变构调节剂（NAM）ML375 的急性给药可减弱大鼠可卡因、乙醇、羟考酮和瑞芬太尼的已建立的自我给药。在本研究中，我们描述了新型短效 M NAM VU6008667 对阿片类药物的强化作用和对雄性 Sprague-Dawley 大鼠中阿片类药物寻求行为的复吸的急性和重复给药的影响，以及对阿片类药物戒断的生理影响。急性 VU6008667 降低了固定比率 3（FR3）和递增比率（PR）强化方案下的阿片类药物自我给药，并且在阿片类药物自我给药消退后减弱了线索诱导的杠杆按压复吸，这是一种常用的复发模型。当给予阿片类药物-naïve 大鼠时，VU6008667 可防止阿片类药物自我给药行为的获得。VU6008667 对纳洛酮诱发的戒断影响很小。急性给药后，VU6008667 不抑制蔗糖自我给药，并且在慢性给药时，延迟但不能防止蔗糖维持的自我给药的获得。VU6008667 也不影响阿片类药物引起的镇痛或运动协调，但轻度降低了新奇性探索。最后，急性或每日 VU6008667 给药不会损害线索恐惧条件反射。总体而言，这些结果表明，通过抑制已建立的 OUD 中的阿片类药物摄入、减少戒断期间的复发以及降低发展为 OUD 的风险，抑制 M mAChR 可能为 OUD 的不同方面提供一种新的、非阿片类的治疗方法。
