Marinho Eduardo A V, Oliveira-Lima Alexandre Justo, Reis Henrique S, Santos-Baldaia Renan, Wuo-Silva Raphael, Hollais Andre W, Yokoyama Thais S, Frussa-Filho Roberto, Berro Lais F
Department of Health Sciences, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brazil.
Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Front Pharmacol. 2023 Feb 6;14:1100527. doi: 10.3389/fphar.2023.1100527. eCollection 2023.
The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20 mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10 mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge.
内源性大麻素系统与阿片类药物使用障碍的神经生物学有关。虽然CB1受体拮抗剂利莫那班已被证明可阻断阿片类药物的一些行为效应，但研究表明治疗环境（即在与药物相关的环境中接受治疗和/或新奇环境）会影响其效果。在本研究中，我们调查了治疗环境在利莫那班对吗啡诱导的行为敏化表达的影响中的作用。成年雌性瑞士小鼠接受行为敏化方案，在此期间它们在旷场装置中接受吗啡（20mg/kg，腹腔注射），随后在旷场、笼内或活动箱（新奇环境）中用溶剂或利莫那班（1或10mg/kg，腹腔注射）进行治疗。分别在随后的生理盐水和吗啡激发试验中评估条件性运动（在无吗啡的情况下旷场装置中运动活动增加）和吗啡诱导的行为敏化（对吗啡敏感的动物运动活动增加）的表达。用吗啡治疗的动物表现出行为敏化，随着时间的推移运动活动显著增加。对吗啡敏感并在笼内用溶剂治疗的动物表现出条件性运动，这种效应被笼内注射利莫那班所阻断。在生理盐水激发试验期间，只有对吗啡敏感并在笼内用生理盐水治疗的动物表现出吗啡诱导的条件性运动。在治疗阶段接受生理盐水的所有吗啡治疗动物（对照组）在吗啡激发试验期间表现出行为敏化。在旷场和活动箱中而非笼内注射利莫那班可阻断吗啡诱导的行为敏化的表达。我们的研究结果表明，即使在笼内给药，CB1受体拮抗作用也可调节对吗啡的条件性反应。然而，在吗啡激发试验期间，暴露于与药物相关的环境或新奇环境对于利莫那班对吗啡诱导的行为敏化的作用表达是必要的。
