Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Biomolecular Sciences, School of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, SP, Brazil; Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark.
Behav Brain Res. 2022 Feb 10;418:113651. doi: 10.1016/j.bbr.2021.113651. Epub 2021 Oct 31.
The antidepressant effect of ketamine has been widely acknowledged and the use of one of its enantiomers, S-ketamine (esketamine), has recently been approved for the clinical management of treatment-resistant depression. As with ketamine, the non-selective opioid receptor-interacting drug buprenorphine is reported to have antidepressant and anxiolytic properties in humans and rodents. Given the fact that antidepressant drugs are also first line treatment for panic disorder, it is surprising that the potential panicolytic effect of these compounds has been scarcely (ketamine), or not yet (buprenorphine) investigated. We here evaluated the effects of ketamine (the racemic mixture), esketamine, and buprenorphine in male Wistar rats submitted to a panicogenic challenge: acute exposure to hypoxia (7% O). We observed that esketamine (20 mg/kg), but not ketamine, decreased the number of escape attempts made during hypoxia, and this effect could be observed even 7 days after the drug administration. A panicolytic-like effect was also observed with MK801, which like esketamine, antagonizes NMDA glutamate receptors. Buprenorphine (0.3 mg/kg) also impaired hypoxia-induced escape, an effect blocked by the non-selective opioid receptor antagonist naloxone, indicating an interaction with classical ligand sites, such as µ and kappa receptors, but not with nociception/orphanin FQ receptors. Altogether, the results suggest that esketamine and buprenorphine cause rapid-onset panicolytic-like effects, and may be alternatives for treating panic disorder, particularly in patients who are refractory to standard pharmacological treatment.
氯胺酮的抗抑郁作用已得到广泛认可，其对映异构体 S-氯胺酮（右美沙芬）最近已被批准用于治疗耐药性抑郁症。与氯胺酮一样，非选择性阿片受体相互作用药物丁丙诺啡在人类和啮齿动物中也具有抗抑郁和抗焦虑作用。鉴于抗抑郁药也是惊恐障碍的一线治疗药物，令人惊讶的是，这些化合物的潜在抗惊恐作用几乎没有（氯胺酮）或尚未（丁丙诺啡）得到研究。我们在这里评估了氯胺酮（外消旋混合物）、右美沙芬和丁丙诺啡在雄性 Wistar 大鼠中的作用，这些大鼠被置于惊恐发作挑战下：急性暴露于低氧（7% O）中。我们观察到，右美沙芬（20 mg/kg），而不是氯胺酮，可减少大鼠在低氧环境下的逃生尝试次数，这种效果甚至可以在给药后 7 天观察到。MK801 也表现出类似惊恐的作用，MK801 像右美沙芬一样，拮抗 NMDA 谷氨酸受体。丁丙诺啡（0.3 mg/kg）也会损害低氧诱导的逃避，这种作用被非选择性阿片受体拮抗剂纳洛酮阻断，表明与经典配体结合部位（如µ和κ受体）相互作用，但与痛觉/孤啡肽 FQ 受体无关。总之，这些结果表明，右美沙芬和丁丙诺啡可引起快速发作的惊恐样作用，并且可能是治疗惊恐障碍的替代药物，特别是在对标准药物治疗有抗药性的患者中。
