Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Physiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
Neuropeptides. 2023 Oct;101:102353. doi: 10.1016/j.npep.2023.102353. Epub 2023 Jun 15.
Orexin signaling in the ventral tegmental area (VTA) plays a critical role in stress and addictive behaviors. On the other hand, exposure to stress potentiates behavioral sensitization to drugs of abuse such as morphine. This study aimed to elucidate the role of orexin receptors within the VTA in restraint stress (RS)-induced morphine sensitization. Adult male albino Wistar rats underwent stereotaxic surgery, and two stainless steel guide cannulae were bilaterally implanted into the VTA. Different doses of SB334867 or TCS OX2 29 as orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists were microinjected into the VTA five min before exposure to RS, respectively. A duration of three hours was considered for applying the RS, and 10 min after RS exposure, animals received a subcutaneous injection of an ineffective dose of morphine (1 mg/kg) for three consecutive days followed by a five-day drug/stress-free period. On the ninth day, the tail-flick test evaluated the sensitivity to the antinociceptive effects of morphine. The results demonstrated that the sole application of RS or morphine (1 mg/kg) could not induce morphine sensitization; however, concurrent application of RS and morphine could induce morphine sensitization. Besides, intra-VTA administration of OX1 R or OX2 R antagonists before paired administration of morphine and RS blocked morphine sensitization. The role of OX1 R and OX2 R in the induction of stress-induced morphine sensitization was almost identical. This study provides new insight into the role of orexin signaling in the VTA in the potentiation of morphine sensitization induced by RS and morphine co-administration.
腹侧被盖区（VTA）中的食欲素信号在应激和成瘾行为中起着关键作用。另一方面，暴露于应激会增强对阿片类药物如吗啡的药物敏化作用。本研究旨在阐明 VTA 内的食欲素受体在束缚应激（RS）诱导的吗啡敏化中的作用。成年雄性白化 Wistar 大鼠接受立体定向手术，双侧 VTA 中植入两根不锈钢引导套管。在暴露于 RS 之前，分别将不同剂量的 SB334867 或 TCS OX2 29 作为食欲素-1（OX1）和食欲素-2（OX2）受体拮抗剂微注射到 VTA 中。应用 RS 的持续时间为 3 小时，RS 暴露 10 分钟后，动物接受无效剂量吗啡（1mg/kg）的皮下注射，连续 3 天，然后是 5 天的药物/无应激期。在第 9 天，尾巴闪烁测试评估了对吗啡的抗伤害作用的敏感性。结果表明，仅应用 RS 或吗啡（1mg/kg）不能诱导吗啡敏化；然而，RS 和吗啡同时应用可诱导吗啡敏化。此外，在吗啡和 RS 配对给药之前，在 VTA 内给予 OX1 R 或 OX2 R 拮抗剂可阻断吗啡敏化。OX1 R 和 OX2 R 在诱导应激诱导的吗啡敏化中的作用几乎相同。本研究为食欲素信号在 VTA 中增强 RS 和吗啡共同给药诱导的吗啡敏化中的作用提供了新的见解。
