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) 的食欲素信号传导在压力和成瘾行为中发挥着关键作用。另一方面，压力会增强对吗啡等滥用药物的行为敏感性。本研究旨在阐明 VTA 内食欲素受体在束缚应激 ( RS ) 诱导的吗啡致敏中的作用。成年雄性白化Wistar大鼠接受立体定位手术，双侧VTA内植入两根不锈钢导向管。在暴露于 RS 之前五分钟，将不同剂量的 SB334867或 TCS OX2 29 作为 orexin-1 (OX1) 和 orexin-2 (OX2) 受体拮抗剂分别显微注射到 VTA 中。考虑应用 RS 的持续时间为 3 小时，RS 暴露后 10 分钟，动物连续三天皮下注射无效剂量的吗啡 (1 mg/kg)，随后进行为期 5 天的药物/应激-免费时间段。第九天，甩尾试验评估吗啡镇痛作用的敏感性。结果表明，单独应用RS或吗啡（1 mg/kg）不能引起吗啡致敏；然而，同时使用RS和吗啡可能会引起吗啡致敏。此外，在配对给予吗啡和RS之前，VTA内给予OX1 R或OX2 R拮抗剂可阻断吗啡致敏。OX1 R 和 OX2 R 在诱导应激诱导的吗啡致敏中的作用几乎相同。这项研究为 VTA 中食欲素信号传导在 RS 和吗啡联合给药诱导的吗啡致敏增强中的作用提供了新的见解。