Restraint stress potentiates sensitivity to the antinociceptive effect of morphine through orexin receptors in the ventral tegmental area

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 sensi-tization. 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, respec-tively. 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 fol-lowed 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 in-duction 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.