Role of orexinergic receptors within the ventral tegmental area in the development of morphine sensitization induced by forced swim stress in the rat

Abstract

The ventral tegmental area (VTA) has been suggested as part of a common system for reward, stress, and morphine sensitization. Repeated exposure to stress enhances sensitivity to drugs such as morphine. The role of orexin receptor type 1 (OX1R) and type 2 (OX2R) within the VTA in cross-sensitization of morphine with stress was assessed in this study. Various doses of OX1R antagonist (SB334867) and OX2R antagonist (TCS OX2 29) were microinjected into the VTA of 134 adult male albino Wistar rats through cannulae, which had been bilaterally implanted above this region. Five min after microinjection, animals were forced to swim for 6 min, and 10 min after forced swim stress (FSS) termination, a low dose of morphine (i.e., ineffective dose for sensitization) was subcutaneously injected (1 mg/kg; sc). This procedure was repeated for three consecutive days as a sensitization period followed by a 5-day drug/stress-free period. On the 9th day, sensitivity to morphine was examined by measuring antinociceptive responses to the ineffective dose of morphine via tail-flick test. The obtained findings revealed that while concurrent administration of FSS and an ineffective dose of morphine (1 mg/kg; sc) for three consecutive days induced sensitivity to morphine, intra-VTA administration of OX1R- and OX2R antagonists, dose-dependently blocked this sensitization. These results suggested that both orexin receptors located in the VTA have a considerable role in morphine sensitization induced by concurrent administration of FSS and a low dose of morphine. So, there is a contribution of the orexin system partly to stress-induced sensitization to morphine.