Role of the Orexinergic System Within the Ventral Tegmental Area in the Development of Sensitization to Morphine Induced by Lateral Hypothalamus Stimulation

INTRODUCTION: The Lateral Hypothalamus (LH) has long been known to implicate the addictive behaviors of drug abuse. The Ventral Tegmental Area (VTA) is a major area of the mesolimbic system that is strongly involved in developing morphine sensitization. The current study aimed to examine the role of intra-VTA orexin receptors in the LH stimulation-induced sensitization to the antinociceptive response of morphine. METHODS: A total of 114 adult male Wistar rats underwent unilateral implantation of two separate cannulae in the LH and VTA using the stereotaxic apparatus. Intra-VTA administration of the Orexin-1 (OX1) and Orexin-2 (OX2) receptor antagonists, SB334867 and TCS OX2 29 (1, 3, and 10 nM/0.3 μL DMSO), respectively, was performed 5 min before concurrent microinjection of carbachol (250 nM/0.5 μL saline) into the LH and an ineffective dose of morphine (0.5 mg/kg; SC) during a 3-day sensitization period. After a 5-day free drug period, on the ninth day, for assessing the morphine sensitization, the nociceptive response was measured before and after morphine injection (1 mg/kg; SC) using the tail-flick test. RESULTS: The results revealed that the concurrent administration of carbachol (250 nM) and an ineffective dose of morphine significantly induced morphine sensitization. Besides, the blockade of OX1 and OX2 receptors within the VTA before intra-LH carbachol injection attenuated morphine sensitization. CONCLUSION: These findings suggest that LH stimulation potentiates the sensitization to morphine antinociceptive responses via affecting orexin receptors located in the VTA. However, OX1 receptors contribute more than OX2 receptors in the VTA to morphine sensitization in rats. HIGHLIGHTS: LH stimulation enhances sensitization to the ineffective dose of morphine. Intra-VTA OX1 receptor involves in morphine sensitization-induced by LH stimulation. Intra-VTA OX2 receptor involves in morphine sensitization-induced by LH stimulation. PLAIN LANGUAGE SUMMARY: Behavioral sensitization, such as sensitization to the antinociceptive response of drugs, which defines as an enhanced systemic reaction to the same dose of addictive drugs, occurs in response to continuous and intermittent administration of these drugs. The Lateral Hypothalamus (LH) sends the orexinergic projections to the various regions of the brain and stimulation of LH induces sensitization to the antinociceptive response of morphine. The Ventral tegmental area (VTA) is a region of the brain that is strongly involved in developing morphine sensitization and receives orexinergic projections of LH. The current study aimed to examine the role of orexin receptors within the VTA in the LH stimulation-induced sensitization to the antinociceptive response of morphine in rats. In this study orexin-1 (OX1) and orexin-2 (OX2) receptors within the VTA region were blocked using their antagonists. After five minutes chemical stimulation of LH was done using carbachol microinjection into this area and ineffective dose of morphine was injected subcutaneously. These interventions were done for three consecutive days as sensitization period. After a 5-day free drug period, on the ninth day, for assessing the morphine sensitization, the nociceptive response was measured. The results revealed that the concurrent administration of LH stimulation and an ineffective dose of morphine significantly induced morphine sensitization. Besides, the blockade of OX1 and OX2 receptors within the VTA before LH stimulation attenuated sensitization to the antinociceptive response of morphine. Therefore, the orexinergic system plays an important role in morphine sensitization and can be considered as one of the potential targets to increase the analgesic effect of morphine.