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

The lateral hypothalamus (LH) has long been known to implicate in the addictive behaviors of drugs of abuse. The ventral tegmental area (VTA) is a major area of the mesolimbic system that is strongly involved in the development of 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. One hundred fourteen adult male Wistar rats underwent unilateral implantation of two separate cannulae into 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 10nM/0.3μl DMSO), respectively, was performed five minutes before concurrent microinjection of carbachol (250nM/0.5μl saline) into the LH and an ineffective dose of morphine (0.5 mg/kg; sc) during 3-day sensitization period. After a 5-day free drug period, on the 9th 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. 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 intraLH carbachol injection attenuated morphine sensitization. These findings suggest that LH stimulation potentiates the sensitization to morphine antinociceptive responses via affecting orexin receptors located in the VTA. However, the contribution of OX1Rs in the VTA was more predominant than that of OX2Rs to morphine sensitization in the rat.