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

Abstract

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 intra-LH 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.

Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats

“…The orexin projections are involved in various behavioral and physiological functions (Sakurai, Amemiya et al ., 1998; Marcus, Aschkenasi et al ., 2001; Sargin, 2019). Previous studies showed orexin receptors are located in the lateral hypothalamic and thalamic nuclei (Haghparast, Fatahi et al ., 2017; Salehi, Kashfi et al ., 2020), locus coeruleus (Safari, Haghparast et al ., 2009, 2011), nucleus accumbens (NAc) (Yazdi, Jahangirvand et al ., 2016; Andreoli, Marketkar et al ., 2017), ventral tegmental area (VTA) (Sadeghi, Reisi et al ., 2013; Ezzatpanah, Babapour et al ., 2016; Haghparast and Rashvand, 2022), hippocampus (Haghparast, Fatahi et al ., 2017; Haghparast, Shafiei et al ., 2018; Brojeni, Rashvand et al ., 2019; Rasouli, Rashvand et al ., 2020; Zargarani, Karimi-Haghighi et al ., 2021), basal ganglia, cerebral cortex, preoptic area, reticular formation (Cluderay, Harrison et al ., 2002; Razavi and Hosseinzadeh, 2017). Indeed, several studies have shown that the orexin system plays an essential role in reward-seeking behaviors (Haghparast, Fatahi et al ., 2017; Zarrabian, Riahi et al ., 2020), sensory modulation (Sakurai, 2014; Andreoli, Marketkar et al ., 2017; Park and Weon, 2017), stress processing (Grafe and Bhatnagar, 2018; Sargin, 2019), endocrine functions (Martyńska, Polkowska et al ., 2006), and pain modulation (Chiou, Lee et al ., 2010; Askari, Oryan et al ., 2021; Li, Chang et al ., 2021).…”