Research ReportsOrexin-2 receptor antagonism in the cornu ammonis 1 region of hippocampus prevented the antinociceptive responses induced by chemical stimulation of the lateral hypothalamus in the animal model of persistent painPourreza, Pooyaa; Haghparast, Amirb; Sadeghi, Mehdic; Nazari-Serenjeh, Farzanehd; Askari, Kobrae; Haghparast, Abbasb Author Information aDepartment of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad university bNeuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran cDepartment of Physiology, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr dDepartment of Biology, Payame Noor University (PNU) eDepartment of Animal Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran Received 4 February 2021 Accepted as revised 16 June 2021 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website Correspondence to Abbas Haghparast, PhD, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O.Box 19615-1178, Tehran, Iran, Tel/fax: +98 21 2243 1624; e-mail: [email protected]; [email protected] Behavioural Pharmacology 32(6):p 515-523, September 2021. | DOI: 10.1097/FBP.0000000000000646 Buy SDC Metrics Abstract Orexins are excitatory neuropeptides, mainly produced by neurons located in the lateral hypothalamus, which project to many brain areas. The orexinergic system plays a fundamental role in arousal, sleep/wakefulness, feeding, energy homeostasis, motivation, reward, stress and pain modulation. As a prominent part of the limbic system, the hippocampus has been involved in formalin-induced nociception modulation. Moreover, hippocampus regions express both orexin-1 (OX1) and orexin-2 (OX2) receptors. The present study investigated the role of OX2 receptors (OX2R) within the cornu ammonis 1 (CA1) region of the hippocampus in the mediation of lateral hypothalamus-induced antinociception. Fifty-three male Wistar rats were unilaterally implanted with two separate cannulae into the lateral hypothalamus and CA1. Animals were pretreated with intra-CA1 TCS OX2 29 as an OX2R antagonist before intra-lateral hypothalamus administration of carbachol (250 nM) as a muscarinic agonist for chemical stimulation of orexinergic neurons. Formalin test was used as an animal model of persistent pain, following intra-lateral hypothalamus carbachol microinjection. Results showed that the chemical stimulation of the lateral hypothalamus significantly attenuated formalin-evoked nociceptive behaviors during both phases of the formalin test, and administration of TCS OX2 29 into the CA1 blocked these antinociceptive responses in both phases, especially in the late phase. These findings suggest that OX2 receptors in the CA1 partially mediate the lateral hypothalamus-induced antinociceptive responses in persistent inflammatory pain. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.