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The endocannabinoid and orexinergic systems, consisting of class A GPCRs and their endogenous ligands, are highly complex and regulate processes such as appetite, sleep, nociception, and energy homeostasis. The shared anatomical distribution of cannabinoid and orexin receptors in various regions of the central nervous system (CNS), coupled with data from previous studies exploring physical and functional interactions between these receptors, suggests that the endocannabinoid and orexinergic systems engage in crosstalk. In this study, we explored how orexin receptors (OX<jats:sub>1<\/jats:sub>, OX<jats:sub>2<\/jats:sub>) altered the in\u00a0vitro signaling of cannabinoid receptors (CB<jats:sub>1<\/jats:sub>, CB<jats:sub>2<\/jats:sub>) in Chinese hamster ovary (CHO)\u2010K1 cells by quantifying cyclic adenosine monophosphate (cAMP) inhibition and \u03b2arrestin2 recruitment. Our results suggest that orexin receptors alter agonist\u2010dependent signaling at the cannabinoid receptors by enhancing cannabinoid receptor\u2010mediated cAMP inhibition while increasing or decreasing cannabinoid receptor\u2010mediated \u03b2arrestin2 recruitment. These initial results are important for understanding the effects associated with cannabinoid ligands and may provide novel insights for therapeutics targeting physiological processes modulated by both systems.<\/jats:p>","DOI":"10.1002\/prp2.70078","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:33:06Z","timestamp":1741750386000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Vitro Signaling Properties of Cannabinoid and Orexin Receptors: How Orexin Receptors Influence Cannabinoid Receptor\u2010Mediated Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Kawthar A.","family":"Mohamed","sequence":"first","affiliation":[{"name":"College of Pharmacy and Nutrition University of Saskatchewan  Saskatoon Saskatchewan 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