The orexinergic-endocannabinoid interface: mechanistic and therapeutic perspectives in Alzheimer's disease, anxiety, and visceral pain.

Bodke S.; Shelke P.; Bhatt L. · Neuropeptides · 2026

**Background & Methods** This is a narrative review article synthesizing evidence on the mechanistic interactions between the orexinergic and endocannabinoid systems. The authors examine preclinical and translational research exploring these system interactions across three disease states: Alzheimer's disease (AD), anxiety disorders, and visceral pain, with emphasis on receptor-level mechanisms and therapeutic potential. **Key Findings** - The orexinergic and endocannabinoid systems interact through multiple mechanisms including CB1-OX1 heteromer formation and orexin-driven synthesis of 2-arachidonoylglycerol (2-AG), a key endocannabinoid ligand. OX1 receptor antagonism potentiates CB2 signaling in microglial AD models, though clinical therapeutic value remains uncertain. - In anxiety models, orexin-A impairs fear extinction through a 2-AG-dependent mechanism involving microglial CB2 receptors in the basolateral amygdala, suggesting orexin-endocannabinoid crosstalk regulates emotional processing and extinction learning. - In visceral pain models, both CB1 and CB2 receptor antagonists block the visceral hyposensitivity induced by central orexin administration, indicating endocannabinoid signaling is necessary for orexin-mediated pain modulation. **Dosage & Administration** Not reported. This review does not evaluate specific drug doses or administration routes, as it synthesizes mechanistic evidence rather than clinical trial data. **Safety & Adverse Effects** Not reported. The review does not present safety data or adverse effect profiles from human trials. No approved pharmacological agents targeting both systems simultaneously are currently available for clinical use. **Evidence Quality** This review is limited to preclinical evidence, primarily from rodent models and heterologous cell systems. The translational relevance to human pathophysiology remains unclear. Major limitations include: (1) lack of human clinical trials evaluating orexin-endocannabinoid interactions; (2) heterogeneous study designs across disease models limiting direct comparison; (3) uncertainty regarding therapeutic value of proposed interventions in AD; and (4) absence of FDA-approved dual-target medications. The evidence represents early-stage basic science findings requiring substantial further development before clinical application. As a narrative review, systematic bias assessment was not performed.

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