Effects of an orexin receptor 2-selective agonist on salivary secretion in rats

Abstract Narcolepsy type 1 (NT1) is caused by a significant loss of orexin-producing neurons. In clinical trials, multiple orexin receptor 2 (OX2R)-selective agonists (e.g., danavorexton, TAK-994, and oveporexton) improved wakefulness and decreased cataplexy in individuals with NT1. However, OX2R-selective agonists were also reported to induce hypersalivation as an adverse event in a small number of healthy volunteers and in individuals with NT1. Importantly, no objective data supporting these observations are available, and multiple factors can indirectly affect saliva secretion. In this study, we assessed the effect of an OX2R-selective agonist, OX-202, on salivary secretion in anesthetized or freely moving rats using a muscarinic acetylcholine receptor agonist, pilocarpine, as a positive control. Subcutaneous administration of pilocarpine at 1 mg/kg significantly increased the amount of saliva in the oral cavity in both anesthetized and freely moving rats. In contrast, intraperitoneal administration of OX-202 at 100 mg/kg under anesthetized conditions did not increase salivary secretion in rats. Moreover, oral administration of OX-202 (30 and 100 mg/kg) at zeitgeber time 6 (sleep phase) or zeitgeber time 15 (active phase) did not increase salivary secretion in the oral cavity in freely moving rats. In conclusion, OX2R-selective agonists may not directly induce salivary secretion in rats.