The hypocretins are weak agonists at recombinant human orexin‐1 and orexin‐2 receptors

The pharmacology of the orexin‐like peptides, hypocretin‐1 and hypocretin‐2, was studied in Chinese hamster ovary (CHO) cells stably expressing orexin‐1 (OX 1 ) or orexin‐2 (OX 2 ) receptors by measuring intracellular calcium ([Ca 2+ ] i ) using Fluo‐3AM. Orexin‐A and orexin‐B increased [Ca 2+ ] i in CHO‐OX 1 (pEC 50 =7.99±0.05 and 7.00±0.10 respectively, n =8) and CHO‐OX 2 (pEC 50 =8.30±0.05 and 8.21±0.07 respectively, n =5). However, hypocretin‐1 and hypocretin‐2 were markedly less potent, with pEC 50 values of 5.31±0.04 and 5.41±0.04 respectively in CHO‐OX 2 cells ( n =5). In CHO‐OX 1 cells 10 μ M hypocretin‐1 only elicited a 37.5±3.4% response whilst 10 μ M hypocretin‐2 elicited a 18.0±2.1% response ( n =8). Desensitisation of OX 1 or OX 2 with orexin‐A (100 n M ) abolished the response to orexin‐A (10 n M ) and the hypocretins (10 μ M ), but not to UTP (3 μ M ). In conclusion, the hypocretins are only weak agonists at the orexin receptors. British Journal of Pharmacology (2000) 129 , 1289–1291; doi: 10.1038/sj.bjp.0703257