Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W‐212393 in rats

We synthesized a small‐molecule opioid receptor‐like 1 (ORL1) receptor agonist, 2‐{3‐[1‐((1 R )‐acenaphthen‐1‐yl)piperidin‐4‐yl]‐2,3‐dihydro‐2‐oxo‐benzimidazol‐1‐yl}‐ N ‐methylacetamide (W‐212393), and investigated its effect on the circadian body temperature rhythm of rats. W‐212393 has high affinity for ORL1 receptors in the rat cerebral cortex and human ORL1 receptors expressed in HEK293 cells with K i values of 0.76 and 0.50 n M , respectively. W‐212393 concentration‐dependently stimulated GTP γ 35 S binding and its efficacy was similar to nociceptin/orphanin FQ (N/OFQ), suggesting that W‐212393 is a full agonist at ORL1 receptors. W‐212393 dose‐dependently occupied ORL1 receptors following intraventricular or intraperitoneal administration, suggesting that W‐212393 is a brain‐penetrating compound. W‐212393 (100 n M ) and N/OFQ (100 n M ) significantly suppressed the activity of spontaneously firing rat suprachiasmatic nucleus neurons. These suppressive effects were blocked by an ORL1 receptor antagonist, J‐113397 (1  μ M ). W‐212393 (3 mg kg −1 , i.p.) induced a significant phase advance at circadian time 6 (CT6) and CT9, but not at other CTs. The magnitude of the W‐212393 (0.3–3 mg kg −1 , i.p.)‐induced phase advance was dose‐dependent and greater than those produced by 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (0.3–3 mg kg −1 , i.p.) or melatonin (0.3–3 mg kg −1 , i.p.). The W‐212393 (3 mg kg −1 , i.p.)‐induced phase advance was antagonized by J‐113397 (10 mg kg −1 , i.p.). W‐212393 (3 mg kg −1 , i.p.) significantly accelerated the re‐entrainment of the body temperature rhythm to a 6 h advanced light–dark cycle. These results indicate that activation of ORL1 receptors contributes to the circadian entrainment and W‐212393 may represent an interesting agent for the study of circadian rhythms.British Journal of Pharmacology (2005) 146 , 33–40. doi: 10.1038/sj.bjp.0706311