A role of nociceptin in the entrainment mechanism of the biological clock

The ORL1 receptor (nociceptin receptor), the fourth member of the opioid receptor family, is widely distributed throughout the central nervous system and mediates diverse physiological functions including pain, emotion, learning and memory. Nociceptin receptors are densely expressed in the suprachiasmatic nucleus, the principal pacemaker of circadian rhythms, and nociceptin inhibits light-induced phase advances (Allen et al, 1999); however, nociceptin's role in nonphotic entrainment has not been described. We used a small-molecule nociceptin receptor agonist capable of crossing the brain blood-brain barrier, and demonstrated that nociceptin acts as a nonphotic zeitgeiber. In this review, we describe a role for nociceptin in the biological clock and discuss the possibility of developing nociceptin receptor agonists for treatment of circadian rhythm disorders.