[Phe1ψ(CH2-NH)Gly2]nociceptin-(1-13)-NH2 activation of an inward rectifier as a partial agonist of ORL1 receptors in rat periaqueductal gray

1 [Phe(1)psi(CH2-NH)Gly(2)]nociceptin-(1-13)-NH2 (Phe psi), a tridecapeptide analogue of orphanin FQ/nociceptin (OFQ/N), was introduced as a competitive antagonist of opioid receptor-like orphan receptor (ORL1) in guinea-pig ileum and mouse vas deferens preparations in vitro but was recently found to act as an agonist in vivo. 2 In the periaqueductal gray, a site enriched with both OFQ/N and ORL1 and involved in OFQ/N-induced hyperalgesia and anti-analgesia, the effects of Phe psi and OFQ/N on the membrane current were studied using whole cell patch clamp recording technique in rat brain slices. 3 OFQ/N (0.01-1 mu M) activated an inwardly rectifying type of K+ channels in ventrolateral neurons of PAG. Phe psi (0.03 - 1 mu M), like OFQ/N, also activated this inward rectifier but had only 30% efficacy of OFQ/N. 4 At maximal effective concentration (1 mu M), Phe psi reversed the increment of K+ conductance induced by OFQ/N (300 nM) by 46%. On the other hand, Phe psi also prevented the effect of OFQ/N if pretreated before OFQ/N. 5 It is suggested that Phe psi acts as a partial agonist of ORL1 that mediates the activation of inwardly rectifying K+ channels in ventrolateral neurons of rat periaqueductal gray.