Pharmacological properties of nociceptin/orphanin FQ-induced stimulation and inhibition of cyclic AMP formation in distinct layers of rat olfactory bulb.

1. We recently reported that nociceptin/orphanin FQ (N/OFQ) inhibited forskolin-stimulated adenylyl cyclase activity and increased basal enzyme activity in membranes of the external plexiform layer (EPL) and granule cell layer (GRL), respectively, of the rat main olfactory bulb. In the present study we have characterized the pharmacological profile of the inhibitory and stimulatory responses by examining the effects of various N/OFQ receptor agonists and antagonists. 2. N/OFQ(1 - 13)NH(2) fully mimicked the inhibitory and stimulatory effects of N/OFQ with EC(50) values of 0.9 and 6.5 nM, respectively. N/OFQ(1 - 7) was inactive at concentrations up to 1 microM, whereas Ac-RYYRIK-NH(2) and [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1 - 13)-NH(2) behaved as partial agonists in eliciting both responses. 3. The nonpeptidyl N/OFQ receptor antagonist J-113397 competitively counteracted the inhibitory and stimulatory effects of N/OFQ with pA(2) values of 8.63 and 8.70, respectively. Similarly, the peptidyl antagonist [Nphe(1)]N/OFQ(1 - 13)NH(2) potently antagonized the two effects with pA(2) values of 8.03 and 8.45, respectively. None of the antagonists per se affected adenylyl cyclase activity. 4. These data show that in distinct layers of rat olfactory bulb both the inhibitory and stimulatory effects of N/OFQ on cyclic AMP formation display pharmacological properties consistent with the involvement of N/OFQ receptors.