Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5‐hydroxytryptamine and noradrenaline release in the rat neocortex

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Abstract
The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5‐hydroxytryptamine (5‐HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl. N/OFQ concentration‐dependently inhibited K+‐evoked [3H]‐5‐HT and [3H]‐NE overflow with similar potency (pEC50 ∼7.9 and ∼7.7, respectively) and efficacy (maximal inhibition ∼40%). N/OFQ (0.1 μM) inhibition of [3H]‐5‐HT and [3H]‐NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe1]N/OFQ(1‐13)NH2 and UFP‐101; 10 and 1 μM, respectively) and non‐peptide (J‐113397 and JTC‐801; both 0.1 μM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre‐application time was necessary for J‐113397 and JTC‐801 to prevent N/OFQ inhibition of [3H]‐NE overflow. The NOP receptor ligand [Phe1ψ(CH2‐NH)Gly2]N/OFQ(1‐13)NH2 ([F/G]N/OFQ(1‐13)NH2; 3 μM) did not affect K+‐evoked [3H]‐NE but inhibited K+‐evoked [3H]‐5‐HT overflow in a UFP‐101 sensitive manner. [F/G]N/OFQ(1‐13)NH2 antagonized N/OFQ actions on both neurotransmitters. The time‐dependency of JTC‐801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin‐stimulated cAMP accumulation and JTC‐801, tested at different concentrations (0.1–10 μM) and pre‐incubation times (0, 40 and 90 min), antagonized this effect in a time‐dependent manner. The Schild‐type analysis excluded a competitive type of antagonism. We conclude that presynaptic NO receptors inhibiting 5‐HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1‐13)NH2 and time‐dependent sensitivity towards non‐peptide antagonists. British Journal of Pharmacology (2003) 138, 91–98. doi:10.1038/sj.bjp.0705005