Vol. 303, Issue 1, 188-195, October 2002

Nociceptin/Orphanin FQ Modulation of Ionic Conductances in Rat Basal Forebrain Neurons

J. H. Chin, K. Harris, D. MacTavish and J. H. Jhamandas

Department of Medicine (Neurology), Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada

Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like heptadecapeptide that plays an important role in a variety of physiological functions. N/OFQ and its receptor opioid receptor-like orphan receptor-1 are abundant in the diagonal band of Broca (DBB), a basal forebrain nucleus where the loss of cholinergic neurons is linked to memory and spatial learning deficits. In the whole animal, central injections of N/OFQ have been shown to disrupt spatial learning. In this study, we investigated the basis for these behavioral observations by examining the cellular effects of N/OFQ on chemically identified DBB neurons. Whole cell patch-clamp recordings were performed on enzymatically dissociated DBB neurons. Under voltage-clamp conditions, bath application of N/OFQ (10 pM-1 µM) resulted in a dose-dependent depression of whole cell currents. Single cell reverse transcription-polymerase chain reaction analysis identified cholinergic and fewer GABAergic cells to be N/OFQ-responsive. [Nphe¹]nociceptin-(1-13)-NH₂ and CompB (J-113397) antagonized the N/OFQ response, but both compounds also displayed partial agonist activity. Using a combination of channel blockers we determined that the effects of N/OFQ were mediated via a suite of Ca²⁺ (N- and L-type) and Ca²⁺-dependent K⁺ (iberiotoxin-sensitive) conductances. In addition, biophysical analysis of voltage subtraction protocols revealed that N/OFQ reduces transient outward and the delayed rectifier K⁺ currents. Because N-type and L-type Ca²⁺ channels are important in the context of neurotransmitter release, our observations indicate that N/OFQ inhibition of Ca²⁺-dependent conductances in cholinergic neurons would be expected to result in depression of acetylcholine release, which may explain the behavioral actions of N/OFQ in the brain.