Nociceptin/orphanin FQ modulation of ionic conductances in rat basal forebrain neurons.
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 microM) 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. [Nphe(1)]nociceptin-(1-13)-NH(2) 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 Ca(2+) (N- and L-type) and Ca(2+)-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 Ca(2+) channels are important in the context of neurotransmitter release, our observations indicate that N/OFQ inhibition of Ca(2+)-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.
Chin
J H
JH
Department of Medicine (Neurology), Centre for Neuroscience, University of Alberta, Edmonton, Canada.
Harris
K
K
MacTavish
D
D
Jhamandas
J H
JH
D000109:Acetylcholine / Q000502:physiology; D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers; D004553:Electric Conductivity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000502:physiology; D016548:Prosencephalon / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000109:Acetylcholine; D000199:Actins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017931:DNA Primers; D009553:Nimodipine; D018847:Opioid Peptides; D011188:Potassium; D011957:Receptors, Opioid; D005680:gamma-Aminobutyric Acid; D020866:omega-Conotoxin GVIA; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722285:Oprl1 protein, rat