Endogenous opioids regulate moment-to-moment neuronal communication and excitability.
Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear.
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Bryony L
BL
Winters
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Gabrielle C
GC
Gregoriou
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Sarah A
SA
Kissiwaa
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Oliver A
OA
Wells
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Danashi I
DI
Medagoda
Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
Sam M
SM
Hermes
Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Neil T
NT
Burford
Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Andrew
A
Alt
Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
Sue A
SA
Aicher
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Elena E
EE
Bagley
D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005239:Fear / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D018847:Opioid Peptides; D011957:Receptors, Opioid; D018698:Glutamic Acid; D011188:Potassium