Spatiotemporal control of opioid signaling and behavior.
Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here, we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically sensitive, mu-opioid-like receptor, which we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels and internalizes with kinetics similar to that of the mu-opioid receptor. To assess in vivo utility, we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways.
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA; Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Edward R
ER
Siuda
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Bryan A
BA
Copits
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA.
Martin J
MJ
Schmidt
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA.
Madison A
MA
Baird
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA.
Ream
R
Al-Hasani
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA.
William J
WJ
Planer
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA.
Samuel C
SC
Funderburk
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA; Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jordan G
JG
McCall
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA; Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Robert W
RW
Gereau
Department of Anesthesiology, Basic Research Division, Washington University in St. Louis, St. Louis, MO 63110, USA; Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: bruchasm@wustl.edu.
Michael R
MR
Bruchas
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002478:Cells, Cultured; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D062308:Optogenetics; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu