Spatiotemporal control of opioid signaling and behavior

Neuron. 2015 May 20;86(4):923-935. doi: 10.1016/j.neuron.2015.03.066. Epub 2015 Apr 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Cells, Cultured
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Optogenetics*
  • Rats
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction / drug effects*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology


  • Analgesics, Opioid
  • Receptors, Opioid, mu