Project Summary / Abstract
Opioid addiction and accidental overdose have emerged as significant health crises in the last decade
as the prevalence and availability of this highly addicting class of drugs have dramatically increased. Opioids
are agonists for the mu opioid receptor (MOR), which in addition to blocking pain signaling, also mediates the
development of unwanted side effects including tolerance and with continued usage, dependence. MOR
signaling is endogenously regulated downstream of the receptor to terminate or tune signaling and to thus
modulate the physiological effects of opioids. Current strategies to curtail opioid side effects include therapeutic
targeting / modulating activation of known MOR regulators such as b-arrestin and regulators of G protein
signaling (RGS). Still, there is no comprehensive list of MOR regulators. Using an unbiased genetic screen, we
recently uncovered a novel orphan G protein-coupled receptor (GPCR) signaling pathway in the brain that
demonstrates an anti-opioid phenotype in two independent animal models. Further, the orphan receptor is co-
localized with MOR in key areas of the brain involved in analgesia and reward. Yet, this novel pathway and how
it may regulate MOR is wholly undefined. The proposed project will test the hypothesis that the orphan GPCR
pathway is a negative regulator of MOR with therapeutic potential to mitigate the unwanted side effects of opioids.
To test this hypothesis, biosensor-based cellular assays will be employed to examine classical MOR signaling
and how it is altered by dynamic activation of the orphan GPCR pathway. Additionally, the signaling emanating
from the orphan GPCR will be determined to further uncover how the signaling pathways endogenously interact.
Finally, the ability of the orphan GPCR to decrease opioid side effects will be determined in mouse models of
opioid-related behaviors. Taken together, this work will delineate a novel anti-opioid signaling pathway that could
find clinical use to lessen negative opioid-related side effects.