Targeting PEN-GPR83 as a as a strategy to reduce opioid abuse liability - Project Summary/Abstract: Targeting PEN-GPR83 as a strategy to reduce opioid abuse liability. Opioid medications, such as morphine and oxycodone, are mainline treatments for pain, however, their use is limited by side effects such as tolerance, dependence, and addiction. Our data demonstrate that GPR83 antagonist Cpd 25, blocks morphine reward while enhancing morphine antinociception suggesting that GRP83-based targeting could be used to reduce the abuse liability of opioids while enhancing their analgesic effects. The first step in validating the potential of GPR83 as a target to reduce abuse liability is to unravel the neurobiological mechanisms by which GPR83 interacts with the antinociceptive pathways. The descending pain modulatory pathway is a critical site for the action of opioids due to the activation of mu-opioid receptors (MOR) on GABAergic inhibitory neurons in the periaqueductal gray (PAG). Our data demonstrate that GPR83, whose endogenous ligand is the neuropeptide PEN, is also expressed in this brain region however, the functional interactions between PEN-GPR83/MOR and sources of PEN in the PAG remain elusive. By using a combination of biochemistry, neuroanatomy, electrophysiology, and imaging, we propose to identify physical and/or functional interactions between PEN-GPR83 and MOR in the PAG. Our preliminary data led us to hypothesize that the neurobiological mechanisms that underlie morphine antinociception in the PAG are determined by an interaction between PEN-activated GPR83 and MOR. To test this hypothesis, we propose three specific aims: 1) to determine physical interactions between PEN-GPR83 and MOR in the PAG, 2) to define the functional interaction between PEN-GPR83 and MOR in the PAG, 3) to determine the impact of endogenous PEN release on MOR function in the PAG. At the completion of this project, we expect to determine if the GPR83 pathway is a valid target for strategies aiming to reduce opioid abuse liability.
