TY - JOUR T1 - Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.122.000541 SP - MOLPHARM-AR-2022-000541 AU - Gissell Sanchez AU - Emily M. Jutkiewicz AU - Susan L. Ingram AU - Alan V. Smrcka Y1 - 2022/01/01 UR - http://molpharm.aspetjournals.org/content/early/2022/09/18/molpharm.122.000541.abstract N2 - Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. Significance Statement Previous work demonstrated that deletion of PLCβ3 in mice potentiates MOR-dependent antinociception. How PLCβ3 is regulated downstream of MOR had not been clearly defined. We show that PLC dependent DAG generation is cooperatively regulated by MOR-Gβγ and Gq-coupled receptor signaling through PLCβ3, and that blockade of either Gq-signaling or Gβγ signaling enhances the potency of opioids in ex vivo brain slices and in vivo. These results reveal potential novel strategies for improving opioid analgesic potency and safety. ER -