PT - JOURNAL ARTICLE AU - Gissell A. Sanchez AU - Emily M. Jutkiewicz AU - Susan Ingram AU - Alan V. Smrcka TI - Coincident Regulation of PLC<em>β</em> Signaling by Gq-Coupled and <em>μ</em>-Opioid Receptors Opposes Opioid-Mediated Antinociception AID - 10.1124/molpharm.122.000541 DP - 2022 Dec 01 TA - Molecular Pharmacology PG - 269--279 VI - 102 IP - 6 4099 - http://molpharm.aspetjournals.org/content/102/6/269.short 4100 - http://molpharm.aspetjournals.org/content/102/6/269.full SO - Mol Pharmacol2022 Dec 01; 102 AB - Pain management is an important 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 human embryonic kidney 293 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 slices increased the potency of the selective MOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate salt in inhibiting presynaptic GABA release. Finally, inhibition of Gq- G protein-coupled receptor 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 phospholipase Cβ3 (PLCβ3) in mice potentiates μ-opioid receptor (MOR)-dependent antinociception. How PLCβ3 is regulated downstream of MOR had not been clearly defined. We show that PLC-dependent diacylglycerol 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.