Coincident Regulation of PLCb Signaling by Gq-Coupled and l-Opioid Receptors Opposes Opioid-Mediated Antinociception

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 l-opioid receptor (MOR). Deletion of phospholipase Cb3 (PLCb3) or selective inhibition of Gbc regulation of PLCb3 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 PLCb3 or pharmacological inhibition of its upstream regulators, Gbc 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 Gbc-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.