Fig. 7.

Model for mechanism of MOR-Gq coincidence detection in feedback inhibition of MOR-dependent antinociception in presynaptic PAG input neurons in the descending pain pathway. Pictured is a GABAergic synapse between a PAG input and output neuron. The boxed inset shows the anatomic location of the PAG in the rodent brain with inputs from the cortex and outputs to the spinal cord. MOR activation in the presynaptic neuron inhibits GABA release resulting in activation of output neurons that ultimately suppress afferent pain transmission in the spinal cord. PLCβ3 activation suppresses MOR actions in presynaptic neuron, and activation of PLCβ3 requires inputs from both Gi/βγ from MOR and Gq from an unknown Gq-coupled receptor. Since PLCβ3 activation requires simultaneous Gα_q and Gβγ binding, blockade of either Gα_q or Gβγ is sufficient to relieve the PLC-dependent inhibition of MOR signaling, leading to enhanced MOR potency and increased antinociception. Figure created with Biorender.com.