CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model.

The medial prefrontal cortex (mPFC) serves executive control functions and forms direct connections with subcortical areas such as the amygdala. Our previous work showed abnormal inhibition of mPFC pyramidal cells and hyperactivity of amygdala output neurons in an arthritis pain model. To restore mPFC activity and hence control pain-related amygdala hyperactivity this study focused on CB1 and mGluR5 receptors, which are important modulators of cortical functions. Extracellular single-unit recordings of infralimbic mPFC pyramidal cells and of amygdala output neurons in the laterocapsular division of the central nucleus (CeLC) were made in anesthetised adult male rats. mPFC neurons were classified as 'excited' or 'inhibited' based on their response to brief innocuous and noxious test stimuli. After arthritis pain induction, background activity and evoked responses of excited neurons and background activity and inhibition of inhibited neurons decreased. Stereotaxic application of an mGluR5-positive allosteric modulator (N-cyclobutyl-6-((3-fluorophenyl)ethynyl) nicotinamide hydrochloride, VU0360172) into the mPFC increased background and evoked activity of excited, but not inhibited, mPFC neurons under normal conditions but not in arthritis. A selective CB1 receptor agonist (arachidonyl-2-chloroethylamide) alone had no effect but restored the facilitatory effects of VU0360172 in the pain model. Coactivation of CB1 and mGluR5 in the mPFC inhibited the pain-related activity increase of CeLC neurons but had no effect under normal conditions. The data suggest that excited mPFC neurons are inversely linked to amygdala output (CeLC) and that CB1 can increase mGluR5 function in this subset of mPFC neurons to engage cortical control of abnormally enhanced amygdala output in pain.