Sexually dimorphic cannabinoid 1 receptors on CaMKIIα neurons in the medial prefrontal cortex mediate sex differences in ACEA-induced antinociception in mice

Patients suffer greatly from neuropathic pain, and pharmacological therapies usually prove insufficient. Although the causes are yet unknown, sex differences in reaction to analgesics help to explain poor outcomes. Cannabinoid-based treatments are more effective in female patients, although the reasons are not well understood. The ventrolateral periaqueductal gray (vlPAG) is a crucial node in the descending pain inhibitory system. Our previous research shows that the GABA-vGlut2 inhibitory circuitry in the vlPAG regulates vGlut2 neuron activity in a sex-specific manner to modulate cannabinoid analgesia. However, it remains unknown whether this circuitry is regulated by upstream neurons. This study identified CaMKIIα neurons in the upstream medial prefrontal cortex (mPFC) that control vlPAG GABA . Deleting cannabinoid receptor 1 (CB 1 R) in this pathway causes severe pain in female mice and diminishes vlPAG vGlut2 inhibition, leading to overall output. These results clarify CB 1 R’s function in the mPFC CaMKIIα -vlPAG GABA -vlPAG vGlut2 circuit, shedding light on sex-specific cannabinoid analgesia and providing a basis for developing more potent analgesics for both sexes.