NMDA RECEPTOR ACTIVITY REGULATED BY DOCK4 DRIVES VLO TO ACTIVATE VLPAG FOR ANTINOCICEPTION

The ventrolateral orbitofrontal cortex (VLO) emerges as a critical region for endogenous antinociception. However, whether and how glutamatergic system participates in the antinociceptive effects of VLO has remained unclear. In this study, we found that inhibition of N-methyl-D aspartate receptors (NMDARs) in the VLO directly causes allodynia due to reduced vlPAG innervation, and decreased NMDAR activity and weakened VLO-ventrolateral periaqueductal gray (vlPAG) circuit were commonly presented in neuropathic and inflammatory pain models. Notably, we revealed that DOCK4, an autism-regulated factor that previously known to regulate NMDAR, is expressed in excitatory neurons in the VLO to control NMDAR expression and activity for antinociception. Dock4 deletion in the VLO inhibited NMDAR activity, leading to impaired VLO-vlPAG circuit and allodynia which could be reversed by chemogenic activation of the circuit. Overexpression of the DOCK4 effector RAC1 in VLO excitatory neurons restored NMDA receptor activity and relieved pain in Dock4 KO and neuropathic pain mice. Importantly, both local and systemic administration of D-cycloserine, a partial agonist of NMDAR, produced analgesia effects in Dock4 KO mice as well as neuropathic and inflammatory pain models. In summary, our findings demonstrate that DOCK4 is a critical regulator of NMDARs in governing VLO-vlPAG circuit for antinociception, and targeted activation of NMDA receptors in the VLO offers a promising new strategy for analgesic development.