N-methyl-D-aspartate receptors in the prelimbic cortex modulate chronic neuropathic pain and comorbid generalised anxiety in a rainbow boa snake threat paradigm.

The prelimbic division (PrL) of the medial prefrontal cortex is implicated in the pathogenesis of generalised anxiety and chronic pain disorders. This study aimed to investigate the role of PrL N-methyl-D-aspartate (NMDA) receptor signalling in the comorbidity between neuropathic pain and psychiatric disorders. Male Wistar rats were exposed to the Enriched Polygonal Arena Snake-Evoked Panic Test involving confrontation by a constrictor snake. Neuropathy was induced by chronic constriction injury (CCI) of the ischiadicus nerve. Rats subjected to a sham surgical procedure were used as controls. Electrophysiological recordings were performed to assess PrL neuronal activity in CCI and sham-operated rats. Exposure to the threatening environment was conducted 21 days after surgery for 5 min following PrL cortical treatment with vehicle or LY235959 (2, 4, and 8 nmol). Neuronal activity in the PrL cortex was reduced in CCI rats. When confronted with a potential predator, threatened CCI rats exhibited increased emotional defensive responses accompanied by a decrease in mechanical paw withdrawal threshold (MWT), whereas sham-operated animals (without neuropathy) showed an increase in MWT following snake confrontation. Furthermore, NMDA receptor blockade in the PrL cortex with LY235959 reduced both defensive behaviours and mechanical allodynia in threatened animals. These findings suggest that NMDA receptor signalling in the PrL cortex plays a key role in the potentiation and maintenance of the comorbidity between anxiety/panic-like states and chronic neuropathic pain.