The medial orbitofrontal cortex mediates neuropathic pain and anxiodepressive-like behaviors via two distinct pathways

Abstract Background Chronic neuropathic pain is frequently accompanied by anxiety and depression, yet the cortical circuit mechanisms underlying this comorbidity remain unclear. The medial orbitofrontal cortex (mOFC) is a key cortical region involved in emotional regulation and valuation, and clinical imaging studies have reported altered mOFC activity in patients with chronic pain. However, it remains unclear how mOFC neuronal activity contributes to both the pain hypersensitivity and anxiodepressive-like behaviors associated with neuropathic pain. This study aimed to determine the pathway-specific roles of mOFC glutamatergic neurons in chronic pain and comorbid affective disturbances. Methods Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain sensitivity and anxiodepressive-like behaviors were assessed using von Frey, Hargreaves, open field, elevated plus maze, tail suspension, and forced swim tests. Electrophysiological recording and fiber photometry were used to monitor neuronal activity. Neuronal projection tracing identified projection patterns of mOFC glutamatergic neurons to mediodorsal thalamus (MD) and basolateral amygdala (BLA). Chemogenetic and optogenetic manipulations were applied to selectively modulate the mOFC CaMKIIα -MD and mOFC CaMKIIα -BLA pathways. Results The mOFC glutamatergic neurons are activated in neuropathic pain mice accompanied by anxiodepressive-like phenotypes. Chemogenetic and optogenetic inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. Retrograde labeling result revealed two non-overlapping mOFC CaMKIIα neurons projecting to the MD and BLA, respectively. Selective inhibition of mOFC CaMKIIα -MD pathway leads to amelioration of CCI-induced pain hypersensitivity. While selective inhibition of mOFC CaMKIIα -BLA pathway leads to amelioration of CCI-induced anxiodepressive-like behaviors. Conclusions The present study has revealed that the critical involvement of mOFC glutamatergic neurons in the comorbidity of chronic pain and affective disturbances. Inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. The discrete mOFC CaMKIIα -MD and mOFC CaMKIIα -BLA pathway independently control the sensory and affective components of neuropathic pain. Graphical Abstract