Adenosine A2A receptors regulate D2-type medium spiny neurons in the nucleus accumbens to mediate pain and depression comorbidity

Persistent pathological pain often induces comorbid depressive-like symptoms, yet the underlying neuronal and molecular mechanisms remain unclear. The nucleus accumbens shell (NAcS) has been implicated in mediating pain sensation and emotional disorders, including depression. However, how it regulates pain-depression comorbidity (PDC) is not well-known. In the present study, we demonstrated that D₂-type medium spiny neurons (D₂-MSNs) in the NAcS bidirectionally modulated pain and its comorbid behavioral despair measured in the forced swimming test (FST), an effect possibly involving adenosine A_2A receptors (A_2ARs). Specifically, acute chemogenetic activation of NAcS D₂-MSNs induced thermal/mechanical pain in naïve mice but did not affect despair-like behavior in the FST, a phenomenon that occurred after repeated activation of these neurons. Conversely, chemogenetic inhibition of NAcS D₂-MSNs alleviated spared nerve injury (SNI) induced neuropathic pain and its comorbid behavioral despair. Our immunofluorescent staining revealed a relatively enriched expression of A_2ARs in NAcS D₂-MSNs. <i>Ex vivo</i> electrophysiological recordings revealed that activating and inhibiting A_2ARs increased and decreased the neuronal excitability of NAcS D₂-MSNs. Consistently, local infusion of the agonist and antagonist of A_2ARs into the NAcS bidirectionally modulated pain and despair-like behaviors in both naïve and SNI mice. Together, these findings demonstrate the functional role of NAcS D₂-MSNs in mediating PDC, which was possibly modulated by local A_2ARs, thus providing a potential therapeutic target for PDC.