The medial shell of nucleus accumbens regulates chronic pain and comorbid depression via separate downstream targets in male mice

Chronic pain frequently co-occurs with depression, forming a vicious cycle that mutually exacerbates both. Although the medial shell of nucleus accumbens (NAcMed) is known to modulate both pain and affective states, the distinct roles of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1- and D2-MSNs) within the NAcMed, as well as their respective circuits, in chronic pain and comorbid depression remain poorly defined. We observed decreased activity in both MSN subtypes during chronic pain and comorbid depression. Notably, activation of D1-MSNs alleviated depressive-like behaviors, whereas activation of D2-MSNs produced analgesic effects. Furthermore, we identified two parallel neural circuits: the NAcMed D1-MSNs →mediodorsal thalamus pathway, which preferentially modulates depressive-like behaviors, and the NAcMed D2-MSNs →lateral hypothalamus pathway, which selectively relieves pain. These findings delineate a circuit-specific dichotomy in which NAcMed D1-MSNs and NAcMed D2-MSNs govern distinct affective and sensory dimensions of chronic pain-depression comorbidity, providing circuit-specific targets for potential treatment.