Anterior Insular-nucleus Accumbens Pathway Controls Refeeding-induced Analgesia under Chronic Inflammatory Pain Condition

Abstract

Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 h refeeding after 24 h fasting (i.e., refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund’s Adjuvant (CFA)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aICCaMKII–NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aICCaMKII–NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aICCaMKII–NAcSD2R neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.