Objectives Feeding behavior is known to have potential to alleviate pain. We recently demonstrated that both 24 h fasting and 2 h refeeding (food intake after 24 h fasting) induce analgesia in inflammatory pain conditions via different brain mechanisms. However, brain structures that distinctly involved fasting-and refeeding-induced analgesia is still unknown. Hence, this study is aimed to reveal brain structures mediating fasting-and refeedinginduced analgesia.Methods Mice were given intraplantar (i.pl.) injection of formalin and complete Freund's adjuvant into the left hind paw to induce acute and chronic inflammatory pain, respectively. We examined changes in c-Fos expression with 24 h fasting and 2 h refeeding under acute and chronic inflammatory pain conditions in the contralateral brain. ResultsUnder acute pain condition, c-Fos expression changed with fasting in the anterior cingulate cortex (ACC), central amygdala (CeA), lateral hypothalamus (LH) and nucleus accumbens core (NAcC). Refeeding changed c-Fos expression in the CeA, LH and lateral parabrachial nucleus (lPBN). On the other hand, under chronic inflammatory pain condition, c-Fos expression changed with fasting in the lPBN, medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcS) while refeeding changed c-Fos expression in the anterior insular cortex, lPBN, mPFC and NAcS. ConclusionThe present results show that brain regions that participated in the fasting-and refeedinginduced analgesia were completely different in acute and chronic inflammatory pain conditions. Also, refeeding recruits more brain regions under chronic inflammatory pain conditions compared to the acute inflammatory pain condition. Collectively, our findings provide novel insights into brain regions involved in fasting-and refeedinginduced analgesia, which can be potential neural circuitbased targets for the development of novel therapeutics.
Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 hr refeeding after 24hr 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.
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