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As a canonical anti\u2010inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro\u2010inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1\u2010SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1\u2010SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin\u2010releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1\u2010SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT\u2010PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In neonatal\u2010CRD\u2010induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL\u20106 levels elevated in PVN. However, infusion of Epac agonist 8\u2010pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV\u2010SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL\u20106 neutralizing antibody also alleviated the visceral hypersensitivity. In na\u00efve rats, Epac antagonist ESI\u201009 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL\u20106 into PVN simulated the visceral hypersensitivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Inactivation of Epac1\u2010SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13880","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T07:41:31Z","timestamp":1655278891000},"page":"1393-1408","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Unraveling the role of <scp>Epac1\u2010SOCS3<\/scp> signaling in the development of neonatal\u2010<scp>CRD<\/scp>\u2010induced visceral hypersensitivity in 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