Docosahexaenoic Acid Attenuates Visceral Pain by Suppressing Spinal CXCL10/CXCR3/ERK Signaling

Background: Visceral pain is the primary symptom of functional gastrointestinal disorders, yet its spinal molecular mechanisms remain poorly defined. Methods: Using a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced chronic inflammatory visceral pain model, the role of the spinal CXCL10/CXCR3/ERK signaling axis and the analgesic effect of docosahexaenoic acid (DHA) were investigated. Results: TNBS significantly upregulated CXCL10 and CXCR3 in spinal dorsal horn neurons and increased ERK phosphorylation. Intrathecal CXCL10-neutralizing antibody or CXCR3 antagonist NBI-74330 reduced visceral hypersensitivity and suppressed spinal ERK activation in TNBS mice. Exogenous CXCL10 induced CXCR3-dependent hyperalgesia and ERK phosphorylation in the spinal cord. Intrathecal DHA attenuated TNBS-induced visceral pain, downregulated spinal CXCL10/CXCR3 expression, and inhibited ERK signaling. In Neuro-2a cells, DHA also blocked LPS-induced activation of the same pathway. Conclusions: This study suggests that the analgesic effect of DHA may involve the inhibition of the spinal CXCL10/CXCR3/ERK signaling pathway.