- BACKGROUND: Oxytocin plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of oxytocin analgesia, but little is known about whether peripheral mechanisms are also involved. METHODS: The mesenteric afferent discharge was recorded in vitro. The expressions of oxytocin receptor (OTR) and neuronal nitric oxide synthase (nNOS) in longitudinal muscle myenteric plexus (LMMP) was identified by immunofluorescence. KEY RESULTS: Oxytocin per se had no effect on the jejunal mesenteric afferent discharge, however, it markedly attenuated the bradykinin- or distention-evoked increase of mesenteric afferent discharge, which was mimiced by the nitric oxide (NO) donor sodium nitroprusside (SNP). Pretreatment of either NOS inhibitor L-NAME or NPLA largely reduced the inhibitory effect of oxytocin on bradykinin-evoked mesenteric afferent discharge. Such effect, to a large extent, was also alleviated by N-and P-type voltage-dependent calcium channel antagonists or KATP blocker glibenclamide. In addition, immunofluorescence studies show strong colocalization of OTR with nNOS in LMMP of the rat jejunum. CONCLUSIONS & INFERENCES: Oxytocin down-regulates the mesenteric afferent sensitivity through nNOS-NO-KATP pathway. Our findings may reveal a new peripheral mechanism for oxytocin analgesia.