Expression and developmental regulation of oxytocin (OT) and oxytocin receptors (OTR) in the enteric nervous system (ENS) and intestinal epithelium

Abstract

Although oxytocin (OT) and oxytocin receptor (OTR) are known for roles in parturition and milk let-down, they are not hypothalamus-restricted. OT is important in nurturing and opposition to stress. Transcripts encoding OT and OTR have been reported in adult human gut, and OT affects intestinal motility. We tested the hypotheses that OT is endogenous to the enteric nervous system (ENS) and that OTR signaling may participate in enteric neurophysiology. Reverse transcriptase polymerase chain reaction confirmed OT and OTR transcripts in adult mouse and rat gut and in precursors of enteric neurons immunoselected from fetal rats. Enteric OT and OTR expression continued through adulthood but was developmentally regulated, peaking at postnatal day 7. Coincidence of the immunoreactivities of OTR and the neural marker Hu was 100% in the P3 and 71% in the adult myenteric plexus, when submucosal neurons were also OTR-immunoreactive. Co-localization with NeuN established that intrinsic primary afferent neurons are OTR-expressing. Because OTR transcripts and protein were detected in the nodose ganglia, OT signaling might also affect extrinsic primary afferent neurons. Although OT immunoreactivity was found only in ~1% of myenteric neurons, extensive OT-immunoreactive varicosities surrounded many others. Villus enterocytes were OTR-immunoreactive through postnatal day 17; however, by postnatal day 19, immunoreactivity waned to become restricted to crypts and concentrated at crypt-villus junctions. Immunoelectron microscopy revealed plasmalemmal OTR at enterocyte adherens junctions. We suggest that OT and OTR signaling might be important in ENS development and function and might play roles in visceral sensory perception and neural modulation of epithelial biology.

Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

“…The rationale for studying OT signaling in gut cells stems from our prior work showing that the OTR is highly expressed in enterocytes of newborn rats during their suckling period (Welch et al 2009). Those studies showed that after weaning, OTR expression declined in the fully developed villi and appeared at the crypt villus junction and at the newly developed crypts, as well as in cell adherens junctions.…”

“…In addition, OT may act differently at various stages of development. In the context of a transient high level OTR expression in enterocytes of postnatal rat pups (Welch et al 2009), OT may be instrumental in protection of enterocytes against the cellular ER stress involved in intense developmental differentiation of colonic surface and small intestine villus structure. Later in life, these biological mechanisms may be redirected to regulate inflammatory responses in the gut.…”

“…The role of OT and its receptor (OTR) in gut function is supported by three of our findings. First, we have demonstrated that OTR expression is developmentally regulated in rat enterocytes (Welch et al 2009). This finding is significant in light of high concentrations of OT in milk (Takeda et al 1986).…”

Calming Cycle Theory and the Co-Regulation of Oxytocin

“…The discovery of the OT receptor (OTR) in both the neurons of the enteric nervous system and intestinal epithelial cells (Welch et al, 2009) led to a systematic examination of gut OT and OTR signalling. OT was found to play an important role in gut development and function.…”

Anti-stress Effect of Hypothalamic Oxytocin, Importance of Somatosensory Stimulation and Social Buffering

“…Thus, central OXT plays a predominant role in regulating stress-induced GI dysmotility. Although OXT and its receptors are expressed on the smooth muscle cells, enteric neurons and intestinal epithelium of the GI tract [19] , peripheral OXT may not have a major role in attenuating stress responses. 1-3.…”