No abstract

As a neurohormone and as a neurotransmitter, oxytocin has been implicated in the stress response. Descending oxytocin‐containing fibres project to the dorsal horn of the spinal cord, an area important for processing nociceptive inputs. Here we tested the hypothesis that oxytocin plays a role in stress‐induced analgesia and modulates spinal sensory transmission. Mice lacking oxytocin exhibited significantly reduced stress‐induced antinociception following both cold‐swim (10 °C, 3 min) and restraint stress (30 min). In contrast, the mice exhibited normal behavioural responses to thermal and mechanical noxious stimuli and morphine‐induced antinociception. In wild‐type mice, intrathecal injection of the oxytocin antagonist dOVT (200 μm in 5 μl) significantly attenuated antinociception induced by cold‐swim. Immunocytochemical staining revealed that, in the mouse, oxytocin‐containing neurones in the paraventricular nucleus of the hypothalamus are activated by stress. Furthermore, oxytocin‐containing fibres were present in the dorsal horn of the spinal cord. To test whether descending oxytocin‐containing fibres could alter nociceptive transmission, we performed intracellular recordings of dorsal horn neurones in spinal slices from adult mice. Bath application of oxytocin (1 and 10 μm) inhibited excitatory postsynaptic potentials (EPSPs) evoked by dorsal root stimulation. This effect was reversed by the oxytocin antagonist dOVT (1 μm). Whole‐cell recordings of dorsal horn neurones in postnatal rat slices revealed that the effect of oxytocin could be blocked by the addition of GTP‐γ‐S to the recording pipette, suggesting activation of postsynaptic oxytocin receptors. We conclude that oxytocin is important for both cold‐swim and restraint stress‐induced antinociception, acting by inhibiting glutamatergic spinal sensory transmission.

The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-b (TGF-b) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-b-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-b signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-b signaling pathway. In nine human gastric cancer cell lines examined, TGF-bresponsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-b signaling in CEA expression, we selected two TGFb unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-b type II receptor and SNU484 cells that express low to undetectable level of the TGF-b pathway intermediate protein, Smad3. Restoration of TGF-b signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-b signaling.