Evidence for a modulatory role of orexin A on the nitrergic neurotransmission in the mouse gastric fundus

The presence of orexins and their receptors in the gastrointestinal tract supports a local action of these peptides. Aim of the present study was to investigate the effects of orexin A (OXA) on the relaxant responses of the mouse gastric fundus. Mechanical responses of gastric strips were recorded via force-displacement transducers. The presence of orexin receptors (OX-1R) was also evaluated by immunocytochemistry. In carbachol precontracted strips and in the presence of guanethidine, electrical field stimulation (EFS) elicited a fast inhibitory response that may be followed, at the highest stimulation frequencies employed, by a sustained relaxation. All relaxant responses were abolished by TTX. The fast response was abolished by the nitric oxide (NO) synthesis inhibitor l-NNA (2 × 10− 4 M) as well as by the guanylate cyclase inhibitor ODQ (1×10−6 M). OXA (3 × 10− 7 M) greatly increased the amplitude of the EFS-induced fast relaxation without affecting the sustained one. OXA also potentiated the amplitude of the relaxant responses elicited by the ganglionic stimulating agent DMPP (1 × 10− 5 M), but had no effects on the direct smooth muscle relaxant responses elicited by papaverine (1 × 10− 5 M) or VIP (1 × 10− 7 M). In the presence of l-NNA, the response to DMPP was reduced in amplitude and no longer influenced by OXA. The OX1 receptor antagonist SB-334867 (1 × 10− 5 M) reduced the amplitude of the EFS-induced fast relaxation without influencing neither the sustained responses nor those to papaverine and VIP. Immunocytochemistry showed the presence of neurons that co-express neuronal nitric oxide synthase and OX-1R. These results indicate that, in mouse gastric fundus, OXA exerts a modulatory action at the postganglionic level on the nitrergic neurotransmission.