Peripheral Mechanisms Involved in Gastric Mucosal Protection by Intracerebroventricular and Intraperitoneal Nociceptin in Rats

Abstract

Nociceptin (N/OFQ) exerts multiple effects in the gastrointestinal tract after central or peripheral administration. In the present study, we examined the possible peripheral mechanisms mediating gastric protection by N/OFQ in rats. Gastric mucosal lesions were induced by 50% ethanol (1 ml/rat intragastrically). N/OFQ, administered either intracerebroventricularly (3 g/rat) or ip (10 g/kg), significantly reduced macroscopic and histological damage. capeptide, isolated from brain extract, which shows a structural homology to the opioid peptide dynorphin A and binds to the orphan opioid receptor-like 1 receptor, now termed NOP receptor (1, 2). Since the early studies, it became evident that N/OFQ was involved in modulation of pain, anxiety, feeding, and memory processes (3-6). Central and peripheral administration of the peptide has also been reported to exert multiple effects in the gastrointestinal tract, affecting gastric and intestinal motility (7-9) and secretion (10, 11).We have recently shown that N/OFQ protects against gastric mucosal damage induced by intragastric (ig) ethanol exposure in the rat and that its effect that is reversed by the selective antagonist UFP-101, suggesting the peptide exerts gastric protection through the NOP receptor (12). The evidence that N/OFQ protects the gastric mucosa after both central and peripheral administration suggests that the peptide interacts with distinct central and peripheral pathways. Accordingly, the NOP receptor has been identified in the central and peripheral nervous systems and along the entire gastrointestinal tract of the rat (13,14). Nerve fibers immunoreactive to N/OFQ were found in the myenteric plexus and circular muscle layer of the rat colon (7).Resistance of the gastric mucosa against damage by endogenous and exogenous aggressors is ensured by a complex system of mediators. A crucial role has been attributed to the neuropeptide calcitonin gene-related peptide (CGRP), released by capsaicin-sensitive extrinsic nerve fibers and to nitric oxide (NO), synthesized by the neuronal and endothelial enzymes. The sensory neuropeptide and NO appear to act in concert in the modulation of mucosal integrity (15,16). There is also evidence for an interaction between autonomic nervous system and peripheral CGRP/NO pathways (17). Indeed, neuropeptides like TRH, peptide YY (PYY), and adrenomedullin, acting at the central level, reduce gastric lesions caused by ethanol in rats through vagal cholinergic pathways associated with peripheral release of CGRP and activation of .The present study was aimed to further characterize the protective activity of N/OFQ, injected centrally or peripherally, against ethanol damage in rats, by evaluating the possible peripheral neural mechanisms mediating the effect of the peptide. In particular, we have examined the role of NO and of afferent nerve fibers as well as of parasympathetic and sympathetic systems. Materials and Methods AnimalsMale Wistar rats, weighing 180 -200 g (Harlan, S. Pietro al Natisone, Italy) were individually hou...

In vivo effects of N/OFQ(1–13)NH2 and its structural analogue [ORN9]N/OFQ(1–13)NH2 on carrageenan-induced inflammation: rat-paw oedema and antioxidant status

“…), the inhibitory effects of N/OFQ are intensively investigated on virtually all systems of the organism: pulmonary [5][6][7], gastrointestinal [8,9], cardiovascular [10,11], immune system [12,13], etc.…”

“…N/OFQ has been found to reduce ethanol-induced gastric lesions [20]. The peptide shows protective activity and increases gastric mucosal resistance to ethanol by operating both in the central nervous system and in the periphery [8]. It has been found that N/OFQ, in concentrations present in cerebrospinal fluid after fluid percussion brain injury (FPI), increases O 2 -production in a cyclooxygenasedependent manner after FPI [21,22].…”

Gastroprotective Oligopeptides

“…Recent papers report that acupuncture can promote the repair of gastric mucosal injury and improve gastrointestinal function and the authors link these effects with reducing plasma beta-endorphin level and upregulating hypothalamic betaendorphin level [46]. It was also noted that endomorphin-2, injected intracerebroventricularly, restored the reduced levels of CGRP and somatostatin in gastric mucosa lesions [27].…”

“…The studies with the use of the method of autoradiography with Н-thymidine showed that the administration of sedatin in different doses stimulated DNA synthesis in epithelium of the gastric mucosa [5,30]. Endogenous opioids have been implicated in the process of gastric sensitivity and gastric motor responses, and impairment of antinociceptive opioid pathways, that is hypothesized to contribute to the pathogenesis of functional dyspepsia [46]. It was also reported that endogenous opioids are involved in the control of gastric accommodation and phasic contractility but not in the control of sensitivity to gastric distension or gastric emptying in healthy volunteers [46].…”

“…It was reported that dalargin (leu-enkephalin) significantly decreased the area of erosive and ulcerative lesions, had a normalizing effect on proliferation of epithelial cells and reduced the degree of oxidative stress [30]. It was also documented that centrally induced gastroprotective effect of neuropeptides may be mediated by a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway results in the stimulation of the release of mucosal prostaglandins and nitric oxide [28].Recent papers report that acupuncture can promote the repair of gastric mucosal injury and improve gastrointestinal function and the authors link these effects with reducing plasma beta-endorphin level and upregulating hypothalamic betaendorphin level [46]. It was also noted that endomorphin-2, injected intracerebroventricularly, restored the reduced levels of CGRP and somatostatin in gastric mucosa lesions [27].…”