Brain neuropeptides in gastric mucosal protection.

The centrally induced gastroprotective effect of neuropeptides has been intensively studied. Besides many similarities, however, differences can also be observed in their gastroprotective actions. The gastroprotective dose-response curve proved to be either sigmoid, or bell-shaped. Additional gastrointestinal effects of neuropeptides can contribute to their mucosal protective effect. Part of the neuropeptides induces gastroprotection by peripheral administration as well. Besides vagal nerve the sympathetic nervous system may also be involved in conveying the central effect to the periphery. Better understanding of the complex mechanism of the maintenance of gastric mucosal integrity may result in the development of new strategy to enhance gastric mucosal resistance against injury

Comparative in vivo analysis of recombinant type II feline coronaviruses with truncated and completed ORF3 region.

Our previous in vitro comparative study on a feline coronavirus (FCoV) pair, differing only in the intactness of their ORF3abc regions, showed that the truncated ORF3abc plays an important role in the efficient macrophage/monocyte tropism of type II feline infectious peritonitis virus (FIPV). In the present study, we describe a challenge experiment with the same recombinant FCoVs in order to gain data on the in vivo characteristics on these viruses. While parent virus FIPV DF-2 developed feline infectious peritonitis in all the infected cats, its recombinant virus PBFIPV-DF-2, differing only in seven nucleotides, proved to be surprisingly low virulent, although caused an acute febrile episode similarly to the original FIPV DF-2. PBFIPV-DF-2 infection induced significantly lower virus neutralization titers than its parent virus, and lacked the second phase of viremia and development of fatal course of the disease. The recombinant PBFIPV-DF-2-R3i with completed ORF3abc gained biological properties that differentiate between the feline enteric coronavirus (FECV) and FIPV biotypes such as intensive replication in the gut, absence of viremia and weak or no serological response. Using reverse genetic approaches our study is the first experimental proof that ORF3abc is indeed responsible for the restriction of FECV replication to the intestine in vivo

Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats.

Feline infectious peritonitis virus (FIPV) is a major pathogen of Felidae. Despite the extensive efforts taken in the past decades, development of the "ideal" live attenuated FIPV vaccine was not successful yet. In the present study, we provide data of immunisation experiments with a recombinant FCoV pair differing only in the truncation (PBFIPV-DF-2) or completion (PBFIPV-DF-2-R3i) of their ORF3abc regions. In our previous in vivo studies, these viruses proved to show the characters of low virulent or avirulent FCoV phenotypes, respectively. Therefore, we hypothesised the ability of these viruses, as possible vaccine candidates, in conferring protection in specific pathogen free (SPF) Domestic Shorthair as well as in conventional purebred British Shorthair cats. In SPF cats, after two oronasal and two intramuscular vaccinations with two weeks intervals, both vaccine candidates provided 100% protection against lethal homologous challenge with the highly virulent FIPV DF-2 strain. In contrast, the conventional purebred British Shorthair cats did not develop protection when they were immunised with the same vaccination regimes. In these groups 100% of the PBFIPV-DF-2-R3i immunised animals developed antibody-dependent enhancement (ADE). Prolonged survival was observed in 40% of the animals, while 60% showed fulminant disease course. Genetic and more probably immunological differences between the SPF and non-SPF purebred kittens can explain the different outcome of the vaccination experiment. Our data highlight the diverse immune responses between SPF and conventional cats and suggest a decisive role of previous infection by heterologous causative agents in the outcome of the vaccination against FIP

Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain

Neocortical and striatal TRPV1 (vanilloid or capsaicin) receptors (TRPV1Rs) are excitatory ligand-gated ion channels, and are implicated in psychiatric disorders. However, the purported presynaptic neuromodulator role of TRPV1Rs in glutamatergic, serotonergic or dopaminergic terminals of the rodent forebrain remains little understood. With the help of patch-clamp electrophysiology and neurochemical approaches, we mapped the age-dependence of presynaptic TRPV1R function, and furthermore, we aimed at exploring whether the presence of CB1 cannabinoid receptors (CB1Rs) influences the function of the TRPV1Rs, as both receptor types share endogenous ligands. We found that the major factor which affects presynaptic TRPV1R function is age: by post-natal day 13, the amplitude of capsaicin-induced release of dopamine and glutamate is halved in the rat striatum, and two weeks later, capsaicin already loses its effect. However, TRPV1R receptor function is not enhanced by chemical or genetic ablation of the CB1Rs in dopaminergic, glutamatergic and serotonergic terminals of the mouse brain. Altogether, our data indicate a possible neurodevelopmental role for presynaptic TRPV1Rs in the rodent brain, but we found no cross-talk between TRPV1Rs and CB1Rs in the same nerve terminal

Shedding light on the pharmacological interactions between µ-opioid analgesics and angiotensin receptor modulators:A new option for treating chronic pain

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia

Lack of Small Intestinal Dysbiosis Following Long-Term Selective Inhibition of Cyclooxygenase-2 by Rofecoxib in the Rat

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it

Evidence for the gastric cytoprotective effect of centrally injected agmatine

Agmatine (decarboxylated arginine) exerts cytoprotective action in several tissues, such as in the brain, heart or kidneys, but there is still controversy over the effects of agmatine on the gastric mucosa. The aim of the present study was to reveal the potential gastroprotective action of agmatine by using an acid-independent ulcer model to clarify which receptors and peripheral factors are involved in it. Gastric mucosal damage was induced by acidified ethanol. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. It was found that agmatine given intracerebroventricularly (i.c.v., 0.044-220nmol/rat) significantly inhibited the development of ethanol-induced mucosal damage, while in the case of intraperitoneal injection (0.001-50mg/kg i.p.) it had only a minor effect. The central gastroprotective action of agmatine was completely antagonized by mixed alpha2-adrenoceptor and imidazoline I1 receptor antagonists (idazoxan, efaroxan), but only partially by yohimbine (selective alpha2-adrenoceptor antagonist) and AGN 192403 (selective I1 receptor ligand, putative antagonist). It was also inhibited by the non-selective opioid-receptor antagonist naloxone and the selective δ-opioid receptor antagonist naltrindole, but not by β-funaltrexamine and nor-Binaltorphimine (selective μ- and κ-opioid receptor antagonists, respectively). Furthermore, the effect of agmatine was antagonized by bilateral cervical vagotomy and by pretreatment with indomethacin and NG-nitro-l-arginine. Agmatine also reversed the ethanol-induced reduction of gastric mucosal CGRP and somatostatin content, but did not have any significant effect on gastric motor activity. These results indicate that agmatine given centrally induces gastric cytoprotection, which is mediated by central imidazoline I1 receptors, alpha2-adrenoceptors and δ-opioid receptors. Activation of these receptors induces the release of different mucosal protective factors, such as NO, prostaglandins, CGRP and somatostatin by a vagal-dependent mechanism. Alterations of gastric motility are not likely to contribute to the observed protective effect

Substance P induces gastric mucosal protection at supraspinal level via increasing the level of endomorphin-2 in rats.

The aim of the present study was to analyze the potential role of substance P (SP) in gastric mucosal defense and to clarify the receptors and mechanisms that may be involved in it. Gastric ulceration was induced by oral administration of acidified ethanol in male Wistar rats. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. We found that central (intracerebroventricular) injection of SP (9.3-74pmol) dose-dependently inhibited the formation of ethanol-induced ulcers, while intravenously injected SP (0.37-7.4nmol/kg) had no effect. The mucosal protective effect of SP was inhibited by pretreatment with neurokinin 1-, neurokinin 2-, neurokinin 3- and mu-opioid receptor antagonists, while delta- and kappa-opioid receptor antagonists had no effect. Endomorphin-2 antiserum also antagonized the SP-induced mucosal protection. In the gastroprotective dose range SP failed to influence the gastric motor activity. Inhibition of muscarinic cholinergic receptors, or the synthesis of nitric oxide or prostaglandins significantly reduced the effect of SP. In addition, centrally injected SP reversed the ethanol-induced reduction of gastric mucosal CGRP content. It can be concluded, that SP may induce gastric mucosal protection initiated centrally. Its protective effect is likely to be mediated by endomorphin-2, and vagal nerve may convey the centrally initiated protection to the periphery, where both prostaglandins, nitric oxide and CGRP are involved in mediating this effect