Acute alcohol intoxication: a clinical overview.

Abstract: Alcohol is a legal and yet detrimental psychoactive substance, capable of establishing addiction and impacting the physical, mental, social, and economic health of people. Alcohol intake causes a large variety of tissue damages severely impacting the nervous system, digestive and cardiovascular systems and causing oral cavity, oropharyngeal, hypopharyngeal, esophageal, colon-rectal, laryngeal, liver and intrahepatic bile duct, and breast cancers. Alcohol can also play a role in the pathogenesis of diabetes mellitus, cardiomyopathy and hemorrhagic strokes. When drunk during pregnancy it is proved to be responsible for serious damage to fetuses causing a wide range of pathological conditions from miscarriage to Fetal Alcoholic Spectrum Disorder (FASD). Acute ethanol intoxication happens when the amount of alcohol consumed is greater than the disposal capacity of the liver, causing an accumulation of its metabolites displayed by initial dysphoria and disinhibition. Nausea, vomiting, memory loss could happen. Although, it can lead to more serious conditions like impaired speaking, impaired coordination, unstable gait, nystagmus, stupor, or coma. Respiratory depression and death could also happen in such cases. Unfortunately, diagnosis of acute alcohol intoxication is difficult because most of the drinkers deny or minimize their assumption. It is dramatically important to assess when the last intake happened to avoid withdrawal syndrome. Alcohol acute intoxication can be considered a serious harm to health and a relevant issue for healthcare provid-ers working in emergency rooms. Differential diagnosis is crucial to avoid serious outcomes. There is no consensus about therapies for acute intoxication, but supportive and symptomatic treatments were proved effective. The repercussions of alcohol misuse over drinkers' social, familiar, economical and working life enhance the importance of a multidisciplinary approach in such cases.

Caesarean Section in Preventing Stillbirths in Pregnancy Complicated with COVID-19: a Narrative Review.

INTRODUCTION: COVID-19 is a complex syndrome caused by SARS-Cov-2. It mainly affects the respiratory system, but it could cause serious harm during pregnancy. An increase in stillbirths and preterm births has been highlighted by many authors. Although WHO and Royal College of Obstetrics and Gynecology don't recommend elective cesarean section in women with confirmed infection, cesarean sections were performed by many clinicians. This short narrative review aims to analyze pieces of evidence found in literature about the effectiveness of cesarean section in preventing stillbirths in COVID-19 positive mothers. METHODS: Studies included in the present review were retrieved searching MEDLINE (last access August 5th, 2021) with the following keywords: "pregnant woman with covid-19", "Caesarean section", "Ab-dominal Delivery" and "Stillbirth". Studies regarding the mode of delive-ry in pregnant women infected with COVID-19 and neonatal outcomes were included. Studies about biology, anesthesiology and necroscopy were excluded. Filters for "human" and "English" were applied. RESULTS: Searching MEDLINE, 24 references were found. Other 103 articles were found searching bibliography. Two references were excluded after duplicate removal, 77 references after the title screen and 27 after the abstract screen. The final number of references included was 23. Most of the included studies were case reports. Most of them were from China. DISCUSSION: Many authors highlighted the increased risk of fetal death in pregnancies complicated with SARS-Cov-2 infection, but it is not clear if Caesarean Section could reduce this risk. Pieces of evidence show that most clinicians choose to perform an elective cesarean section mostly because of maternal conditions or the fear of possible vertical transmission. Data show that mode of delivery doesn't affect the neonatal outcome and Caesarean Section doesn't reduce the positivity rate among neonates. Different opinions were found about the possible infection of amniotic fluid, cord blood and placenta. The risk of vertical transmission is considered moderate or low by most of the authors. Positivity to SARS-Cov-2 isn't an indication of elective cesarean section by itself, but this mode of delivery should be optioned in patients with other obstetrical indications or with severe conditions due to COVID. The recent increase in stillbirths could be related to the overall deterioration of maternal conditions.

Challenges for Midwives' Healthcare Practice in the Next Decade: COVID-19 - Global Climate Changes - Aging and Pregnancy - Gestational Alcohol Abuse.

Midwives are multifaceted healthcare professionals whose competence spectrum includes a large variety of knowledge and skills going from antenatal care to education and research. The aim of this review is to suggest the future challenges midwives are going to face in the upcoming decade of this Century. COVID-19 and other infections will reasonably impact healthcare workers all over the world. Midwives are frontline healthcare professionals who are constantly at risk of contagion as their job implies close contact with women, physical support and hand touch. Also, menstruation waste plays a large role in the pollution of waters, severely impacting hygiene in the developing countries and fueling climate change. Appropriate disposal of used menstrual material is still insufficient in many countries of the world especially because of lack of sanitary education on girls. As educators, midwives will be more involved into preventing inappropriate disposal of menstrual hygiene devices by educating girls around the world about the green alternatives to the commercial ones. Despite the evidences about the fertility decrement that occurs with aging, women keep postponing reproduction and increasing their chance being childless or suffering complications related to the advanced maternal age. Teen pregnancies are as well an important issue for midwives who will be called to face more age-related issues and use a tailored case to case approach, enhancing their family planning skills. Another crucial role of midwifery regards the information about the risk of drinking alcohol during gestation. Alcohol assumption during pregnancy is responsible for serious damage to the fetus causing a wide range of pathological conditions related to Fetal Alcoholic Spectrum Disorder, leading cause of mental retardation in children of western countries. On the whole, midwives have demonstrated their willingness to expand their practice through continuing professional development, and through specialist and advanced roles especially in preventive and educational positions.

Staying tuned for post-COVID-19 syndrome: looking for new research to sniff out.

Post-COVID-19 syndrome was defined as a persistent and protracted illness, which follows acute COVID-19 infection. This condition continues for more than 12 weeks and cannot be attributed to other clinical situations. Researchers and clinicians are allied in unraveling the molecular pathogenetic mechanisms and the clinical development of this unexpected SARS-CoV-2 infectious evolution. Anosmia, dysgeusia, fatigue, dyspnea, and 'brain fog' are common symptoms observed in the Post-COVID-19 syndrome, depicting a multiorgan involvement associated with injuries involving mainly cardiovascular, pulmonary, musculoskeletal, and neuropsychiatric systems. This commentary analyzes the state of the art of Post-COVID-19 interdisciplinary studies, confirming that we are facing a truly intricate biomedicine story.

Physiological Responses to Induced Stress in Individuals Affected by Alcohol Use Disorder with Dual Diagnosis and Alexithymia.

Alcohol use disorders (AUD) are among the most common and undertreated mental disorders in developed countries. The co-occurrence of psychiatric comorbidity and AUD has already been well documented. Moreover, alexithymia was found associated with heavy drinking and alcohol dependence. A large part of AUD individuals, between 45 and 67%, have been identified as alexithymics. Both psychiatric comorbidity and alexithymia can negatively impact the course of recovery from alcohol. Alcohol consumption has also been shown to significantly influence autonomic responses. Chronic use of alcohol may induce significant changes in heart rate variability, respiratory frequency, electrodermal activity and skin temperature. To date, only a few studies have comprehensively investigated the comorbidity of alexithymia in AUD individuals with dual diagnosis. Thus, the aim and also the novelty of the present investigation were to disclose in individuals with AUD the emotional and cognitive stress responses to selected physiological parameters measured by ProComp5 Infiniti™ encoder in AUD patients suffering alexithymia with or without concomitant dual diagnosis. Quite interestingly, in AUD subjects with concomitant dual diagnosis we found that the alexithymia elevated skin temperature, heart rate variability and decreased respiratory frequency. Alexithymia, if associated with the dual diagnosis condition in AUD individuals, can be considered as a further vulnerability factor to stressing factors, impacting psychosomatic processing and inducing alterations in physiological parameters. In this paper, we discuss the implications of these findings in the early treatment of alexithymic AUD individuals.

The gastric effects of UFP-112, a new nociceptin/orphanin receptor agonist, in physiological and pathological conditions.

Nociceptin/orphanin FQ (N/OFQ), the endogenous NOP receptor ligand, centrally modulates gastric motor and secretory functions and prevents ethanol-induced gastric lesions in rats. A recently synthesized N/OFQ analog, [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), acts as a highly potent and selective peptide agonist for NOP receptors and produces longer-lasting in vitro and in vivo effects in mice than the natural ligand N/OFQ. In this study, we evaluated the effects of centrally (intracerebroventricularly/icv) and peripherally (intraperitoneally/ip) injected UFP-112 on gastric emptying and gastric acid secretion, and on the development of gastric mucosal lesions induced by 50% ethanol in the rat. When injected icv, it dose-dependently delayed gastric emptying of a phenol red meal (by up to 70%), decreased gastric secretion in water-loaded rats after 90 pylorus ligature, and reduced ethanol-induced gastric lesions (by up to 87%). In all three assays, UFP-112 was more effective than N/OFQ. The highly selective NOP receptor antagonist, UFP-101, decreased the efficacy of UFP-112, thus confirming that central NOP receptors mediate inhibitory control on these functional and pathological conditions in rats. Ip injected N/OFQ and UFP-112 induced non-dose-related gastric hypersecretory and antiulcer effects, which UFP-101 partially abolished. Ip N/OFQ appeared equiactive but about 30-100 times less potent than ip UFP-112 in stimulating gastric acid secretion and preventing lesion formation. When ip injected, both UFP-112 and N/OFQ left gastric emptying in rats unchanged, suggesting that peripheral NOP receptors have a role in mediating gastric hypersecretory and antiulcer effects but are not involved in regulating gastric motility. In addition, the inhibitory effects induced by this novel NOP receptor agonist lasted longer than those induced by N/OFQ. In conclusion, UFP-112 is a promising new pharmacological tool for studying the functional roles of the central and peripheral N/OFQ receptor system.

Appropriate intervention strategies for weight gain induced by olanzapine: a randomized controlled study.

Weight gain induced by antipsychotics is the second most frequently given reason for noncompliance with pharmacologic therapy; excessive sedative effects rank first, with extrapyramidal side effects ranking third. Frequently, weight gain leads to inconsistent pharmacologic treatment; this exposes patients to the risk of recurrent symptoms. In fact, one of the key contributors to good clinical outcomes in schizophrenic patients is compliance with pharmacologic treatment. The goals of this study were to evaluate weight gain in a group of patients treated with olanzapine, diet modifications, and moderate physical activity and to compare the findings with those from a second group of patients who were given only olanzapine treatment. For 8 wk, investigators followed 2 groups of patients suffering from schizophrenia and hypomania in bipolar disorder, according to the nosographic criteria of The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The first group (A) of 18 patients (9 female, 9 male) affected by manic episodes in bipolar disorder received olanzapine (10-20 mg/d), jogged lightly for 30 min 3 times a week, and complied with a diet that consisted of 500 kcal/d less than usual. The second group (B) of 10 patients (4 female, 6 male) with schizophrenia received only olanzapine (10-20 mg/d). All patients from both groups were weighed at the beginning of the observation period and weekly thereafter for 2 mo. After 2 mo of observation, group A showed a mean weight gain of 1.47 kg, whereas group B exhibited a mean weight gain of 3.5 kg; the difference between the 2 groups was almost 2 kg (P<.005). Group A showed a statistically significant reduction in weight gain compared with group B, clearly demonstrating the effectiveness of moderate physical activity and diet therapy in reducing weight gain in atypical antipsychotic treatment. Therefore, patient weight and body mass index must be monitored during the first weeks of antipsychotic treatment, with the goals of avoiding significant weight gain and treatment interruption.

Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization.

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease. However, the development of an NGF-based therapy is limited by its potent pain activity. We have developed a "painless" derivative form of human NGF (NGF61/100), characterized by identical neurotrophic properties but a reduced nociceptive sensitization activity in vivo. Here we characterized the response of rat dorsal root ganglia neurons (DRG) to the NGF derivative NGF61/100, in comparison to that of control NGF (NGF61), analyzing the expression of noxious pro-nociceptive mediators. NGF61/100 displays a neurotrophic activity on DRG neurons comparable to that of control NGF61, despite a reduced activation of PLCγ, Akt and Erk1/2. NGF61/100 does not differ from NGF61 in its ability to up-regulate Substance P (SP) and Calcitonin Gene Related Peptide (CGRP) expression. However, upon Bradykinin (BK) stimulation, NGF61/100-treated DRG neurons release a much lower amount of SP and CGRP, compared to control NGF61 pre-treated neurons. This effect of painless NGF is explained by the reduced up-regulation of BK receptor 2 (B2R), respect to control NGF61. As a consequence, BK treatment reduced phosphorylation of the transient receptor channel subfamily V member 1 (TRPV1) in NGF61/100-treated cultures and induced a significantly lower intracellular Ca2+ mobilization, responsible for the lower release of noxious mediators. Transcriptomic analysis of DRG neurons treated with NGF61/100 or control NGF allowed identifying a small number of nociceptive-related genes that constitute an "NGF pain fingerprint", whose differential regulation by NGF61/100 provides a strong mechanistic basis for its selective reduced pain sensitizing actions.

The effects of [Arg14, Lys15] nociceptin/orphanin FQ, a highly potent agonist of the NOP receptor, on in vitro and in vivo gastrointestinal functions.

Nociceptin/orphanin FQ (N/OFQ) administered into the lateral left cerebral ventricle of rats has been reported to inhibit in vivo gut motor and secretory functions. Recently, a novel N/OFQ analog, [Arg14, Lys15] N/OFQ, was synthesized and demonstrated to behave as a highly potent agonist at the human recombinant N/OFQ peptide (NOP) receptors and to produce long-lasting effects in vivo in mice compared with the natural ligand N/OFQ. In the present study, the pharmacological profile of [Arg14, Lys15] N/OFQ was further evaluated and compared with that of N/OFQ in vitro on guinea pig exocrine pancreas and in vivo on gastric emptying, colonic propulsion and gastric acid secretion in rats. [Arg14, Lys15] N/OFQ and N/OFQ significantly decreased the KCl-evoked amylase secretion from isolated pancreatic lobules of the guinea pig. In in vivo experiments, [Arg14, Lys15] N/OFQ mimicked the effects of N/OFQ, inducing, after intracerebroventricular injection, a delay (up to 70%) in the gastric emptying of a phenol red meal, an increase (about 40 times) of the mean bead colonic expulsion time and a decrease (up to 90%) of gastric acid secretion in water loaded rats after 90 min pylorus ligature. In all these assays, [Arg14, Lys15] N/OFQ was more effective than N/OFQ, and its effective doses were at least 10-fold lower than N/OFQ effective doses. The highly selective NOP receptor antagonist, UFP-101, decreased the efficacy of [Arg14, Lys15] N/OFQ in in vitro and in vivo assays above reported. These findings: (a) show that pancreatic NOP receptors mediate an in vitro inhibitory effect on stimulated guinea pig amylase secretion; (b) confirm that the stimulation of central NOP receptors exerts an inhibitory control on gastric emptying, colonic motility and gastric secretion in rats and (c) put in evidence that [Arg14, Lys15] N/OFQ, being more potent and effective than the natural ligand N/OFQ, represents a new pharmacological tool for the study of the physiological and pharmacological roles mediated by the N/OFQ-NOP receptor system.

Nociceptin/orphanin FQ-induced delay in gastric emptying: role of central corticotropin-releasing factor and glucocorticoid receptors.

When injected intracerebroventricularly (i.c.v.) in rats, nociceptin/orphanin FQ (N/OFQ) delays gastric emptying and increases plasma corticosterone levels. Our aim in this study was to investigate changes in gastric emptying of a phenol red meal, and the plasma corticosterone response to N/OFQ in adrenalectomized (ADX) rats, in ADX rats injected with corticosterone at 1, 24 and 72 h before the gastric emptying assay, and in intact rats i.c.v. pretreated with a glucocorticoid antagonist (RU486) and with a corticotropin-releasing factor receptor antagonist (alpha-helical CRF9-41). In adrenal intact rats, i.c.v. injection of N/OFQ (2.5 nmol rat-1) significantly delayed gastric emptying (by 70%) and increased plasma corticosterone concentrations. Conversely, in ADX rats, N/OFQ left gastric emptying unchanged. In ADX rats, corticosterone injected at 1, 24 and 72 h before the gastric emptying assay almost restored the N/OFQ-induced delay in gastric emptying. Finally, pretreatment with RU486- and alpha-helical CRF9-41 abolished the N/OFQ-induced inhibition of gastric emptying. These findings suggest that central N/OFQ inhibits gastric emptying through an integrated orphaninergic system-CRF interaction in which corticosterone plays a permissive role.

Use of sibutramine, an inhibitor of the reuptake of serotonin and noradrenaline, in the treatment of binge eating disorder: a placebo-controlled study.

Binge-eating disorder, which is characterized by repeated episodes of uncontrolled eating, is common in obese patients and is often accompanied by comorbid psychiatric disorders, especially depression. In previous studies, selective serotonin reuptake inhibitors have demonstrated efficacy in reducing the frequency of binge eating and addressing comorbid psychiatric disorders, but they have not shown the ability to promote weight loss. Sibutramine, a new serotonin and norepinephrine reuptake inhibitor, has been shown in short- and long-term studies to be effective in promoting and maintaining weight loss in obese patients who have binge-eating disorder. In this randomized, double-blind, placebo-controlled study, the efficacy, safety, and tolerability of sibutramine were evaluated in the treatment of binge-eating disorder in obese patients. Twenty patients were randomly assigned in equal numbers to receive either sibutramine 10 mg/day or placebo for 12 weeks. Assessments were made at baseline and every 2 weeks throughout the study. Binge frequency, defined as the number of days during the previous week that included binge-eating episodes, was the primary outcome measure. By the end of the study, the binge frequency among patients given sibutramine was significantly lower than that among those given placebo. The main adverse events in the sibutramine group were dry mouth and constipation. The findings suggest sibutramine is an effective medication in the treatment of binge-eating disorders and is well tolerated. In addition, it addresses the 3 main goals in the treatment of binge-eating disorder: reducing the frequency of binge eating, promoting and maintaining weight loss, and treating the comorbid psychiatric conditions.

Treatment of bulimia nervosa with sertraline: a randomized controlled trial.

Bulimia nervosa (BN) is one of the most frequently encountered eating disorders in industrialized societies. It has been suggested that reduced serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Thus, pharmacologic treatment of BN is mainly based on the use of selective serotonin reuptake inhibitors, which have proved effective. At present, the biological basis of this disorder is not completely clear. The aim of this randomized, controlled trial was to verify the efficacy of sertraline, a selective serotonin reuptake inhibitor, in a group of patients with a diagnosis of BN. Twenty female outpatients, with an age range of 24 to 36 years and a diagnosis of purging type BN as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV), were assigned randomly to two treatment groups. The first group received sertraline 100 mg/day for 12 weeks; the second group received placebo. The study was conducted for 12 weeks, with weekly clinical assessments. At the end of the observation period, the group treated with sertraline had a statistically significant reduction in the number of binge eating crises and purging compared with the group who received placebo. In no case was treatment interrupted because of side effects. This study confirms that sertraline is well tolerated and effective in reducing binge-eating crises and purging in patients with BN.

The endogenous nociceptin/orphanin FQ-NOP receptor system as a potential therapeutic target for intestinal disorders.

In 1995, by reverse pharmacology approach, used here for the first time in the history of pharmacology, nociceptin/orphanin FQ (N/OFQ) has been discovered as the endogenous ligand of a preidentified receptor named opioid receptor like 1. Subsequent studies showed that N/OFQ and its receptor (N/OFQergic system) are widely distributed in central and peripheral nervous systems as well as in peripheral organs of human and animals, and represent a system that is involved in a very large range of biological functions such as pain perception, intestinal motility and secretion, immune modulation, stress. From the time of its discovery to now, a high number of NOP agonists and antagonists have been synthesized and tested in various pathologies. Nevertheless, none of the molecules targeting N/OFQergic system have currently succeeded in going through clinical trials concerning gut pathologies, indicating that further studies are required. The work from Dr. Fichna et al., published in the present issue of Neurogastroenterology and Motility, adds another brick in the wall of understanding the role of N/OFQergic system in IBS-D pathology by the pharmacological evaluation of a new NOP receptor agonist, SCH 221510, in animal models of intestinal alterations (diarrhea and visceral hyperalgesia). Interestingly, authors report clinical data confirming the involvement of N/OFQergic system in IBS-D patients and, consequently, suggest this system as a valuable therapeutic target for IBS-D pathology. This minireview aims to give a brief summary of experimental and clinical studies focusing on the N/OFQergic system as pharmacological target for the therapeutic treatment of intestinal pathologies such as IBS and IBD.

Relaxant effect of proton pump inhibitors on in vitro myometrium from pregnant women.

AIM: In this study we investigate in in vitro myometrial tissue samples of pregnant women: (a) the effects of proton pomp inhibitors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole) on spontaneous contractions; (b) the muscle-relaxant efficacy of the most active PPI considered (pantoprazole) in comparison with that of other known tocolytics (nifedipine, atosiban, MgSO4, isoxsuprine); (c) the effect of pantoprazole on contractions induced by calcium (Ca(++)), KCl, oxytocin and prostaglandin (PGE2); (d) the possible mediators of pantoprazole relaxant effect. METHODS: Organ bath studies were performed on myometrial tissue samples (40×10×10 mm) from pregnant women (38-42 weeks of gestational age) undergoing elective caesarian section. RESULTS: All the PPIs studied reduce the spontaneous contraction of the myometrial smooth muscle. Pantoprazole is the most effective and most potent inhibitor among those analyzed. Pantoprazole also reduces the contractions induced by Ca(++), KCl, oxytocin and PGE2. Neither NO, nor PGs, or the activation of Ca(++)-dependent K(+) currents mediate the muscle-relaxant effect of this PPI. CONCLUSION: These data, together with the fact that PPIs almost do not present side effects, suggest that these drugs can offer new therapeutic strategies for preterm delivery. Undoubtedly, further investigations and clinical studies are necessary before adding PPIs to the list of drugs available for the treatment of preterm delivery.

TLQP-21, a VGF-derived peptide, stimulates exocrine pancreatic secretion in the rat.

The aims of this paper were to study: (1) the effects of TLQP-21 (non-acronic name), the C-terminal region of the VGF (non-acronic name), polypeptide (from residue 557 to 576 of VGF), on in vitro amylase release from rat isolated pancreatic lobules and acinar cells; (2) the mechanism through which TLQP-21 regulates exocrine pancreatic secretion, by using the muscarinic receptor antagonist atropine (10(-6)M) and the cyclo-oxygenase inhibitor, indomethacin (10(-6)M). On pancreatic lobules of rats, concentrations of TLQP-21 from 10(-7) to 10(-5)M significantly (p<0.05) induced a 2-3-fold increase of baseline pancreatic amylase release, measured at the end of 60 min incubation period. Co-incubation with atropine 10(-6)M did not antagonise the enzyme outflow induced by the peptide. On the contrary, co-incubation of TLQP-21 (10(-7) and 10(-6)M) with indomethacin, at concentration of 10(-6)M, which alone did not modify enzyme secretion, completely suppressed the increase of amylase evoked by TLQP-21 on pancreatic lobules. On rat pancreatic acinar cells, TLQP-21, at all the concentrations tested, was unable to affect exocrine pancreatic secretion, indicating an indirect mechanism of action on acinar cells. These results put in evidence, for the first time, that TLQP-21, a VGF-derived peptide, modulates exocrine pancreatic secretion in rats through a stimulatory mechanism involving prostaglandin release. In conclusion, TLQP-21 could be included among the neurohumoral signals regulating pancreatic exocrine secretion, and increases the knowledge concerning the systems controlling this function.

Cannabinoid agonist WIN55,212 in vitro inhibits interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) release by rat pancreatic acini and in vivo induces dual effects on the course of acute pancreatitis.

BACKGROUND: Cannabinoids (CBs) evoke their effects by activating the cannabinoid receptor subtypes CB1-r and CB2-r and exert anti-inflammatory effects altering chemokine and cytokine expression. Various cytokines and chemokines are produced and released by rodent pancreatic acini in acute pancreatitis. Although CB1-r and CB2-r expressed in rat exocrine pancreatic acinar cells do not modulate digestive enzyme release, whether they modulate inflammatory mediators remains unclear. We investigated the CB-r system role on exocrine pancreas in unstimulated conditions and during acute pancreatitis. METHODS: We evaluated in vitro and in vivo changes induced by WIN55,212 on the inflammatory variables amylasemia, pancreatic edema and morphology, and on acinar release and content of the cytokine interleukin-6 (IL-6) and chemokine monocyte chemo-attractant protein-1 (MCP-1) in untreated rats and rats with caerulein (CK)-induced pancreatitis. KEY RESULTS: In the in vitro experiments, WIN55,212 (10(-6) mol L(-1)) inhibited IL-6 and MCP-1 release from acinar cells of unstimulated rats and after CK-induced pancreatitis. In vivo, when rats were pretreated with WIN55,212 (2 mg kg(-1), intraperitoneally) before experimentally-induced pancreatitis, serum amylase, pancreatic edema and IL-6 and MCP-1 acinar content diminished and pancreatic morphology improved. Conversely, when rats with experimentally-induced pancreatitis were post-treated with WIN55,212, pancreatitis worsened. CONCLUSIONS & INFERENCES: These findings provide new evidence showing that the pancreatic CB1-r/CB2-r system modulates pro-inflammatory factor levels in rat exocrine pancreatic acinar cells. The dual, time-dependent WIN55,212-induced changes in the development and course of acute pancreatitis support the idea that the role of the endogenous CB receptor system differs according to the local inflammatory status.

Involvement of cannabinoid CB1- and CB2-receptors in the modulation of exocrine pancreatic secretion.

The role of the cannabinoid system in the regulation of exocrine pancreatic secretion was investigated by studying the effects of the synthetic CB1- and CB2-receptors agonist, WIN55,212, on amylase secretion in isolated lobules and acini of guinea pig and rat, and the expression of CB-receptors in rat pancreatic tissue by immuno-chemistry and Western-blot analysis in both basal and cerulein (CK)-induced pancreatitis condition. In pancreatic lobules of guinea pig and rat, WIN55,212 significantly inhibited amylase release stimulated by KCl depolarization through inhibition of presynaptic acetylcholine release, but did not modify basal, carbachol- or CK-stimulated amylase secretion. The effect of WIN55,212 was significantly reduced by pre-treatment with selective CB1- and CB2-receptor antagonists. The antagonists, when given alone, did not affect the KCl-evoked response. Conversely, WIN55,212 was unable to affect basal and CK- or carbachol-stimulated amylase release from pancreatic acini of guinea pig and rat. Immunofluorescent staining of rat pancreatic tissues showed that CB1- and CB2-receptors are expressed in lobules and in acinar cells and their presence in acinar cells was also shown by Western-blot analysis. After CK-induced pancreatitis, the expression of CB1-receptors in acinar cells was not changed, whilst a down-regulation of CB2-receptors was observed. In conclusion, the present study shows that WIN55,212 inhibits amylase release from guinea pig and rat pancreatic lobules and, for the first time, that cannabinoid receptors are expressed in lobules of the rat pancreas, suggesting an inhibitory presynaptic role of this receptor system. Finally, in rat pancreatic acinar cells, CB1- and CB2-receptors, expressed both in basal conditions and after CK-induced pancreatitis but inactive on amylase secretion, have an unknown role both in physiological and pathological conditions.

In vitro and in vivo pharmacological role of TLQP-21, a VGF-derived peptide, in the regulation of rat gastric motor functions.

BACKGROUND AND PURPOSE: Vgf gene expression has been detected in various endocrine and neuronal cells in the gastrointestinal tract. In this study we investigated the pharmacological activity of different VGF-derived peptides. Among these, TLQP-21, corresponding to the 556-576 fragment of the protein was the unique active peptide, and its pharmacological profile was further studied. EXPERIMENTAL APPROACH: The effects of TLQP-21 were examined in vitro by smooth muscle contraction in isolated preparations from the rat gastrointestinal tract and, in vivo, by assessing gastric emptying in rats. Rat stomach tissues were also processed for immunohistochemical and biochemical characterization. KEY RESULTS: In rat longitudinal forestomach strips, TLQP-21 (100 nmol x L(-1)-10 micromol x L(-1)) concentration-dependently induced muscle contraction (in female rats, EC(50) = 0.47 micromol.L(-1), E(max): 85.7 +/- 7.9 and in male rats, 0.87 micromol x L(-1), E(max): 33.4 +/- 5.3; n = 8), by release of prostaglandin (PG)E(2) and PGF(2a) from the mucosal layer. This effect was significantly antagonized by indomethacin and selective inhibitors of either cyclooxygenase-1 (S560) or cyclooxygenase-2 (NS398). Immunostaining and biochemical studies confirmed the presence of VGF in the gastric neuronal cells. TLQP-21, injected i.c.v. (2-32 nmol per rat), significantly decreased gastric emptying by about 40%. This effect was significantly (P < 0.05) blocked by i.c.v. injection of indomethacin, suggesting that, also in vivo, this peptide acts in the brain stimulating PG release. CONCLUSIONS AND IMPLICATIONS: The present results demonstrate that this VGF-derived peptide plays a central and local role in the regulation of rat gastric motor functions.

Central and peripheral role of the nociceptin/orphaninFQ system on normal and disturbed colonic motor function and faecal pellet output in the rat.

In this study, seeking further information on the role of the nociceptin/orphanin FQ (N/OFQ)-ergic system in normal and disturbed colonic motor function in rats, we compared the colonic effects of UFP-112, a novel highly potent agonist, with those of N/OFQ. When injected intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.), UFP-112 and N/OFQ increased bead expulsion time in a statistically significant and dose-related manner and reduced the percentage of rats with castor oil-induced diarrhoea. UFP-112 showed greater efficacy, higher potency and longer-lasting inhibitory effects than N/OFQ, and pretreatment with UFP-101, a selective antagonist, blocked the N/OFQ analogue-induced responses in both tests. When injected i.c.v., UFP-112 and N/OFQ inhibited corticotrophin releasing factor- and restrain stress-stimulated faecal pellet excretion significantly and in a dose-related manner. Conversely, when injected peripherally both peptides significantly inhibited colonic propulsive motility but did so in a non-dose-related manner. In conclusion, these findings indicate that, in the rat, the central and peripheral N/OFQ systems have an inhibitory role in modulating distal colonic propulsive motility under physiological and pathological conditions. UFP-112 therefore promises to be a useful pharmacological tool for investigating the role of the N/OFQ system in motor functions in the distal colonic tract under physiological and pathological conditions.