The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.

Nutraceuticals and peripheral glial cells: a possible link?

A nutraceutical is a food-derived molecule that provides medical or health benefits beyond its basic nutritional role, including the prevention and treatment of disease and its symptoms. In the peripheral nervous system, satellite glial cells are found in close relationship with neurons, mainly in peripheral sensory ganglia, but, compared with other glial cells, the relationship between these cells and nutraceuticals has received little attention. After describing satellite glial cells and their role and changes in physiology and pathology, we review the studies on the effects of nutraceuticals as modulators of their functions. Maybe due to the difficulties in selectively labeling these cells, only a few studies, performed mainly in rodent models, have analyzed nutraceutical effects, showing that N-acetylcysteine, curcumin, quercetin, osthole and resveratrol may palliate neuropathic pain through satellite glial cells-dependent pathways, namely antioxidant mechanisms and/or interference with purinergic signaling. Neither other conditions in which satellite glial cells are involved (visceral pain, nerve regeneration) nor other nutraceuticals or mechanisms of action have been studied. Although more preclinical and clinical research is needed, the available reports support the general notion that nutraceuticals may become interesting alternatives in the prevention and/or treatment of peripheral gliopathies and their associated conditions, including those affecting the satellite glial cells.

Nutraceuticals and Enteric Glial Cells.

Until recently, glia were considered to be a structural support for neurons, however further investigations showed that glial cells are equally as important as neurons. Among many different types of glia, enteric glial cells (EGCs) found in the gastrointestinal tract, have been significantly underestimated, but proved to play an essential role in neuroprotection, immune system modulation and many other functions. They are also said to be remarkably altered in different physiopathological conditions. A nutraceutical is defined as any food substance or part of a food that provides medical or health benefits, including prevention and treatment of the disease. Following the description of these interesting peripheral glial cells and highlighting their role in physiological and pathological changes, this article reviews all the studies on the effects of nutraceuticals as modulators of their functions. Currently there are only a few studies available concerning the effects of nutraceuticals on EGCs. Most of them evaluated molecules with antioxidant properties in systemic conditions, whereas only a few studies have been performed using models of gastrointestinal disorders. Despite the scarcity of studies on the topic, all agree that nutraceuticals have the potential to be an interesting alternative in the prevention and/or treatment of enteric gliopathies (of systemic or local etiology) and their associated gastrointestinal conditions.

Desensitization of transient receptor potential vanilloid type-1 (TRPV1) channel as promising therapy of irritable bowel syndrome: characterization of the action of palvanil in the mouse gastrointestinal tract.

TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS). Therefore, the aim of this study is to assess the action of fast desensitizing agonist of TRPV1, palvanil (N-palmitoyl-vanillamine), in the murine GI tract and on nociception to evaluate its potential application in the therapy of IBS. The effect of palvanil on smooth muscle contractility was evaluated using organ baths. The impact of palvanil on intestinal secretion was assessed in Ussing chambers. In vivo, the action of palvanil (0.1-1 mg/kg) was assessed in whole GI transit, fecal pellet output, and colonic bead expulsion tests. The antinociceptive potency of palvanil was tested in the mustard oil-induced pain test. Palvanil inhibited colonic contractions (evoked by electrical field stimulation, EFS) and decreased the ion transport in the colon stimulated with forskolin. It did not affect secretion in experiments with veratridine. In vivo, palvanil prolonged whole GI transit at all doses tested. At the lower dose tested, it accelerated colonic motility during first 60 min following injection. By contrast, at the dose of 1 mg/kg, colonic motility was inhibited. Palvanil induced antinociceptive action at all tested doses in mustard oil-induced pain test. TRPV1 fast-desensitizing compounds, i.e., palvanil, may be promising agents in the therapy of IBS since it modulates intestinal motility and reduces visceral pain.

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2.

Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2 (F-81). The ability of these peptides to cross the blood-brain barrier was tested in the parallel artificial membrane permeability (PAMPA) assay. On the basis of the hot-plate test in mice after central and peripheral administration, analog F-81 was selected for the anti-nociceptive and anti-inflammatory activity assessment after peripheral administration.

Neuropharmacological characterization of the oneirogenic Mexican plant Calea zacatechichi aqueous extract in mice.

This study evaluates the neuropharmacological effects of the aqueous extract of the Mexican plant Calea zacatechichi Schltdl., which is commonly used in folk medicine to treat cough, asthma, and gastrointestinal disorders. Moreover, it has been used for centuries in traditional rituals based on divination and is thought to possess hallucinogenic activity. To test the neuropharmacological effects of the aqueous extract of C. zacatechichi we used mouse models of convulsions, an elevated plus-maze test and measured locomotor activity. We also evaluated the effect of the extract on antidepressant-like behavior in forced swim test, as well as on muscular strength in a grip test. Moreover the antinociceptive action of the extract was evaluated in the hot-plate and writhing tests. The chemical composition of the extract was evaluated using LC-MS techniques. The aqueous extract of C. zacatechichi did not affect any of the parameters measured in seizure models. It had also no influence on anxiety, exploratory behavior and muscular strength in the applied doses. On the other hand, the extract exhibited antinociceptive effect in the mouse model of abdominal pain. Chemical characterization of the extract showed the presence of chlorogenic acid, acacetin, and germacranolides. Based on this report we suggest that aqueous extract of C. zacatechichi has insignificant neuropharmacological effects in vivo and reduces abdominal pain perception. Our results, together with previous studies showing beneficial effects of the extracts obtained from C. zacatechichi suggest that these preparations may be used to treat medical conditions.

Orally administered novel cyclic pentapeptide P-317 alleviates symptoms of diarrhoea-predominant irritable bowel syndrome.

OBJECTIVE: The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal (GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D). METHODS: The effect of P-317 on mouse intestinal motility was characterized in vitro and in vivo in physiological and pathophysiological conditions. The antinociceptive action of P-317 was characterized in the mustard oil-induced abdominal pain model and the writhing test. Locomotor activity and grip-strength tests were used to evaluate the effect of P-317 in the central nervous system (CNS). To translate our study to clinical conditions, the semi-quantitative expression of µ-opioid receptors (MOP) and κ-opioid receptors (KOP) messenger RNA (mRNA) in human colonic samples from IBS-D patients was quantified. KEY FINDINGS: In vitro, P-317 (10(-10) -10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, ß-funaltrexamine and nor-binaltorphimine-reversible manner. In vivo, P-317 (0.1 mg/kg, i.p. and 1 mg/kg, p.o.) inhibited GI transit, displayed a potent antinociceptive action in abdominal pain tests and did not influence the CNS. CONCLUSION: P-317 produced a potent analgesic and antidiarrhoeal action in the mouse GI tract after oral administration. Given lower expression of MOP and KOP mRNA in IBS-D patients, P-317 is a promising peptide-based drug candidate for IBS-D therapy.