Inflammatory pain in peripheral tissue depends on the activation of the TNF-α type 1 receptor in the primary afferent neuron.

The mechanism underlying the role of tumor necrosis factor alpha (TNF-α) in the development of inflammatory hyperalgesia has been extensively studied, mainly the role of TNF-α in the release of pro-inflammatory cytokines. The current concept relies in the fact that TNF-α stimulates the cascade release of other pro-inflammatory cytokines, such as IL-1ß, IL-6, and IL-8 (CINC-1 in rats), triggering the release of the final inflammatory mediator prostaglandin E2 (PGE2 ) and sympathetic amines that directly sensitize the nociceptors. However, this may not be the sole mechanism involved as the blockade of TNF-α synthesis by thalidomide prevents hyperalgesia without interrupting the synthesis of IL-1ß, IL-6, and CINC-1. Therefore, we hypothesized that activation of TNF-α receptor type 1 (TNFR1) by TNF-α increases nociceptors' susceptibility to the action of PGE2 and dopamine. We have found out that intrathecal administration of oligodeoxynucleotide-antisense (ODN-AS) against TNFR1 or thalidomide prevented carrageenan-induced hyperalgesia. The co-administration of TNF-α with a subthreshold dose of PGE2 or dopamine that does not induce hyperalgesia by itself in the hind paw of Wistar rats pretreated with dexamethasone (to prevent the endogenous release of cytokines) induced a robust hyperalgesia that was prevented by intrathecal treatment with ODN-AS against TNFR1. We consider that the activation of neuronal TNFR1 by TNF-α decisively increases the susceptibility of the peripheral afferent neuron to the action of final inflammatory mediators - PGE2 and dopamine - that ultimately induce hyperalgesia. This mechanism may also underlie the analgesic action of thalidomide.

Recent Trends in Pharmacological Activity of Alkaloids in Animal Colitis: Potential Use for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and disrupted inflammation of the gastrointestinal tract. IBD have two main conditions, Crohn's disease and ulcerative colitis, and have been extensively investigated in recent years. Antibiotics derived from salicylates, steroids, immunosuppressors, and anti-TNF therapy are part of the therapeutic arsenal for IBD. However, very often patients stop responding to treatments over the time. In this context, searching for alternative agents is crucial for IBD clinical management. Natural products derived from medicinal plants are an interesting therapeutic alternative, since several studies have proven effective treatments in animal models of intestinal inflammation. Several naturally occurring compounds are potent antioxidants, both as free radical scavengers and as modulators of antioxidant enzymes expression and activity. A number of natural compounds have also been proved to inhibit the release of proinflammatory cytokines, decreasing the activation of nuclear factor κB (NF-κB), which is important to the inflammatory response in IBD. The alkaloids are substances of a very diverse class of plant secondary metabolites; an extensive list of biological activities has been attributed to alkaloids, such as being anticholinergic, antitumor, diuretic, antiviral, antihypertensive, antiulcer, analgesic, and anti-inflammatory. In the present work, studies on the pharmacological activity of alkaloids in experimental models of IBD were reviewed.

Antihyperalgesic effect of CB1 receptor activation involves the modulation of P2X3 receptor in the primary afferent neuron.

Cannabinoid system is a potential target for pain control. Cannabinoid receptor 1 (CB1) activation play a role in the analgesic effect of cannabinoids once it is expressed in primary afferent neurons. This study investigates whether the anti-hyperalgesic effect of CB1 receptor activation involves P2X3 receptor in primary afferent neurons. Mechanical hyperalgesia was evaluated by electronic von Frey test. Cannabinoid effect was evaluated using anandamide or ACEA, a non-selective or a selective CB1 receptor agonists, respectively; AM251, a CB1 receptor antagonist, and antisense ODN for CB1 receptor. Calcium imaging assay was performed to evaluated α,ß-meATP-responsive cultured DRG neurons pretreated with ACEA. Anandamide or ACEA administered in peripheral tissue reduced the carrageenan-induced mechanical hyperalgesia. The reduction in the carrageenan-induced hyperalgesia induced by ACEA was completely reversed by administration of AM251 as well as by the intrathecal treatment with antisense ODN for CB1 receptor. Also, ACEA reduced the mechanical hyperalgesia induced by bradykinin and by α,ß-meATP, a P2X3 receptor non-selective agonist, but not by tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and chemokine-induced chemoattractant-1 (CINC-1). Finally, CB1 receptors are co-localized with P2X3 receptors in DRG small-diameter neurons and the treatment with ACEA reduced the number of α,ß-meATP-responsive cultured DRG neurons. Our data suggest that the analgesic effect of CB1 receptor activation is mediated by a negative modulation of the P2X3 receptor in the primary afferent neurons.

Royal Jelly and its dual role in TNBS colitis in mice.

Royal Jelly (RJ) is widely consumed in diets throughout the world due to its beneficial effects: antioxidant, antitumor and anti-inflammatory. We have investigated the role of RJ in the development of TNBS colitis in mice. Colitis was induced by a rectal instillation of TNBS at 0.1 mL per mouse. Intestine samples of the animals orally treated with RJ (100, 150, and 200 mg/kg) were collected for antioxidant assays (GSH and GSH-Px), proinflammatory protein quantification (COX-2 and NF-κB), and histological analyses. RJ 100 mg/kg maintained GSH levels and increased the activity of GSH-Px, downregulated key inflammatory mediators (COX-2 and NF-κB), and decreased the lesions caused by TNBS as shown by the histological analyses. In conclusion, RJ showed anti-inflammatory and antioxidant properties in experimental colitis, resulting in the amelioration of the macroscopic and histological analyses. These results corroborate with the RJ supplementation in diets.

Effects of Rhizophora mangle on Experimental Colitis Induced by TNBS in Rats.

Male Unib-WH rats were pretreated for two weeks with butanolic (BuOH) and ethyl acetate (EtOAc) fractions. Colitis was induced by rectal administration of TNBS, the treatment continued, and animals were sacrificed on day 7 after the TNBS administration. Phytochemical studies were performed in order to provide the characterization of the tannins present in the bark of R. mangle. Results showed that EtOAc fraction increased the levels of IL-10 (∗∗P < 0.01) and diminished the levels of TNF-α (∗∗∗P < 0.001) and IL-6 (∗∗P < 0.01). BuOH fraction reduced the MPO activity (∗∗P < 0.01) and levels of TBARS (∗∗∗P < 0.001); it also increased COX-1 expression, diminished the levels of TNF-α (∗∗∗P < 0.001), and increased the levels of IL-12 (∗∗∗P < 0.001). Besides, both treatments augmented the levels of GSH (∗P < 0.05), the activity of GSH-Px (∗∗P < 0.01 for BuOH fraction and ∗∗∗P < 0.001 for EtOAc fraction), and CAT (∗∗P < 0.01). In conclusion, both treatments ameliorated the injury induced by TNBS through different mechanisms, probably by their chemical composition which directed its activity into an antioxidant or anti-inflammatory response, leading to an immune modulation.

Gastroprotective effects of essential oil from Protium heptaphyllum on experimental gastric ulcer models in rats

Peptic ulcers are a common disorder of the entire gastrointestinal tract, its etiology has not been completely elucidated. The basic physiopathological of peptic ulcers result from an imbalance between some endogenous aggressive factor and cytoprotective factors. The treatment of this disease is usually done with antacids or proton pump, but are currently being used plants derivated compounds. We evaluated the gastroprotective properties and its possible mechanisms of action of the essential oil from Protium heptaphyllum (Aubl.) Marchand, Burseraceae (BB). The formation of ulcers, were evaluated in three experimental models, through the induction of gastric lesions by ethanol, nonsteroidal anti-inflammatory drugs and acetic acid. The mechanisms of action were evaluated through the pylorus ligature experiment, western blot, GSH, GR, SOD, GPx, MDA and MPO activities. BB significantly inhibited the formation of ulcers induced by the three different models, increased the GSH and GR levels and maintained the same levels of SOD and GPx of the sham group, inhibited MPO and MDA, did not produce significant modification in gastric juice content and showed increased COX-2 and EGF. BB exerts its gastroprotective activity, possibly, by increasing COX-2 and EGF expression and due to its possible antioxidant property.

Gastroprotective and ulcer healing effects of essential oil from Hyptis spicigera Lam. (Lamiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Hyptis Jacq. (Lamiaceae) is being used in traditional medicine to treat fever, inflammation and gastric disturbances. Hyptis spicigera Lam. is a native plant distributed across the central region of Brazil. The essential oil extracted from this plant is used in folk medicine as antipyretic. AIM OF THE STUDY: The effects of the essential oil obtained from the aerial parts of Hyptis spicigera (OEH) were evaluated for their gastroprotective and healing activities. MATERIALS AND METHODS: OEH chemical composition was analyzed by gas chromatography-mass spectrometry (GC-MS). The gastroprotective action of the OEH was evaluated in rodent experimental models (ethanol and NSAID). To elucidate mechanisms of action, the antisecretory action and involvements of NO, SH, mucus and PGE2 were evaluated. The acetic acid-induced gastric ulcer model and Western Blot assay (COX-2 and EGF) were also used to evaluate the OEH healing capacity. RESULTS: GC-MS analysis of OEH indicated three monoterpenes as major compounds: alpha-pinene (50.8%), cineole (20.3%) and beta-pinene (18.3%) and, at the dose of 100 mg/Kg, p.o., OEH provided effective gastroprotection against lesions induced by absolute ethanol (97%) and NSAID (84%) in rats. OEH do not interfere with H+ secretion in gastric mucosa and its gastric protection does not depend on nitric oxide (NO) and sulfhydryl compounds (SH). The gastroprotective action of OEH occurs due to an increase in the gastric mucus production (28%) induced by PGE2 levels. Furthermore, OEH demonstrated a great healing capacity with 87% of reduction in ulcerative lesion area. It accelerated the healing of acetic acid-induced gastric lesions due to an increase in COX-2 (75%) and EGF (115%) expression in gastric mucosa. No sign of toxicity was observed in this study, considering the analyzed parameters. CONCLUSIONS: All these results suggest the efficacy and safety of Hyptis spicigera in combating and healing gastric ulcer. Considering the results, it is suggested that the OEH could probably be a good therapeutic agent for the development of new phytotherapeutic medicine for the treatment of gastric ulcer.