Kappa opioid receptors mediate an initial aversive component of paclitaxel-induced neuropathy.

RATIONALE: Cancer patients receiving the antineoplastic drug paclitaxel report higher incidences and longer duration of treatment-resistant depression than patients receiving other classes of chemotherapeutics. Rodents treated with paclitaxel exhibit a suite of changes in affect-like behaviors. Further, paclitaxel causes chemotherapy-induced peripheral neuropathy (CIPN) in humans and rodents. Kappa opioid receptors (KOR) have a well-established role in depression and neuropathy. The contributions of KOR signaling to paclitaxel-induced aversive-like state and CIPN in rodents remain to be explored. OBJECTIVES: We aimed to investigate whether dysregulation of the KOR/dynorphin system is associated with paclitaxel-mediated pain-like behavior and depression-like behavior. METHODS: Cancer-free male C57BL/6J mice were treated with four injections of vehicle or paclitaxel (32 mg/kg cumulative). The effects of the selective KOR antagonist norbinaltorphimine (norBNI) on paclitaxel-induced sucrose preference deficits and mechanical hypersensitivity were measured. Prodynorphin mRNA and receptor-mediated G protein activation were measured at two time points following the last paclitaxel injection using quantitative real-time polymerase chain reaction and agonist-stimulated [35S]guanosine-5'-O'-(γ-thio)-triphosphate ([35S]GTPγS) binding, respectively, in the nucleus accumbens (NAc), caudate-putamen, amygdala, and spinal cord. RESULTS: Paclitaxel produced a norBNI-reversible sucrose preference deficit, whereas mechanical hypersensitivity was not reversed by norBNI. Paclitaxel treatment increased the levels of mRNA for prodynorphin, a precursor for endogenous KOR agonists, in the NAc. Paclitaxel also had time-dependent effects on KOR-mediated G protein activation in the NAc. CONCLUSIONS: These results suggest that KOR signaling mediates an initial aversive component of paclitaxel, but not necessarily paclitaxel-induced mechanical hypersensitivity.

Allosteric modulation of α4ß2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain.

BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The α4ß2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4ß2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4ß2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at α4ß2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. METHODS: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. RESULTS: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the α4ß2 nAChRs by using competitive α4ß2 antagonist dihydro-ß-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to α4ß2 nAChRs. CONCLUSIONS: The present results suggest that allosteric modulation of α4ß2 nAChR may provide new strategies in chronic neuropathic pain. SIGNIFICANCE: α4ß2 nAChRs are involved in pain modulation. dFBr, a PAM at α4ß2 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of α4ß2* nAChR may provide new strategies in chronic neuropathic pain.

Evaluation of the analgesic and antiedematogenic activities of Quassia amara bark extract.

We evaluated the possible antiedematogenic, antinociceptive and/or sedative effects of four different extracts obtained from the bark of Quassia amara namely, 70% ethanol (70EtOH), 100% ethanol (100EtOH), dichloromethane (DCM) and hexane extracts (HEX). The oral administration (100, 250 and 500 mg/kg) of these extracts did not show significant effects in any experiment. However, when administered intraperitoneally, the HEX extract decreased the paw edema induced by carrageenan, showed antinociceptive effects on the hot-plate test and on acetic acid-induced writhing, and showed sedative effects on pentobarbital-induced sleep. Naloxone did not reverse the antinociceptive effect of this extract. In conclusion, although the mechanisms are uncertain, the results demonstrated that these effects are apparently related to sedative and muscle relaxant or psychomimetic activities of the HEX extract of the plant.

Antiulcerogenic activity of ethanol extract of Solanum variabile (false "jurubeba").

The ethanol extract (EE) of the aerial parts of Solanum variabile Mart. (Solanaceae) was investigated for its ability to prevent ulceration of the gastric and duodenal mucosa at different doses. Its ability to heal chronic ulcer processes was also evaluated. When the HCl/ethanol solution was used to induce gastric ulcer, the EE produced a significant dose-dependent reduction of lesion formation of 51, 74 and 89%, at doses of 250, 500 and 1000 mg/kg, respectively. The 100 mg/kg dose had no significant activity. The EE also significantly reduced the gastric lesions induced by the combination of indomethacin and bethanechol (60 and 72%) at doses of 500 and 1000 mg/kg and also reduced stress-induced gastric ulcer (41%) but only at the doses of 1000 mg/g (P < 0.05). The pylorus-ligature experiment demonstrated that the highest EE dose affected significantly the gastric juice parameters by increasing pH values from 4.08 (negative control) to 5.42 and decreasing acid output from 7.16 (negative control) to 4.26 mEq.mL, 4h. A decrease of gastric contents from 370 mg (negative control) to 240 mg was also observed. The results obtained in the chronic gastric ulcer model indicated that a single oral dose of Solanum variabile (1000 mg/kg) administered for 14 consecutive days accelerated the ulcer healing by 46% compared to a 55% effect of cimetidine. Also, at the dose of 1000 mg/kg, the EE inhibited the onset of duodenal lesions by 64%. The data suggest that the EE of Solanum variabile has a significant preventive, curative and duodenal anti-ulcer effect.

Evaluation of anti-ulcerogenic activity in an Aqueous Extract obtained from Bauhinia forficata leaves / Evaluation of anti-ulcerogenic activity in an Aqueous Extract obtained from Bauhinia forficata leaves

Bauhinia forficata Link, popularly known as pata-de- vaca, unha-de-vaca, casco-de-vaca, has been widely used in traditional medicine to treat several diseases. Leaves of B. forficata are used in popular medicine as a diuretic, hypoglycemic, tonic and cleanser, and to combat elephantiasis. However, despite the wide range of ethnopharmacological data surrounding the plant, there are no scientific data demonstrating a probable anti-ulcerogenic activity conferred by use of that species. The present study aimed to evaluate the antiulcer properties of an infusion of fresh leaves of B. forficata Link. From the leaves of B. forficata, an Aqueous extract (AqE) was obtained and the phytochemical analysis showed the presence of flavonols in this extract. In the gastric ulcer induced by administration of HCl- Ethanol model performed with four different doses of AqE (125, 250, 500 and 1000 mg.Kg -1 ), the AqE showed significant preventive activity (*p<0.01) at doses of 1000 mg.Kg -1 . The antiulcer activity of AqE (1000 mg.Kg -1 ) could also be demonstrated in experimental models of NSAID-bethanechol (**p<0.001) and absolute ethanol (**p<0.001). Moreover, AqE (1000 mg.Kg -1 ) promoted a significant increase (**p<0.001) in the amount of gastric mucus. The data presented here demonstrated the potential gastroprotective activity from AqE, possibly attributed to the presence of flavonols in this extract. These results may serve as a s Medicinal plants as an alternative therapy to increase immune resistanceupport for the development of new treatments related to the pathology of gastric ulcer.(AU)

The gastroprotective effect of the essential oil of Croton cajucara is different in normal rats than in malnourished rats.

It has been shown previously that malnourished rats are resistant to acute gastric lesions but not to subchronic gastric ulceration. It also has been demonstrated that the essential oil obtained from the bark of Croton cajucara (Sacaca) has antiulcer properties. In the present study, the ability of this essential oil to prevent the formation of gastric ulcers in rats fed a diet with 17% protein (normoproteic rats) or 6% protein (malnourished rats) was investigated. At a dose of 100 mg/kg body weight, orally, the essential oil significantly reduced the gastric injury caused by indomethacin (25% after 2 h and 70% after 4 h) only in normoproteic rats. In the pylorus ligature model, the essential oil increased the pH and gastric volume, but decreased the total acid concentration in both groups when compared to the respective control group. The essential oil significantly increased prostaglandin E2 production in glandular cells by 50% compared to the controls in both groups of rats. In addition, the amount of gastric mucus was two-fold higher in malnourished rats than in normoproteic rats. The present results show that the enhanced protective effect of essential oil in malnourished rats involved an increase in prostaglandin E2 production and mucus secretion, which are both factors that protect the gastric mucosa against damage. In agreement with this, malnourished rats always had a lower number of acute gastric ulcers.

Preliminary studies of Mammea americana L. (Guttiferae) bark/latex extract point to an effective antiulcer effect on gastric ulcer models in mice.

Plant extracts are some of the most attractive sources of new drugs and have shown promising results for the treatment of gastric ulcers. Several folk medicinal plants and herbs have been used to treat gastrointestinal disorders, including gastric ulcers. Mammea americana L. (Guttiferae) fruit is very common in the diet of the population of northern South America. Our research interest in this plant arose because of its potential medicinal value as a tonic and against stomachache, as used in folk medicine. In this paper we evaluated three different extracts (ethanolic/EtOH, methanolic/MeOH and dichloromethane/DCM) obtained from M. americana L., for their ability to protect the gastric mucosa against injuries caused by necrotizing agents (0.3 M HCl/60% EtOH), hypothermic restraint stress, nonsteroidal anti-inflammatory drugs (NSAID, indomethacin) and pylorus ligation. In the HCl/EtOH-induced gastric-ulcer model, EtOH and DCM extracts demonstrated significant inhibition of the ulcerative lesion index by 54% (12.0 +/- 2.6 mm) and 86% (3.7 +/- 1.8 mm), respectively, in relation to the control value (26.0 +/- 1.4 mm) (p<0.0001). In the NSAID/cholinomimetic-induced lesion model, both EtOH and DCM extracts showed antiulcerogenic effects with significant reduction in the damage to these gastric lesions of 36% (8.3 +/- 2.0 mm) and 42% (7.5 +/- 1.4 mm), respectively, as compared to the control group (13.0 +/- 0.9 mm) (p<0.0001). In the gastric ulcer induced by hypothermic-restraint stress, both extracts also showed significant activity, and inhibited the gastric lesion index by 58% and 75%, respectively. The EtOH and DCM extracts also changed gastric juice parameters as well as those of cimetidine, decreased gastric acid secretion significantly (p<0.0001), increased pH values and promoted reduced acid output (p<0.0001). In all gastric-ulcer-induced models, MeOH extract did not show any significant antiulcerogenic activity, nor did it change gastric-juice parameters (p>0.05). The results suggest that EtOH and DCM extracts obtained from M. americana possess excellent antisecretory and/or gastrotective effect in all gastric ulcer models. These results suggest that the antiulcerogenic compound(s) present in M. americana may be clustered in the apolar fraction, which will be investigated by our group for the probable mechanisms of action.

Is gastric ulceration different in normal and malnourished rats?

Protein malnutrition can adversely affect all tissues. The aim of the present study was to test the hypothesis that protein deprivation influences gastric ulcer formation, as well as metabolism and organ growth, in rats. In the present study, there was a significant reduction in the body and organ weight of rats fed a low-protein diet (P<0.001). Malnourished rats were less susceptible to ulceration of the gastric mucosa in ethanol and indomethacin models of acute gastric ulcers when compared with rats fed a normoproteic diet (17 % protein). Mucus production and prostaglandin E2 formation increased in malnourished rats, possibly explaining the lower number of acute ulcers in these animals. Pylorus ligature altered gastric juice composition (increased pH and gastric volume, and decreased total acid concentration) in the animal group fed a low-protein diet compared with the group fed a diet containing 17 % protein (P<0.05). The gastric mucosa was more damaged in malnourished rats than in normal rats evaluated for 14 d after acetic acid injection (P<0.001). Malnourished rats exhibited resistance to acute gastric lesions, owing to an increase in prostaglandin GE2 release and mucus secretion, which protected their gastric mucosa. This phenomenon was not seen in subchronic gastric ulceration.

The effect of intramammary antibiotic therapy at calving on udder health traits.

The effect of intramammary antibiotic therapy at calving on mastitis infection prevalence, linear score milk somatic cell count, and milk NAGase activity, 30 d postpartum, and on milk production, 90 to 120 d postpartum, was tested. Cows (n = 175) were split into treatment and control groups at drying off. All cows received commercial dry cow therapy. At calving, treated cows received commercial lactating cow therapy in all quarters after the first two milkings; control cows were not treated. Composite milk samples were aseptically collected from all cows at drying off, calving, and 30 d postpartum. Udder health traits: linear score milk SCC, NAGase activity, and bacterial content in milk, were determined on all samples. The first three DHI milk weights were recorded for all cows. Treatment and control cows had similar prevalences of intramammary infections during the dry and 30-d postpartum periods. Least squares means of linear score milk SCC and NAGase activities were similar at drying off and calving. Cell count scores were similar between groups; NAGase activities were higher in control cows at 30 d postpartum. Control cows tended to produce more milk postpartum. Results demonstrated no advantage of intramammary therapy at calving in improving milk production or udder health.

Gastroprotective effect of aparisthman, a diterpene isolated from Aparisthmium cordatum, on experimental gastric ulcer models in rats and mice.

Aparisthmium cordatum (Juss.) Bail. (Euphorbiaceae), known in the State of Pará, Brazil as "ariquena queimosa", is a medium-sized tree which is native to the North Brazilian coastal region. Previous phytochemical studies of the bark of A. cordatum yielded a furan diterpenoid with a clerodane skeleton, called aparisthman. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), a furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of aparisthman. When previously administered (p.o.) at the dose of 100 mg/kg(-1), aparisthman reduced significantly (p < 0.01) gastric injury induced by the indomethacin/bethanechol (71%), ethanol (71%), pylorus ligature, (59%) and hypothermic restraint-stress models (50%), in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 250 mg/kg(-1), aparisthman from A. cordatum reduced significantly (p < 0.001) the formation of gastric lesions by 59% and 66%, respectively, as compared with control. In the pylorus-ligature model, aparisthman (p.o.) decreased the volume of gastric juice as compared with control (p < 0.001). When aparisthman (100 mg/kg(-1)) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity as compared with control. In the animals pre-treated with aparisthman, free mucus production increased by 19% in the gastric mucosa (p < 0.05). The results suggest that aparisthman from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an increase of the defensive mechanisms of the stomach such as prostaglandin synthesis and mucus production. The good yield of aparisthman obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.

Evaluation of the gastroprotective activity of cordatin, a diterpene isolated from Aparisthmium cordatum (Euphorbiaceae).

Aparisthmium cordatum (Juss.) BAIL. (Euphorbiaceae) is a medium sized tree native to the North Brazilian coastal region, which is known in the State of Pará as "ariquena queimosa." To our knowledge it has no popular use. Phytochemical studies of the benzene extract of the bark of A. cordatum yielded a furan diterpene with a clerodane skeleton, called cordatin. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), another furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of cordatin, another compound of the clerodane diterpene group present in A. cordatum bark. When previously administered (p.o.) at the dose of 100 mg/kg, cordatin significantly reduced (p<0.01) gastric injury induced by the indomethacin/bethanechol (78%), ethanol (76%), and hypothermic restraint-stress models (66%) and by pylorus ligature (50%) in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 250 mg/kg, cordatin from A. cordatum significantly reduced (p<0.001) the formation of gastric lesions by 70% and 77%, respectively, when compared to the control. In the pylorus-ligature model, cordatin (p.o.) only decreased the volume of gastric juice compared to the control (p<0.001). When cordatin (100 mg/kg) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity compared to the control (p<0.05). In the animals pre-treated with cordatin, free mucus production was not altered when compared with the control group. The results suggest that cordatin from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an anti-secretory property but the involvement of mucosal defensive mechanisms are not to be ignored. The good yield of cordatin obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.