Analgesia and pain: Dual effect of dopamine on the peripheral nociceptive system is dependent on D2-or D1-like receptor activation.

In this study, a pharmacological approach, together with the paw pressure test, was used to investigate the role of dopamine and its receptors in the peripheral processing of the nociceptive response in mice. Initially, the administration of dopamine (5, 20, and 80 ng/paw) in the hind paw of male Swiss mice (30-40 g) promoted antinociceptive effects in a dose-dependent manner. This was considered a peripheral effect, as it did not produce changes in the nociceptive threshold of the contralateral paw. The D2, D3, and D4 dopamine receptor antagonists remoxipride (4 µg/paw), U99194 (16 µg/paw), and L-745,870 (16 µg/paw), respectively, reversed the dopamine-mediated antinociception in mice with PGE2-induced hyperalgesia. The D1 and D5 dopamine receptor antagonists SKF 83566 (2 µg/paw) and SCH 23390 (1.6 µg/paw), respectively, did not alter dopamine antinociception. In contrast, dopamine at higher doses (0.1, 1, and 10 µg/paw) caused hyperalgesia in the animals, and the D1 and D5 receptor antagonists reversed this pronociceptive effect (10 µg/paw), whereas the D2 receptor antagonist remoxipride did not. Our data suggest that dopamine has a dual effect that depends on the dose, as it causes peripheral antinociceptive effects at small doses via the activation of D2-like receptors and nociceptive effects at higher doses via the activation of D1-like receptors.

Kahweol, a natural diterpene from coffee, induces peripheral antinociception by endocannabinoid system activation.

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 µg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 µg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 µg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 µg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 µg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 µg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.

PHARMACOLOGICAL SCREENING OF MUCUS PRODUCED BY THE PACAMÃ FISH, Lophiosilurus alexandri

Recently, fish byproducts have been appraised as a source of structurally diverse bioactive compounds. In this context, fish mucus has revealed a myriad of pharmacological activities. This study describes a new bioactive molecule release system composed of protein nanoparticles from pacamã (Lophiosilurus alexandri) mucus, an endemic fish to the São Francisco River (Brazil). The process of obtaining and applying these nanoparticles, composed of proteins present in the pacamã mucus, as biocompatible carriers of bioactive molecules is also addressed herein. Therefore, the external mucus of the fish was collected, lyophilized and hydrated in deionized water containing the template molecule. After pH adjustment to 7.5, followed by sonication and centrifugation, the formed nanoparticles were collected in the supernatant. Additionally, the mucus and the particles were characterized, and pharmacological effects were evaluated regarding their antifungal, antibacterial, anticancer, anti or pro-inflammatory and antinociceptive proprieties. NP-Mucus did not exhibit antibacterial activity against Pseudomonas aeruginosa or Staphylococcus aureus. However, it showed potential effects against Candida albicans with a minimum inhibitory concentration (MIC) of 1 µg/mL, and significant pro-inflammatory role, reflected by cellular recruitment activity and healing effects. Therefore, future studies a

META-ANALYSIS OF THE THERAPEUTIC USE OF DIPYRONE IN DOGS: PHARMACOLOGICAL EFFECTS AND CLINICAL SAFETY

Dipyrone (metamizole) is well-known for its powerful effect with central and peripheral activity. This meta-analysis involved articles published between 1973 and 2021, revealing that Brazil is the country which most published scientific articles relating the use of dipyrone in dogs, and this drug is widely recommended as an analgesic to control pain in cases of postoperative and cancer. Dipyrone is one of the favorite drugs used in small animal clinic in Brazil, and 12 commercial brands are available to use in dogs at doses among 25 to 50mg/kg for oral, intravenous and intramuscular administration. The effects of dipyrone may be potentiated when used in combination with other analgesic agents such as tramadol. In several studies, the occurrence of vomiting has been observed as an adverse effect, especially when the drug is used during surgical procedures, but metamizole has presented a low potential to cause gastric ulceration. The meta-analysis study of the use of dipyrone in dogs shows the clinical importance of this drug in Brazil, being an effective and safe medication, as long as it is used in the indicated dose of 25 mg/kg.

Pharmacological screening of mucus produced by the pacamã fish, Lophiosilurus alexandri / Triagem farmacológica de muco produzido pelo pacamã, Lophiosilurus alexandri

Recently, fish byproducts have been appraised as a source of structurally diverse bioactive compounds. In this context, fish mucus has revealed a myriad of pharmacological activities. This study describes a new bioactive molecule release system composed of protein nanoparticles from pacamã (Lophiosilurus alexandri) mucus, an endemic fish to the São Francisco River (Brazil). The process of obtaining and applying these nanoparticles, composed of proteins present in the pacamã mucus, as biocompatible carriers of bioactive molecules is also addressed herein. Therefore, the external mucus of the fish was collected, lyophilized and hydrated in deionized water containing the template molecule. After pH adjustment to 7.5, followed by sonication and centrifugation, the formed nanoparticles were collected in the supernatant. Additionally, the mucus and the particles were characterized, and pharmacological effects were evaluated regarding their antifungal, antibacterial, anticancer, anti or pro-inflammatory and antinociceptive proprieties. NP-Mucus did not exhibit antibacterial activity against Pseudomonas aeruginosa or Staphylococcus aureus. However, it showed potential effects against Candida albicans with a minimum inhibitory concentration (MIC) of 1 µg/mL, and significant pro-inflammatory role, reflected by cellular recruitment activity and healing effects. Therefore, future studies are now needed in order to identify specific compounds in NP-mucus responsible for the observed effects in order to provide new pharmacological and therapeutic strategies.(AU)

Recentemente, os subprodutos de peixes foram avaliados como uma fonte de compostos bioativos estruturalmente diversos. Nesse contexto, o muco dos peixes revelou uma miríade de atividades farmacológicas. Este estudo descreve um novo sistema de liberação de moléculas bioativas compostas por nanopartículas de proteínas do muco do pacamã (Lophiosilurus alexandri), um peixe do Rio São Francisco (Brasil). O processo de obtenção e aplicação dessas nanopartículas, compostas por proteínas presentes no muco do pacamã, como carreadores biocompatíveis de moléculas bioativas também são abordados neste artigo. Para tanto, o muco externo dos peixes foi coletado, liofilizado e hidratado em água deionizada contendo a molécula template. Após ajuste do pH para 7,5, seguido de sonicação e centrifugação, as nanopartículas formadas foram coletadas no sobrenadante. Adicionalmente, foram caracterizados o muco e as partículas, sendo avaliados os efeitos farmacológicos quanto às propriedades antifúngicas, antibacterianas, anticancerígenas, anti ou pró-inflamatórias e antinociceptivas. NP-Mucus não exibiu atividade antibacteriana contra Pseudomonas aeruginosa ou Staphylococcus aureus. No entanto, apresentou efeitos potenciais contra Candida albicans com concentração inibitória mínima (MIC) de 1 µg/mL, além de importante papel próinflamatório, refletido pela atividade de recrutamento celular e efeitos cicatrizantes. Portanto, estudos são necessários para identificar compostos no NP-muco responsáveis pelos efeitos observados, a fim de fornecer novas estratégias farmacológicas e terapêuticas.(AU)

Meta-analysis of the therapeutic use of dipyrone in dogs: pharmacological effects and clinical safety / Meta-análise do uso terapêutico da dipirona em cães: efeitos farmacológicos e segurança clínica

Dipyrone (metamizole) is well-known for its powerful effect with central and peripheral activity. This meta-analysis involved articles published between 1973 and 2021, revealing that Brazil is the country which most published scientific articles relating the use of dipyrone in dogs, and this drug is widely recommended as an analgesic to control pain in cases of postoperative and cancer. Dipyrone is one of the favorite drugs used in small animal clinic in Brazil, and 12 commercial brands are available to use in dogs at doses among 25 to 50mg/kg for oral, intravenous and intramuscular administration. The effects of dipyrone may be potentiated when used in combination with other analgesic agents such as tramadol. In several studies, the occurrence of vomiting has been observed as an adverse effect, especially when the drug is used during surgical procedures, but metamizole has presented a low potential to cause gastric ulceration. The meta-analysis study of the use of dipyrone in dogs shows the clinical importance of this drug in Brazil, being an effective and safe medication, as long as it is used in the indicated dose of 25 mg/kg.

A dipirona (metamizol) é bem conhecida por seu poderoso efeito com atividade central e periférica. Esta meta-nálise envolveu estudos publicados entre os anos de 1973 a 2021, revelando que o Brasil é o país que mais publicou artigos científicos envolvendo o uso de dipirona em cães, sendo este fármaco amplamente recomendado como analgésico para controlar a dor em casos de câncer e dor pós-operatória. É um dos medicamentos preferidos da clínica médica de pequenos animais no Brasil. 12 marcas comerciais estão disponíveis para uso em cães em doses que variam de 25 a 50g para administração oral, intravenosa e intramuscular. Os efeitos da dipirona podem ser potencializados quando usada em combinação com outros analgésicos, como o tramadol. Em vários estudos, a ocorrência de vômito tem sido observada como efeito adverso, principalmente quando o medicamento é usado durante procedimentos cirúrgicos, mas tem baixo potencial para causar ulceração gástrica. O estudo de meta-análise do uso de dipirona em cães evidencia a importância do uso clínico deste fármaco no Brasil, sendo um medicamento eficaz e seguro para cães, desde que utilizada na dose indicada de 25 mg / kg.

Pharmacological screening of mucus produced by the pacamã fish, Lophiosilurus alexandri / Triagem farmacológica de muco produzido pelo pacamã, Lophiosilurus alexandri

Recently, fish byproducts have been appraised as a source of structurally diverse bioactive compounds. In this context, fish mucus has revealed a myriad of pharmacological activities. This study describes a new bioactive molecule release system composed of protein nanoparticles from pacamã (Lophiosilurus alexandri) mucus, an endemic fish to the São Francisco River (Brazil). The process of obtaining and applying these nanoparticles, composed of proteins present in the pacamã mucus, as biocompatible carriers of bioactive molecules is also addressed herein. Therefore, the external mucus of the fish was collected, lyophilized and hydrated in deionized water containing the template molecule. After pH adjustment to 7.5, followed by sonication and centrifugation, the formed nanoparticles were collected in the supernatant. Additionally, the mucus and the particles were characterized, and pharmacological effects were evaluated regarding their antifungal, antibacterial, anticancer, anti or pro-inflammatory and antinociceptive proprieties. NP-Mucus did not exhibit antibacterial activity against Pseudomonas aeruginosa or Staphylococcus aureus. However, it showed potential effects against Candida albicans with a minimum inhibitory concentration (MIC) of 1 µg/mL, and significant pro-inflammatory role, reflected by cellular recruitment activity and healing effects. Therefore, future studies are now needed in order to identify specific compounds in NP-mucus responsible for the observed effects in order to provide new pharmacological and therapeutic strategies.

Recentemente, os subprodutos de peixes foram avaliados como uma fonte de compostos bioativos estruturalmente diversos. Nesse contexto, o muco dos peixes revelou uma miríade de atividades farmacológicas. Este estudo descreve um novo sistema de liberação de moléculas bioativas compostas por nanopartículas de proteínas do muco do pacamã (Lophiosilurus alexandri), um peixe do Rio São Francisco (Brasil). O processo de obtenção e aplicação dessas nanopartículas, compostas por proteínas presentes no muco do pacamã, como carreadores biocompatíveis de moléculas bioativas também são abordados neste artigo. Para tanto, o muco externo dos peixes foi coletado, liofilizado e hidratado em água deionizada contendo a molécula template. Após ajuste do pH para 7,5, seguido de sonicação e centrifugação, as nanopartículas formadas foram coletadas no sobrenadante. Adicionalmente, foram caracterizados o muco e as partículas, sendo avaliados os efeitos farmacológicos quanto às propriedades antifúngicas, antibacterianas, anticancerígenas, anti ou pró-inflamatórias e antinociceptivas. NP-Mucus não exibiu atividade antibacteriana contra Pseudomonas aeruginosa ou Staphylococcus aureus. No entanto, apresentou efeitos potenciais contra Candida albicans com concentração inibitória mínima (MIC) de 1 µg/mL, além de importante papel próinflamatório, refletido pela atividade de recrutamento celular e efeitos cicatrizantes. Portanto, estudos são necessários para identificar compostos no NP-muco responsáveis pelos efeitos observados, a fim de fornecer novas estratégias farmacológicas e terapêuticas.

Meta-analysis of the therapeutic use of dipyrone in dogs: pharmacological effects and clinical safety / Meta-análise do uso terapêutico da dipirona em cães: efeitos farmacológicos e segurança clínica

Dipyrone (metamizole) is well-known for its powerful effect with central and peripheral activity. This meta-analysis involved articles published between 1973 and 2021, revealing that Brazil is the country which most published scientific articles relating the use of dipyrone in dogs, and this drug is widely recommended as an analgesic to control pain in cases of postoperative and cancer. Dipyrone is one of the favorite drugs used in small animal clinic in Brazil, and 12 commercial brands are available to use in dogs at doses among 25 to 50mg/kg for oral, intravenous and intramuscular administration. The effects of dipyrone may be potentiated when used in combination with other analgesic agents such as tramadol. In several studies, the occurrence of vomiting has been observed as an adverse effect, especially when the drug is used during surgical procedures, but metamizole has presented a low potential to cause gastric ulceration. The meta-analysis study of the use of dipyrone in dogs shows the clinical importance of this drug in Brazil, being an effective and safe medication, as long as it is used in the indicated dose of 25 mg/kg.(AU)

A dipirona (metamizol) é bem conhecida por seu poderoso efeito com atividade central e periférica. Esta meta-nálise envolveu estudos publicados entre os anos de 1973 a 2021, revelando que o Brasil é o país que mais publicou artigos científicos envolvendo o uso de dipirona em cães, sendo este fármaco amplamente recomendado como analgésico para controlar a dor em casos de câncer e dor pós-operatória. É um dos medicamentos preferidos da clínica médica de pequenos animais no Brasil. 12 marcas comerciais estão disponíveis para uso em cães em doses que variam de 25 a 50g para administração oral, intravenosa e intramuscular. Os efeitos da dipirona podem ser potencializados quando usada em combinação com outros analgésicos, como o tramadol. Em vários estudos, a ocorrência de vômito tem sido observada como efeito adverso, principalmente quando o medicamento é usado durante procedimentos cirúrgicos, mas tem baixo potencial para causar ulceração gástrica. O estudo de meta-análise do uso de dipirona em cães evidencia a importância do uso clínico deste fármaco no Brasil, sendo um medicamento eficaz e seguro para cães, desde que utilizada na dose indicada de 25 mg / kg.(AU)

Kahweol, a natural diterpene from coffee, induces peripheral antinociception by endocannabinoid system activation

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 μg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 μg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 μg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 μg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 μg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 μg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.

Anti-inflammatory and immune properties of the peltatoside, isolated from the leaves of Annona crassiflora Mart., in a new experimental model zebrafish.

Establishing new animal models for the study of inflammation is very important in the process of discovering new drugs, since the inflammatory event is the basis of many pathological processes. Whereas rodent models have been the primary focus of inflammation research, we defend the zebrafish (Danio rerio) test as a feasible alternative for preclinical studies. Moreover, despite all the technological development already achieved by humanity, nature can still be considered a relevant source of new medicines. In this context, the aim of this work was to evaluate the anti-inflammatory effect of a substance isolated from the medicinal plant Annona crassilfora Mart, the peltatoside, in an inflammatory model of zebrafish. It was determined: (i) total leukocyte count in the coelomate exudate; (ii) N-acetyl-ß-d-glucuronidase (NAG); (iii) myeloperoxidase (MPO); (iv) and the histology of liver, intestine and mesentery. Peltotoside (25, 50 and 100 µg) and dexamethasone (25 µg) were administered intracelomatically (i.c.) 30 min before carrageenan (i.c.). Pretreatment with peltatoside at three doses significantly inhibited leukocyte recruitment in the coelomic cavity, and inhibited NAG and MPO activity against the action of Cg, in a similar manner as dexamethasone. However, some microlesions in the evaluated organs were detected. The dose of 25 µg showed an anti-inflammatory effect with lower undesirable effects in the tissues. Our results suggest that the zebrafish test was satisfactory in performing our analyzes and that the peltotoside has a modulatory action in reducing leukocyte migration.

Evaluation of the effects of extracts of Maytenus imbricata (Celastraceae) on the treatment of inflammatory and metabolic dysfunction induced by high-refined carbohydrate diet.

The Maytenus genus is a member of the Celastraceae family. Numerous medicinal uses were assigned to species of this genus, with the use of roots, bark, and leaves for the treatment of gastric ulcers, as anti-inflammatory, analgesic, antiallergic, antitumor, among others. Several studies have demonstrated that natural products derived from plants have an important role in the prevention and treatment of obesity. Accordingly, we evaluated the effect of Maytenus imbricata extracts in the treatment of obesity induced by diet rich in refined carbohydrate (HC). BALB/c mice were fed chow or HC diet for 8 weeks. At the beginning of the 9th week, the HC group was subdivided into three groups: (i) group of animals that continued to consume only HC diet; (ii) the group of animals fed HC diet supplemented with ethyl acetate extract of M. imbricata roots (HC + EAE); (iii) the group of animals fed HC diet supplemented with extract in hexane/ethyl ether (HC + HEE). The period of extracts supplementation was 4 weeks. It was observed that EAE and EHE when added to the HC diet modulated the metabolic and inflammatory changes, such as: reduced the adipocytes area, improved glucose intolerance, reduced the levels of triglycerides and resistin in serum, and the number of total leukocytes in blood. In the epididymal adipose tissue, the extracts reduced proinflammatory mediators' concentration. According to the results, it was concluded that the species Maytenus imbricata has the potential to be used for the treatment of obesity.

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to cannabinoid receptors activation in mice.

Several works have shown that triterpenes induce peripheral antinociception by activation of cannabinoid receptors and endocannabinoids; besides, several research groups have reported activation of cannabinoid receptors in peripheral antinociception. The aim of this study was to assess the involvement of the cannabinoid system in the antinociceptive effect induced by tingenone against hyperalgesia evoked by prostaglandin E2 (PGE2) at peripheral level. The paw pressure test was used and the hyperalgesia was induced by intraplantar injection of PGE2 (2 µg/paw). All drugs were injected subcutaneously in the hind paws of male Swiss mice. Tingenone (200 µg/paw) administered into the right hind paw induced a local antinociceptive effect, that was antagonized by AM630, a selective antagonist to CB2 cannabinoid receptor. AM251, a selective antagonist to CB1 cannabinoid receptor, did not alter the peripheral antinociceptive effect of tingenone. MAFP, a fatty acid amide hydrolase (FAAH) inhibitor; VDM11, an anandamide reuptake inhibitor; and JZL184, monoacylglycerol lipase (MAGL) inhibitor did not potentiate the peripheral antinociceptive effect of the lower dose of tingenone (50 µg/paw). The results suggest that tingenone induced a peripheral antinociceptive effect via cannabinoid receptor activation. Therefore, this study suggests a pharmacological potential for a new analgesic drug.

St36 electroacupuncture activates nNOS, iNOS and ATP-sensitive potassium channels to promote orofacial antinociception in rats.

Orofacial pain is pain perceived in the face and/or oral cavity, generally caused by diseases or disorders of regional structures, by dysfunction of the nervous system, or through referral from distant sources. Treatment of orofacial pain is mainly pharmacological, but it has increased the number of reports demonstrating great clinical results with the use of non-pharmacological therapies, among them electroacupuncture. However, the mechanisms involved in the electroacupuncture are not well elucidated. Thus, the present study investigate the involvement of the nitric oxide synthase (NOS) and ATP sensitive K+ channels (KATP) in the antinociception induced by electroacupuncture (EA) at acupoint St36. Thermal nociception was applied in the vibrissae region of rats, and latency time for face withdrawal was measured. Electrical stimulation of acupoint St36 for 20 minutes reversed the thermal withdrawal latency and this effect was maintained for 150 min. Intraperitoneal administration of specific inhibitors of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and a KATP channels blocker reversed the antinociception induced by EA. Furthermore, nitrite concentration in cerebrospinal fluid (CSF) and plasma, increased 4 and 3-fold higher, respectively, after EA. This study suggests that NO participates of antinociception induced by EA by nNOS, iNOS and ATP-sensitive K+ channels activation.

Central release of nitric oxide mediates antinociception induced by aerobic exercise.

Nitric oxide (NO) is a soluble gas that participates in important functions of the central nervous system, such as cognitive function, maintenance of synaptic plasticity for the control of sleep, appetite, body temperature, neurosecretion, and antinociception. Furthermore, during exercise large amounts of NO are released that contribute to maintaining body homeostasis. Besides NO production, physical exercise has been shown to induce antinociception. Thus, the present study aimed to investigate the central involvement of NO in exercise-induced antinociception. In both mechanical and thermal nociceptive tests, central [intrathecal (it) and intracerebroventricular (icv)] pretreatment with inhibitors of the NO/cGMP/KATP pathway (L-NOArg, ODQ, and glybenclamide) prevented the antinociceptive effect induced by aerobic exercise (AE). Furthermore, pretreatment (it, icv) with specific NO synthase inhibitors (L-NIO, aminoguanidine, and L-NPA) also prevented this effect. Supporting the hypothesis of the central involvement of NO in exercise-induced antinociception, nitrite levels in the cerebrospinal fluid increased immediately after AE. Therefore, the present study suggests that, during exercise, the NO released centrally induced antinociception.

Proteinase-activated receptor-4 plays a major role in the recruitment of neutrophils induced by trypsin or carrageenan during pleurisy in mice.

BACKGROUND/AIMS: The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment. Here, we examined the effects of aprotinin, a potent inhibitor of trypsin proteinase and the kallikrein-kinin system, and the PAR-4 antagonist YPGKF-NH(2) (tcY-NH(2)) on neutrophil recruitment in response to carrageenan and trypsin in the pleural cavity of mice. METHODS: BALB/c mice were intrapleurally injected with trypsin or PAR-4-activating peptide AY-NH(2), pretreated with aprotinin or tcY-NH(2) (1 µg/cavity) prior to an intrapleural injection of trypsin or carrageenan, or pretreated with leukotriene B(4) antagonist U-75302 (3 µg/cavity) prior to a trypsin injection. The number of infiltrating neutrophils was evaluated after 4 h. RESULTS: PAR-4-activating peptide AY-NH(2) and trypsin-induced neutrophil recruitment was inhibited by aprotinin, tcY-NH(2) or U-75302. Aprotinin and tcY-NH(2) also inhibited neutrophil recruitment induced by carrageenan. CONCLUSION: These data suggest a key role for PAR-4 in mediating neutrophil recruitment in a mouse model of pleurisy induced by the activity of trypsin or trypsin-like enzymes.

Participation of endogenous opioids in the antinociception induced by resistance exercise in rats

Exercise is a low-cost intervention that promotes health and contributes to the maintenance of the quality of life. The present study was designed to investigate the influence of different resistance exercise protocols on the nociceptive threshold of rats. Female Wistar rats were used to perform exercises in a weight-lifting exercise model. The following groups were examined (N = 6 per group): untrained rats (control group); an acute protocol group consisting of rats submitted to 15 sets of 15 repetitions of resistance exercise (acute group); rats exercised with 3 sets of 10 repetitions, three times per week for 12 weeks (trained group), and a group consisting of trained rats that were further submitted to the acute protocol (trained-acute group). The nociceptive threshold was measured by the paw-withdrawal test, in which the withdrawal threshold (escape reaction) was measured by an apparatus applying force to the plantar surface of the animal paw. The opioid antagonist naloxone (2 mg/kg) was administered subcutaneously 10 min before the exercise protocols. The trained group demonstrated antinociception only up to day 45 of the 12-week training period. A significant increase (37 percent, P < 0.05) in the nociceptive threshold was produced immediately after exercise, decreasing to 15 percent after 15 min, when the acute exercise protocol was used. Naloxone reversed this effect. These data show that the acute resistance exercise protocol was effective in producing antinociception for 15 min. This antinociceptive effect is mediated by the activation of opioid receptors.

Participation of endogenous opioids in the antinociception induced by resistance exercise in rats.

Exercise is a low-cost intervention that promotes health and contributes to the maintenance of the quality of life. The present study was designed to investigate the influence of different resistance exercise protocols on the nociceptive threshold of rats. Female Wistar rats were used to perform exercises in a weight-lifting exercise model. The following groups were examined (N = 6 per group): untrained rats (control group); an acute protocol group consisting of rats submitted to 15 sets of 15 repetitions of resistance exercise (acute group); rats exercised with 3 sets of 10 repetitions, three times per week for 12 weeks (trained group), and a group consisting of trained rats that were further submitted to the acute protocol (trained-acute group). The nociceptive threshold was measured by the paw-withdrawal test, in which the withdrawal threshold (escape reaction) was measured by an apparatus applying force to the plantar surface of the animal paw. The opioid antagonist naloxone (2 mg/kg) was administered subcutaneously 10 min before the exercise protocols. The trained group demonstrated antinociception only up to day 45 of the 12-week training period. A significant increase (37%, P < 0.05) in the nociceptive threshold was produced immediately after exercise, decreasing to 15% after 15 min, when the acute exercise protocol was used. Naloxone reversed this effect. These data show that the acute resistance exercise protocol was effective in producing antinociception for 15 min. This antinociceptive effect is mediated by the activation of opioid receptors.

Opioidergic orofacial antinociception induced by electroacupuncture at acupoint St36.

The participation of opioids in the antinociceptive effect of electroacupuncture was evaluated in terms of nociception produced by thermal stimuli applied to the face of male Wistar rats, weighing 180-230 g. Electrical stimulation (bipolar and asymmetric square wave with 0.5 mA intensity for 20 min) of acupoint St36, located in the anterior tibial muscle 10 mm distal to the knee joint, induced antinociception in the present model, which was maintained for 150 min. Acupoint LI4, located in the junction of the first and second metacarpal bones, did not achieve antinociception at any frequency studied (5 Hz: 1.7 +/- 0.1; 30 Hz: 1.8 +/- 0.1; 100 Hz: 1.7 +/- 0.1 vs 1.4 +/- 0.2). The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency 100 Hz (3.0 +/- 0.2 vs 1.0 +/- 0.1) was used, and not with 5 or 30 Hz (1.2 +/- 0.2 and 0.7 +/- 0.1 vs 1.0 +/- 0.1). The antinociceptive effect of acupuncture occurred by opioid pathway activation, since naloxone (1 and 2 mg/kg, subcutaneously) antagonized it (1.8 +/- 0.2 and 1.7 +/- 0.2 vs 3.0 +/- 0.1).

Opioidergic orofacial antinociception induced by electroacupuncture at acupoint St36

The participation of opioids in the antinociceptive effect of electroacupuncture was evaluated in terms of nociception produced by thermal stimuli applied to the face of male Wistar rats, weighing 180-230 g. Electrical stimulation (bipolar and asymmetric square wave with 0.5 mA intensity for 20 min) of acupoint St36, located in the anterior tibial muscle 10 mm distal to the knee joint, induced antinociception in the present model, which was maintained for 150 min. Acupoint LI4, located in the junction of the first and second metacarpal bones, did not achieve antinociception at any frequency studied (5 Hz: 1.7 ± 0.1; 30 Hz: 1.8 ± 0.1; 100 Hz: 1.7 ± 0.1 vs 1.4 ± 0.2). The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency 100 Hz (3.0 ± 0.2 vs 1.0 ± 0.1) was used, and not with 5 or 30 Hz (1.2 ± 0.2 and 0.7 ± 0.1 vs 1.0 ± 0.1). The antinociceptive effect of acupuncture occurred by opioid pathway activation, since naloxone (1 and 2 mg/kg, subcutaneously) antagonized it (1.8 ± 0.2 and 1.7 ± 0.2 vs 3.0 ± 0.1).

Antinociceptive effect from Davilla elliptica hydroalcoholic extract.

Davilla elliptica St Hill (Dilleniaceae) is widely used for multiple purposes in Brazil. The aim of this study was to verify the pharmacological support of this folk use and evaluate its use as antinociceptive. The hydroalcoholic extract of the stems (100-1000 mg/kg, p.o.) induced reduction of response in the formalin test inflammatory phase in mice. This antinociceptive effect does not involve the opioidergic pathway since it was not reverted by pre-treatment with naloxone nor due to myorelaxant activity since it did not affect rota-rod and tail-flick performance. Our results indicate a participation of the nitrergic pathway and may be of particular potential importance in clinical medicine, in view of the current interest in the assessment of new medicines originated from plants.