RESUMO
The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.
Assuntos
Analgésicos , Peróxido de Hidrogênio , Animais , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Feminino , Analgésicos/farmacologia , Óxido Nítrico/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Relação Dose-Resposta a Droga , Dinoprostona/metabolismoRESUMO
It has already been shown that serotonin can release endocannabinoids at the spinal cord level, culminating in inhibition of the dorsal horn. At the peripheral level, cannabinoid receptors modulate primary afferent neurons by inhibiting calcium conductance and increasing potassium conductance. Studies have shown that after the activation of opioid receptors and cannabinoids, there is also the activation of the NO/cGMP/KATP pathway, inducing cellular hyperpolarization. In this study, we evaluated the participation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway in the peripheral antinociceptive effect of serotonin. The paw pressure test of mice was used in animals that had their sensitivity to pain increased due to an intraplantar injection of PGE2 (2 µg). Serotonin (250 ng/paw), administered locally in the right hind paw, induced antinociceptive effect. CB1 and CB2 cannabinoid receptors antagonists, AM251 (20, 40 and 80 µg) and AM630 (25, 50 and 100 µg), respectively, reversed the serotonin-induced antinociceptive effect. MAFP (0.5 µg), an inhibitor of the FAAH enzyme that degrades anandamide, and JZL184 (3.75 µg), an inhibitor of the enzyme MAGL that degrades 2-AG, as well as the VDM11 (2.5 µg) inhibitor of anandamide reuptake, potentiated the antinociceptive effect induced by a low dose (62. 5 ng) of serotonin. In the evaluation of the participation of the NO/cGMP/KATP pathway, the antinociceptive effect of serotonin was reversed by the administration of the non-selective inhibitor of NOS isoforms L-NOarg (12.5, 25 and 50 µg) and by the selective inhibitor for the neuronal isoform LNPA (24 µg), as well as by the soluble guanylate cyclase inhibitor ODQ (25, 50 and 100 µg). Among potassium channel blockers, only Glibenclamide (20, 40 and 80 µg), an ATP-sensitive potassium channel blocker, reversed the effect of serotonin. In addition, intraplantar administration of serotonin (250 ng) was shown to induce a significant increase in nitrite levels in the homogenate of the plantar surface of the paw of mice. Taken together, these data suggest that the antinociceptive effect of serotonin occurs by activation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway.
Assuntos
Canabinoides , Camundongos , Animais , Canabinoides/metabolismo , Analgésicos/farmacologia , Serotonina/farmacologia , Bloqueadores dos Canais de Potássio , Receptores de Canabinoides , Trifosfato de Adenosina , Hiperalgesia/metabolismoRESUMO
Cannabidiol (CBD) is the most abundant non-psychoactive component found in plants of the genus Cannabis. Its analgesic effect for the treatment of neuropathy has been widely studied. However, little is known about its effects in the acute treatment when Cannabidiol is administered peripherally. Because of that, this research was aimed to evaluate the antinociceptive effects of the CBD when administered peripherally for the treatment of acute neuropathic pain and check the involvement of the 5-HT1A and the TRPV1 receptors in this event. Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mouse paw. The technique used proved to be efficient to induce neuropathy, and the CBD (5, 10 and 30 µg/paw) induced the antinociception in a dosage-dependent manner. The dosage used that induced a more potent effect (30 µg/paw), did not induce a systemic response, as demonstrated by both the motor coordination assessment test (RotaRod) and the antinociceptive effect restricted to the paw treated with CBD. The administration of NAN-190 (10 µg/paw), a selective 5-HT1A receptor antagonist, and SB-366791 (16 µg/paw), a selective TRPV1 antagonist, partially reversed the CBD-induced antinociception. The results of the research suggest that the CBD produces the peripheral antinociception during the acute treatment of the neuropathic pain and it partially involved the participation of the 5-HT1A and TRPV1 receptors.
Assuntos
Canabidiol , Neuralgia , Camundongos , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Serotonina , Neuralgia/tratamento farmacológico , Modelos Animais de Doenças , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Receptor 5-HT1A de Serotonina , Canais de Cátion TRPVRESUMO
BACKGROUND: Curcumin is one of the compounds present in plants of the genus Curcuma sp., being very used not only as condiment but also with medicinal purposes. As an analgesic, papers highlight the efficacy of curcumin in the treatment of various types of pain. AIMS: In this study we evaluated the peripheral antinociceptive effect of curcumin and by which mechanisms this effect is induced. MAIN METHODS: The mice paw pressure test was used on animals which had increased pain sensitivity by intraplantar injection of carrageenan. All the drugs were administered in the right hind paw. KEY FINDINGS: Curcumin was administered to the right hind paw animals induced antinociceptive effect. Non -selective antagonist of opioid receptors naloxone reverted the antinociceptive effect induced by curcumin. Selective antagonists for µ, δ and κ opioid receptors clocinnamox, naltrindole and nor- binaltorphimine, respectively, reverted the antinociceptive effect induced by curcumin. Bestatin, enkephalinases inhibitor that degrade peptides opioids, did not change the nociceptive response. Selective antagonists for CB1 and CB2 cannabinoid receptors, AM251 and AM630, respectively, reversed the antinociceptive effect induced by curcumin. The MAFP inhibitor of the enzyme FAAH which breaks down anandamide, JZL184, enzyme inhibitor MAGL which breaks down the 2-AG, as well as the VDM11 anandamide reuptake inhibitor potentiated the antinociceptive effect of curcumin. SIGNIFICANCE: These results suggest that curcumin possibly peripheral antinociception induced by opioid and cannabinoid systems activation and possibly for endocannabinoids and opioids release.
Assuntos
Analgésicos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Curcumina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Receptores Opioides/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Agonistas de Receptores de Canabinoides/farmacologia , Carragenina/toxicidade , Cinamatos/farmacologia , Curcumina/farmacologia , Relação Dose-Resposta a Droga , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Derivados da Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/uso terapêuticoRESUMO
BACKGROUND: Xylazine is an α2 adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine. METHODS: The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E2, was performed. RESULTS: Xylazine administered via an intraplantar injection (25, 50 and 100 µg) induced a peripheral antinociceptive effect against prostaglandin E2 (2 µg)-induced hyperalgesia. This effect was blocked by treatment with the selective CB1 cannabinoid antagonist AM251 (20, 40 and 80 µg) but not by the selective CB2 cannabinoid antagonist AM630 (100 µg). The anandamide reuptake inhibitor VDM11 (2.5 µg) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 µg), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 µg), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 µg) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE2. CONCLUSIONS: The present results provides evidence that the peripheral antinociceptive effect of the α2 adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB1 cannabinoid receptor activation.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Hiperalgesia/tratamento farmacológico , Alcamidas Poli-Insaturadas/metabolismo , Xilazina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Xilazina/administração & dosagemRESUMO
Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective µ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced ß-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for µ- and δ-opioid receptors and for the endogenous opioid ß-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.
Assuntos
Analgésicos/uso terapêutico , Ketamina/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides delta , Receptores Opioides mu , Analgésicos/farmacologia , Animais , Cinamatos/farmacologia , Dinoprostona , Ketamina/farmacologia , Masculino , Camundongos , Derivados da Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidoresRESUMO
BACKGROUND: Annona crassiflora Mart., popularly known as "Araticum", is a native tree of the Brazilian Cerrado used in folk medicine for treatment of pain and inflammatory diseases. We proposed to analyze analgesic and anti-inflammatory properties of the filtrate (F1) and the precipitate (F2) of the hydroalcoholic fraction from the leaves of Annona crassiflora Mart. in mice. MATERIALS AND METHODS: Swiss mice were submitted to formalin-induced nociception test and tail-flick reflex test, to assess antinociceptive properties, and to the rota-rod test, for motor performance analyses. To evaluate anti-inflammatory properties, F1 and F2 were orally administered 1 h prior to the intrathoracic injection of carrageenan, zymosan, LPS, CXCL8, or vehicle in Balb/c mice and neutrophil infiltration was evaluated 4 h after injection. RESULTS: F1 and F2 reduced the licking time in the second phase of formalin-induced nociception test, but only F2 showed a dose-dependent response. Neither F1 nor F2 reduced the latency time in the tail-flick reflex test. In addition, motor performance alteration was not observed in F1- or F2-treated mice. F2 treatment significantly inhibited the neutrophilia induced by carrageenan, LPS, or CXCL8, but not zymosan. CONCLUSIONS: The experimental data demonstrated that hydroalcoholic fractions of Annona crassiflora Mart. leaves have remarkable anti-inflammatory and antinociceptive activities.
Assuntos
Analgésicos/farmacologia , Annona/química , Anti-Inflamatórios/farmacologia , Medição da Dor/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Carragenina/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB CRESUMO
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.
Assuntos
Analgésicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Triterpenos Pentacíclicos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Triterpenos/farmacologia , Amidoidrolases , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Benzodioxóis/farmacologia , Canabinoides/metabolismo , Endocanabinoides/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Indóis/farmacologia , Masculino , Camundongos , Monoacilglicerol Lipases/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Pirazóis/farmacologiaRESUMO
PURPOSE: Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. METHODS: The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 µg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. RESULTS: The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 µg), naltrindole (60 µg) and nor-binaltorfimina (200 µg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 µg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). CONCLUSIONS: These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.
Assuntos
Analgésicos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides/efeitos dos fármacos , Serotonina/farmacologia , Analgésicos/administração & dosagem , Animais , Cinamatos/farmacologia , Dinoprostona/administração & dosagem , Modelos Animais de Doenças , Masculino , Camundongos , Derivados da Morfina/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/metabolismo , Dor/patologia , Receptores Opioides/metabolismo , Serotonina/administração & dosagemRESUMO
Ketamine has been widely used as an analgesic and produces dissociative anesthetic effects. The antinociceptive effects of ketamine have been studied, but the involvement of endocannabinoids in these effects has not yet been investigated. In this study, we evaluated the involvement of the endocannabinoid system in the peripheral antinociceptive effects induced by ketamine. All drugs were administered via the intraplantar route. To induce hyperalgesia, rat paws were injected with prostaglandin E2 (2 µg per paw). The nociceptive threshold for mechanical stimulation was measured in the right hind paw of Wistar rats using the Randall-Selitto test. The tissue levels of anandamide (AEA), 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide were measured using liquid chromatography coupled to single quadrupole mass spectrometry. The administration of the cannabinoid receptor type 1 (CB1) antagonist, N(piperidine-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl 1 pyrazolcarboxamide (20, 40, and 80 µg per paw), but not the cannabinoid receptor type 2 antagonist, 6-iodo-2-methyl-1-(2-morpholinoethyl)-1H-indol-3-yl) (4-methoxyphenyl) methanone (100 µg per paw), antagonized the ketamine-induced peripheral antinociception in a dose-dependent manner. Additionally, the administration of the endocannabinoid metabolizing enzyme inhibitor (.5 µg per paw) or an AEA reuptake inhibitor, (5Z,8Z,11Z,14Z)N(4Hydroxy2methylphenyl)5,8,11,14 eicosatetraenamide (2.5 µg per paw) significantly enhanced low-dose ketamine-induced peripheral antinociception. AEA paw levels were increased only after ketamine administration to prostaglandin E2-injected paws. These data suggest that ketamine, in the presence of a nociceptive stimulus, induces a selective release of AEA levels and subsequent CB1 cannabinoid activation at the peripheral level. PERSPECTIVE: This study suggests that ketamine antinociception depends at least in part on AEA release and CB1 cannabinoid receptor activation in inflammatory conditions. This study could potentially help clinicians in the use of ketamine as a peripheral analgesic for inflammatory pain.
Assuntos
Analgésicos/uso terapêutico , Endocanabinoides/metabolismo , Ketamina/uso terapêutico , Dor/tratamento farmacológico , Dor/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Analgésicos/farmacologia , Animais , Ácidos Araquidônicos/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/uso terapêutico , Ketamina/farmacologia , Masculino , Alcamidas Poli-Insaturadas/metabolismo , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistasRESUMO
The role of serotonin (5-HT) in nociception will vary according to the subtypes of receptors activated. When administered peripherally, it induces pain in humans and in rats by activation of 5-HT1, 5-HT2 and 5-HT3 receptors. In addition, endogenous 5-HT produced in situ, is involved in the nociceptive response induced by formalin in rat's paw inflammation, possibly via 5-HT3 receptors. Moreover, it has been shown that 5-HT released in the dorsal horn of the spinal cord by stimulation of the periaqueductal gray causes activation of inhibitory interneurons, resulting in inhibition of spinal neurons. In the present study we evaluated the effect of serotonin and its receptors at peripheral antinociception. The mice paw pressure test was used in animals that had increased sensitivity by an intraplantar injection of PGE2 (2 µg). We used selective antagonists of serotonin receptors (isamoltan 5-HT1B, BRL 15572 5-HT1D, ketanserin 5-HT2A, ondansetron 5-HT3 and SB-269970 5-HT7). Administration of serotonin into the right hind paw (62.5, 125, 250 and 500 ng and 1 µg) produced a dose-dependent peripheral mechanical antihyperalgesic effect of serotonin in mice. Selective antagonists for 5-HT1B, 5-HT2A, 5-HT3 receptors at doses of 0.1, 1 and 10 µg, reversed the antihyperalgesic effect induced by 250 ng serotonin. In contrast, selective antagonists for 5-HT1D and 5-HT7 receptors were unable to reverse the antihyperalgesic effect induced by serotonin. These results demonstrated for the first time, the peripheral mechanical antihyperalgesic effect of serotonin, and participation of 5-HT1B, 5-HT2A and 5-HT3 receptors in this event.
Assuntos
Hiperalgesia/prevenção & controle , Medição da Dor/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Dinoprostona , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Ketanserina/farmacologia , Masculino , Camundongos , Ondansetron/farmacologia , Fenóis/farmacologia , Piperazinas/farmacologia , Propanolaminas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologiaRESUMO
BACKGROUND: Kahweol is a diterpene present in the oil derived from coffee beans. Although several pharmacological activities of kahweol are already well described in the literature, no study was done in order to assess the analgesic activity of this substance. Thus, the aim of this study was to investigate the possible peripheral antinociceptive effect of kahweol. Considering that the opioid peptides have been implicated in peripheral antinociception induced by non-opioidergic compounds, the present study also evaluated the endogenous opioids involvement in this effect. METHODS: The rat paw pressure test was used, and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2µg/paw). All drugs were administered subcutaneously in the hindpaws of male Wistar rats. The expression of ß-endorphin was examined by immunohistochemistry in the skin tissue samples of the plantar surface of rat right hindpaws. RESULTS: Intraplantar injection of kahweol (40 and 80µg) induced significant peripheral antinociception. The antinociceptive effect of kahweol was due to a local peripheral action because the higher dose (80µg/paw) did not produce any effect in the contralateral paw. The opioid receptor antagonist naloxone (50 and 100µg/paw) prevented action of kahweol (80µg/paw) and the aminopeptidases inhibitor bestatin (400µg/paw) potentiated the antinociceptive effect of kahweol (40µg/paw). Furthermore, kahweol treatment increased the intensity of ß-endorphin immunoreactivity in the epithelium of rat paws. CONCLUSIONS: The results discussed here provide evidence that kahweol treatment has peripheral antinociceptive effect and suggest that this effect is mediated by the release of endogenous opioids.
Assuntos
Analgésicos/farmacologia , Café/química , Diterpenos/farmacologia , Peptídeos Opioides/farmacologia , Animais , Dinoprostona , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor , Peptídeos/farmacologia , Pressão , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/metabolismo , beta-Endorfina/biossínteseRESUMO
Angiotensin-(1-7) [Ang-(1-7)] develops its functions interacting with Mas receptor. Mas receptor was recently identified in the DRG and its activation by Ang-(1-7) resulted in peripheral antinociception against PGE2 hyperalgesia in an opioid-independent pathway. Nevertheless, the mechanism by which Ang-(1-7) induce peripheral antinociception was not yet elucidated. Considering that endogenous noradrenaline could induce antinociceptive effects by activation of the adrenoceptors the aim of this study was verify if the Ang-(1-7) is able to induce peripheral antinociception by interacting with the endogenous noradrenergic system. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2µg). Ang-(1-7) was administered locally into the right hindpaw alone and after either agents, α2-adrenoceptor antagonist, yohimbine (5, 10 and 20 µg/paw), α2C-adrenoceptor antagonist rauwolscine (10, 15 and 20 µg/paw), α1-adrenoceptor antagonist prazosin (0.5, 1 and 2 µg/paw), ß-adrenoceptor antagonist propranolol (150, 300 and 600 ng/paw). Noradrenaline (NA) reuptake inhibitor reboxetine (30 µg/paw) was administered prior to Ang-(1-7) low dose (20 ng) and guanetidine 3 days prior to experiment (30 mg/kg/animal, once a day), depleting NA storage. Intraplantar Ang-(1-7) induced peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, rauwolscine, prazosin and propranolol. Reboxetine intensified the antinociceptive effects of low-dose of Ang-(1-7) and guanethidine, which depletes peripheral sympathomimetic amines, reversed almost 70% the Ang-(1-7)-induced peripheral antinociception. Then, this study provides evidence that Ang-(1-7) induce peripheral antinociception stimulating an endogenous noradrenaline release that activates peripheral adrenoceptors inducing antinociception.
Assuntos
Analgésicos/metabolismo , Angiotensina I/metabolismo , Norepinefrina/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Antagonistas Adrenérgicos beta/administração & dosagem , Analgésicos/administração & dosagem , Angiotensina I/administração & dosagem , Animais , Dinoprostona/administração & dosagem , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Medição da Dor , Fragmentos de Peptídeos/administração & dosagem , Prazosina/administração & dosagem , Proto-Oncogene Mas , Ratos , Receptores Adrenérgicos beta/metabolismo , Ioimbina/administração & dosagemRESUMO
AIMS: We evaluated the role of adrenergic systems on the peripheral antinociception induced by dipyrone and diclofenac. Mainmethods: The rat pawpressure test, inwhich sensitivity is increased by intraplantar injection of prostaglandin E2, was used to examine the peripheral effects of locally administered drugs. KEY FINDINGS: Dipyrone (10, 20 and 40 µg) and diclofenac (5, 10 and 20 µg) administered locally into the right paw elicited a dose-dependent antinociceptive effect, which was demonstrated to be local; the injection of drugs into the ipsilateral and contralateral hindpaws demonstrated an effect only in the ipsilateral paw because only the treated paw produced an antinociceptive effect. To test the adrenergic system, we used guanethidine (30 mg/kg) to deplete noradrenalin from noradrenergic vesicles. Guanethidine antagonized the peripheral antinociception induced by diclofenac and dipyrone. Yohimbine (2.5, 5, 10, or 20 µg/paw) a nonselective α2-adrenergic receptor antagonist antagonized the peripheral antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). Rauwolscine (Rau; 10, 15, 20 µg), a selective α2C-adrenoreceptor, was able to block the peripheral antinociception induced by NSAIDs. The other specific α2A,B and D-adrenoreceptor antagonists (BRL 44480, imiloxan and RX 821002, respectively) did not modify the peripheral antinociception. However, prazosin (0.5, 1, and 2 µg/paw), an α1 receptor antagonist, and propranolol (0.3, 0.6 or 1.2 µg/paw), a ß-adrenoreceptor antagonist, antagonized the antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). SIGNIFICANCE: Dipyrone and diclofenac produce peripheral antinociception, which involves the release of NA and interaction with α1, α2C and ß-adrenoreceptors.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Dipirona/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Dipirona/administração & dosagem , Relação Dose-Resposta a Droga , Guanetidina/farmacologia , Masculino , Norepinefrina/metabolismo , Prazosina/administração & dosagem , Prazosina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Ioimbina/administração & dosagem , Ioimbina/farmacologiaRESUMO
This study aimed to assess the possible systemic antinociceptive activity of mangiferin and to clarify the underlying mechanism, using the acute models of chemical (acetic acid, formalin, and capsaicin) and thermal (hot-plate and tail-flick) nociception in mice. Mangiferin at oral doses of 10 to 100 mg/kg evidenced significant antinociception against chemogenic pain in the test models of acetic acid-induced visceral pain and in formalin- and capsaicin-induced neuro-inflammatory pain, in a naloxone-sensitive manner, suggesting the participation of endogenous opiates in its mechanism. In capsaicin test, the antinociceptive effect of mangiferin (30 mg/kg) was not modified by respective competitive and non-competitive transient receptor potential vanilloid 1 (TRPV1) antagonists, capsazepine and ruthenium red, or by pretreatment with L-NAME, a non-selective nitric oxide synthase inhibitor, or by ODQ, an inhibitor of soluble guanylyl cyclase. However, mangiferin effect was significantly reversed by glibenclamide, a blocker of K(ATP) channels and in animals pretreated with 8-phenyltheophylline, an adenosine receptor antagonist. Mangiferin failed to modify the thermal nociception in hot-plate and tail-flick test models, suggesting that its analgesic effect is only peripheral but not central. The orally administered mangiferin (10-100 mg/kg) was well tolerated and did not impair the ambulation or the motor coordination of mice in respective open-field and rota-rod tests, indicating that the observed antinociception was unrelated to sedation or motor abnormality. The findings of this study suggest that mangiferin has a peripheral antinociceptive action through mechanisms that involve endogenous opioids, K(ATP)-channels and adenosine receptors.
Assuntos
Trifosfato de Adenosina/fisiologia , Adenosina/fisiologia , Analgésicos/farmacologia , Modelos Animais de Doenças , Peptídeos Opioides/fisiologia , Dor/tratamento farmacológico , Canais de Potássio/fisiologia , Xantonas/farmacologia , Trifosfato de Adenosina/metabolismo , Analgésicos/uso terapêutico , Animais , Camundongos , Canais de Potássio/metabolismo , Xantonas/uso terapêuticoRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E2 (PGE2, 2 μg/paw) in the rat’s hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 μg/paw) and AM-630 (100 μg/paw) were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 μg dipyrone (mean = 5.825 ± 2.842 g), 20 μg diclofenac (mean = 4.825 ± 3.850 g) and 40 μg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and indomethacin.