RESUMO
The purpose of this study was to evaluate the effect of acute toluene exposure on formalin (0.5% and 1%)-induced acute and long-lasting nociceptive hypersensitivity in rats. In addition, we sought to investigate the role of peripheral 5-HT3 receptors in the pronociceptive effect of toluene. Toluene exposure (6000ppm) for 30min enhanced 0.5% or 1% formalin-induced acute nociception and long-lasting secondary allodynia and hyperalgesia. In contrast, exposition to toluene for 30min in rats previously injected (six days before) with 1% formalin did not affect long-lasting hypersensitivy. Local peripheral pre-treatment with alosetron (5-HT3 receptor antagonist, 10-100 nmol) reduced the pronociceptive effect of toluene in acute nociception and long-lasting secondary allodynia and hyperalgesia. Alosetron (100nmol) was also able to reduce the nociceptive effects of 1% formalin in absence of toluene. Moreover, local peripheral injection of m-CPBG (5-HT3 receptor agonist, 300 nmol) enhanced 0.5% formalin-induced acute and long-lasting nociception in air- and toluene-exposed rats. Alosetron (10nmol) blocked the pronociceptive effects of m-CPBG (300nmol) on 0.5% formalin-induced acute and long-lasting hypersensitivity in rats exposed to toluene. Alosetron (at 10nmol) did not modify formalin-induced nociceptive behaviors. Finally, local peripheral pre-treatment with methiothepin (non-selective 5-HT receptor antagonist, 1.5nmol), did not affect the pronociceptive effect of toluene on 1% formalin-induced acute and long-lasting hypersensitivity. Our data demonstrate that acute exposure to toluene has pronociceptive effects in formalin-induced acute nociception and long-lasting hypersensitivity. Our data suggest that this pronociceptive effect depend on activation of peripheral 5-HT3, but not methiothepin-sensitive 5-HT, receptors.
Assuntos
Desinfetantes/toxicidade , Formaldeído/toxicidade , Nociceptividade/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Solventes/toxicidade , Tolueno/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Wistar , Serotoninérgicos/farmacologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
BACKGROUND: The purpose of this study was to determine the role of spinal 5-HT2A, 5-HT2B and 5-HT2C receptors in the development and maintenance of formalin-induced long-lasting secondary allodynia and hyperalgesia in rats, as well as their expression in the dorsal root ganglia (DRG) during this process. METHODS: 0.5-1% formalin was used to produce long-lasting secondary allodynia and hyperalgesia in rats. Western blot was used to determine 5-HT2 receptors expression in DRG. RESULTS: Formalin (0.5-1%) injection produced long-lasting (1-12 days) secondary allodynia and hyperalgesia in both ipsilateral and contralateral hind paws. Intrathecal pre-treatment or post-treatment with the 5-HT2 receptor agonist, DOI (1-10nmol), increased 0.5% formalin-induced secondary allodynia and hyperalgesia in both paws. In contrast, intrathecal pre-treatment with the selective 5-HT2A (ketanserin 1-100nmol), 5-HT2B (RS 127445 1-100nmol) or 5-HT2C (RS 102221 1-100nmol) receptor antagonists prevented and reversed, respectively, 1% formalin-induced secondary allodynia and hyperalgesia in both paws. Likewise, the pronociceptive effect of DOI (10nmol) was blocked by ketanserin, RS 127445 or RS 102221 (0.01nmol). 5-HT2A/2B/2C receptors were expressed in DRG of naïve rats. Formalin injection (1%) increased bilaterally 5-HT2A/2B receptors expression in DRG. In contrast, formalin injection decreased 5-HT2C receptors expression bilaterally in DRG. CONCLUSION: Data suggest that spinal 5-HT2A/2B/2C receptors have pronociceptive effects and participate in the development and maintenance of formalin-induced long-lasting hypersensitivity. These receptors are expressed in DRG and their expression is modulated by formalin.
Assuntos
Formaldeído/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Medula Espinal/metabolismo , Animais , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Ketanserina/farmacologia , Medição da Dor/métodos , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologiaRESUMO
The antinociceptive role of spinal 5-HT5A receptors in rat models of pain along with their expression was evaluated in the spinal cord and dorsal root ganglion (DRG). Nociception was assessed in the formalin, capsaicin, and acetic acid writhing tests. The expression of 5-HT5A receptors was determined by Western blot analysis. Intrathecal treatment with serotonin (5-HT, 10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) dose-dependently prevented 1% formalin-induced nociception. Furthermore, 5-HT reduced capsaicin- and acetic acid-induced nociception. 5-HT- or 5-CT-induced antinociception in the formalin test was diminished by the selective 5-HT5A receptor antagonist N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino] methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride (SB-699551; 3 and 10 nmol). In addition, 5-HT-induced spinal antinociception in the capsaicin and acetic acid tests was blocked by SB-699551 (10 nmol). Given alone, intrathecal injection of SB-699551 did not affect nociception induced by any irritant. 5-HT5A receptors were expressed in the dorsal spinal cord and DRG, even though formalin injection increased after 24h 5-HT5A receptor expression only in the spinal cord. Data suggest that 5-HT and 5-CT produce antinociception by activation of spinal 5-HT5A receptors in both the spinal cord and DRG. Furthermore, our results suggest that spinal 5-HT5A receptors play an antinociceptive role in several pain models in rats. 5-HT5A receptors may provide a therapeutic target to develop analgesic drugs.
Assuntos
Dor/induzido quimicamente , Dor/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Serotonina , Medula Espinal/metabolismo , Ácido Acético , Animais , Capsaicina , Feminino , Medição da Dor , Ratos , Ratos Wistar , Receptores de Serotonina/biossíntese , Serotonina/análogos & derivados , Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacosRESUMO
AIMS: The purpose of this study was to investigate the antinociceptive effect of epicatechin as well as the possible mechanisms of action in diabetic rats. MAIN METHODS: Rats were injected with streptozotocin to produce hyperglycemia. The formalin test was used to assess the nociceptive activity. KEY FINDINGS: Acute pre-treatment with epicatechin (0.03-30 mg/kg, i.p.) prevented formalin-induced nociception in diabetic rats. Furthermore, daily or every other day treatment for 2 weeks with epicatechin (0.03-30 mg/kg, i.p.) also prevented formalin-induced nociception in diabetic rats. Acute epicatechin-induced antinociception was prevented by l-NAME (N(ω)-nitro-l-arginine methyl ester hydrochloride, 1-10mg/kg, non-selective nitric oxide synthesis inhibitor), 7-nitroindazole (0.1-1mg/kg, selective neuronal nitric oxide synthesis inhibitor), ODQ (1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one, 0.2-2mg/kg, guanylyl cyclase inhibitor) or glibenclamide (1-10mg/kg, ATP-sensitive K(+) channel blocker). Moreover, epicatechin (3mg/kg)-induced antinociception was fully prevented by methiothepin (0.1-1mg/kg, serotonergic receptor antagonist), WAY-100635 (0.03-0.3mg/kg, selective 5-HT1A receptor antagonist) or SB-224289 (0.03-0.3mg/kg, selective 5-HT1B receptor antagonist). In contrast, BRL-15572 (0.03-0.3mg/kg, selective 5-HT1D receptor antagonist) only slightly prevented the antinociceptive effect of epicatechin. Naloxone (0.1-1mg/kg, opioid antagonist) did not modify epicatechin's effect. SIGNIFICANCE: Data suggest the involvement of the nitric oxide-cyclic GMP-K(+) channel pathway as well as activation of 5-HT1A and 5HT1B, and at a lesser extent, 5-HT1D, but not opioid, receptors in the antinociceptive effect of epicatechin in diabetic rats. Our data suggest that acute or chronic treatment with epicatechin may prove to be effective to treat nociceptive hypersensitivity in diabetic patients.
Assuntos
Analgésicos/farmacologia , Catequina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Analgésicos/antagonistas & inibidores , Animais , Compostos de Bifenilo/farmacologia , Catequina/antagonistas & inibidores , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Feminino , Glibureto/farmacologia , Hiperalgesia/complicações , Indazóis/farmacologia , Metiotepina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Oxidiazóis/farmacologia , Medição da Dor/efeitos dos fármacos , Piperazinas/farmacologia , Piperidonas/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Compostos de Espiro/farmacologiaRESUMO
The purpose of this study was to investigate the possible antinociceptive effect of mangiferin, a glucosylxanthone present in Mangifera indica L., in inflammatory pain. Furthermore, we sought to investigate the possible mechanisms action that contributes to these effects. The ipsilateral local peripheral (1-30 µg/paw), intrathecal (1-30 µg/rat) and oral (1-30 mg/kg) administration of mangiferin produced a dose-dependent reduction in formalin-induced nociception. The antinociceptive effect of this drug was similar to that induced by diclofenac after oral and local peripheral administration. Furthermore, mangiferin was also able to reduce 0.1% capsaicin- and serotonin-induced nociceptive behavior. The local peripheral antinociceptive effect of mangiferin in the formalin test was blocked by naloxone (50 µg/paw), naltrindole (1 µg/paw), 5-guanidinonaltrindole (5-GNTI, 1 µg/paw), N(G)-L-nitro-arginine methyl ester (L-NAME, 100 µg/paw), 1H-(1,2,4)-oxadiazolo [4,2-a]quinoxalin-1-one (ODQ, 50 µg/paw) and glibenclamide (50 µg/paw), but not by methiothepin (30 µg/paw). These results suggest that the antinociceptive effects induced by mangiferin are mediated by the peripheral opioidergic system involving the activation of δ, κ, and probably µ, receptors, but not serotonergic receptors. Data also suggests that mangiferin activates the NO-cyclic GMP-ATP-sensitive K(+) channels pathway in order to produce its local peripheral antinociceptive effect in the formalin test. Mangiferin may prove to be effective in treating inflammatory pain in humans.
Assuntos
Analgésicos/farmacologia , Formaldeído/farmacologia , Nociceptividade/efeitos dos fármacos , Xantonas/farmacologia , Animais , Capsaicina/farmacologia , Glibureto/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Serotonina/farmacologiaRESUMO
In this study we assessed the role of local peripheral and spinal serotonin 2B (5-HT(2B)) receptors in rats submitted to the formalin test. For this, local peripheral ipsilateral, but not contralateral, administration of the highly selective 5-HT(2B) receptor antagonist 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyridine (RS-127445, 0.01-1 nmol/paw) significantly prevented 1% formalin-induced flinching behavior. Moreover, local peripheral ipsilateral, but not contralateral, of the selective 5-HT(2) receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 1-10 nmol/paw) augmented 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of the 5-HT(2) receptor agonist DOI (10 nmol/paw) was significantly prevented by the local injection of RS-127445 (0.01 nmol/paw). Moreover, intrathecal injection of the selective 5-HT(2B) receptor antagonist RS-127445 (0.1-10 nmol/rat) also prevented 1% formalin-induced nociceptive behavior. In contrast, spinal injection of the 5-HT(2) receptor agonist DOI (1-10 nmol/rat) significantly increased flinching behavior induced by 0.5% formalin. The spinal pronociceptive effect of the 5-HT(2) receptor agonist DOI (10 nmol/rat) was prevented by the intrathecal injection of the 5-HT(2B) receptor antagonist RS-127445 (0.1 nmol/rat). Our results suggest that the 5-HT(2B) receptors play a pronociceptive role in peripheral as well as spinal sites in the rat formalin test. 5-HT(2B) receptors could be a target to develop analgesic drugs.
Assuntos
Medição da Dor/métodos , Dor/metabolismo , Dor/fisiopatologia , Nervos Periféricos/fisiologia , Receptor 5-HT2B de Serotonina/fisiologia , Medula Espinal/metabolismo , Anfetaminas/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Feminino , Injeções Espinhais , Dor/prevenção & controle , Medição da Dor/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Pirimidinas/administração & dosagem , Ratos , Ratos Wistar , Receptor 5-HT2B de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologiaRESUMO
The role of peripheral and spinal 5-HT(3) receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In experiments where the test drug was anticipated to augment or antagonize the response, 0.5 or 1% formalin, respectively, was used for injection. Peripheral ipsilateral, but not contralateral, pre-treatment (-10 min) with serotonin (5-HT, 10-100 nmol/paw) and the selective 5-HT(3) receptor agonist 1-(m-chlorophenyl)-biguanide (m-CPBG, 10-300 nmol/paw) increased 0.5% formalin-induced secondary allodynia and hyperalgesia in both paws. Moreover, spinal pre-treatment with m-CPBG (10-300 nmol/rat) increased 0.5% formalin-induced secondary hyperalgesia but not allodynia in both paws. Accordingly, peripheral ipsilateral (30-300 nmol/paw), but not contralateral (300 nmol/paw), and spinal (10-100 nmol) pre-treatment with the selective 5-HT(3) receptor antagonist ondansetron prevented 1% formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. The peripheral pronociceptive effects of 5-HT (100 nmol/paw) and m-CPBG (300 nmol/paw) as well as the spinal effect of m-CPBG (300 nmol/rat) were completely prevented by the peripheral (10 nmol/paw) and spinal (1 nmol/rat) injection, respectively, of ondansetron. At these doses, ondansetron did not modify per se formalin-induced nociceptive behaviors. Spinal (30-300 nmol/rat), but not peripheral (300 nmol/paw), post-treatment (on day 6) with ondansetron reversed established formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT(3) receptors participates in the development of formalin-induced long-term secondary allodynia and hyperalgesia in the rat. In addition, our data suggest that spinal 5-HT(3) receptors play an important role during development and maintenance of these evoked long-term behaviors.