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1.
Int J Mol Sci ; 21(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32570786

RESUMO

Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.

2.
Drug Chem Toxicol ; : 1-5, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899978

RESUMO

Chemotherapy-induced peripheral neuropathy has an important impact on the quality of life of cancer patients. Vincristine-induced neuropathy is a major dose-limiting side effect. Symptoms of peripheral neuropathy are spontaneous pain, allodynia, and hyperalgesia. To analyze the contribution of substance P to the development of vincristine-induced mechanical allodynia/hyperalgesia, substance P levels in the rat spinal dorsal horn were analyzed after vincristine treatment. Mechanical allodynia/hyperalgesia was tested with the von Frey filaments 14 days after intraperitoneal (i.p.) administration of vincristine 0.1 mg/kg/day in rats. Vincristine-induced mechanical allodynia/hyperalgesia after day 14 was significantly inhibited by the neurokinin 1 receptor antagonist, aprepitant (20 mg/kg, s.c.). Immunohistochemistry showed that vincristine treatment significantly increased substance P expression (30.3% ± 2.4%) compared to saline treatment in the superficial layers of the spinal dorsal horn. Moreover, vincristine treatment significantly increased the substance P level in the spinal cord. These results suggest that vincristine treatment increases substance P in the spinal dorsal horn, and that aprepitant attenuates mechanical allodynia/hyperalgesia in vincristine-induced neuropathic rats.

3.
Neuropeptides ; 67: 95-101, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29274843

RESUMO

Transient receptor potential (TRP) receptors are involved in the development of chemotherapy-induced peripheral neuropathic pain, which is a common side effect of selected chemotherapeutic agents such as oxaliplatin. However, the precise contribution of TRPs to this condition remains unknown. Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, so we used a preclinical model of oxaliplatin-induced cold hypersensitivity in rats to determine the effects of oxaliplatin on TRP channels. To this end, immunohistochemistry was used to examine TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) expression in the rat dorsal root ganglion (DRG) after 4days of oxaliplatin treatment. Behavioral assessment using the acetone spray test showed that oxaliplatin significantly increased acute cold hypersensitivity after 4days of treatment. Double-staining immunohistochemistry showed that 4days after oxaliplatin treatment, there was increased co-expression of TRPA1 and TRPV1 in isolectin B4-positive small-sized DRG neurons, as well as a significant increase in the co-localization of TRPM8 and neurofilament 200 in medium-sized DRG neurons. In addition, in situ hybridization revealed that TRPV1 protein was co-expressed with TRPA1 mRNA on day 4 after oxaliplatin administration. Thus, at an early stage following oxaliplatin treatment there is an increased expression of TRPA1 and TRPV1 in small-sized DRG neurons and of TRPM8 in medium-sized DRG neurons. Collectively, these changes may contribute to the development of oxaliplatin-induced peripheral neuropathic pain.


Assuntos
Antineoplásicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Canais de Receptores Transientes de Potencial/efeitos dos fármacos , Animais , Temperatura Baixa , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxaliplatina , Ratos Wistar , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Receptores Transientes de Potencial/metabolismo
4.
J Pharmacol Sci ; 133(4): 254-260, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28410966

RESUMO

The clinical anti-cancer efficacy of vincristine is limited by the development of dose-dependent peripheral neuropathy. Up-regulation of transient receptor potential vanilloid 1 (TRPV1) is correlated with peripheral neuropathy following anti-cancer drug treatment. To analyze the contribution of TRPV1 to the development of vincristine-induced mechanical allodynia/hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after vincristine treatment. Mechanical allodynia/hyperalgesia was tested with von Frey filaments 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in rats. TRPV1 expression in DRGs following vincristine treatment was assessed with western blot analysis and in situ hybridization histochemistry. Vincristine-induced mechanical allodynia/hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Vincristine treatment increased the expression of TRPV1 protein in DRG neurons. In situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small in size. Immunohistochemistry showed that isolectin B4-positive small DRG neurons co-expressed TRPV1 protein 14 days after treatment. These results suggest that vincristine treatment increases TRPV1 expression in small DRG neurons. TRPV1 expression may contribute to the development of vincristine-induced painful peripheral neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Expressão Gênica/efeitos dos fármacos , Neuralgia/induzido quimicamente , Neuralgia/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Vincristina/toxicidade , Animais , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Masculino , Neuralgia/tratamento farmacológico , Neurônios/metabolismo , Neurônios/patologia , Ratos Wistar , Rutênio Vermelho/farmacologia , Rutênio Vermelho/uso terapêutico , Canais de Cátion TRPV/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos
5.
J Pharmacol Sci ; 130(2): 117-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26883453

RESUMO

Oxaliplatin is a chemotherapeutic agent that is effective against various types of cancer including colorectal cancer. Acute cold hyperalgesia is a serious side effect of oxaliplatin treatment. Although the therapeutic drug pregabalin is beneficial for preventing peripheral neuropathic pain by targeting the voltage-dependent calcium channel α2δ-1 (Cavα2δ-1) subunit, the effect of oxaliplatin-induced acute cold hypersensitivity is uncertain. To analyze the contribution of the Cavα2δ-1 subunit to the development of oxaliplatin-induced acute cold hypersensitivity, Cavα2δ-1 subunit expression in the rat spinal cord was analyzed after oxaliplatin treatment. Behavioral assessment using the acetone spray test showed that 6 mg/kg oxaliplatin-induced cold hypersensitivity 2 and 4 days later. Oxaliplatin-induced acute cold hypersensitivity 4 days after treatment was significantly inhibited by pregabalin (50 mg/kg, p.o.). Oxaliplatin (6 mg/kg, i.p.) treatment increased the expression level of Cavα2δ-1 subunit mRNA and protein in the spinal cord 2 and 4 days after treatment. Immunohistochemistry showed that oxaliplatin increased Cavα2δ-1 subunit protein expression in superficial layers of the spinal dorsal horn 2 and 4 days after treatment. These results suggest that oxaliplatin treatment increases Cavα2δ-1 subunit expression in the superficial layers of the spinal cord and may contribute to functional peripheral acute cold hypersensitivity.


Assuntos
Antineoplásicos/toxicidade , Canais de Cálcio/metabolismo , Expressão Gênica/efeitos dos fármacos , Compostos Organoplatínicos/toxicidade , Medula Espinal/metabolismo , Doença Aguda , Animais , Canais de Cálcio/genética , Síndromes Periódicas Associadas à Criopirina/induzido quimicamente , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/prevenção & controle , Masculino , Oxaliplatina , Pregabalina/administração & dosagem , Pregabalina/uso terapêutico , Ratos Wistar
6.
Brain Res Bull ; 121: 201-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26876935

RESUMO

1,2,3,4-Tetrahydroisoquinoline (TIQ) and some of its derivatives, such as 1-benzyl-TIQ and 1-methyl-TIQ, are endogenously present in human brain and are thought to contribute to induction or prevention of Parkinson's disease. In the present study, we estimated the effects of the artificially synthesized TIQ derivatives 1-cyclohexyl-TIQ (1-cHex-TIQ) and 1-cyclohexyl-N-propargyl-TIQ (1-cHex-N-proTIQ) on spontaneous nigral dopaminergic discharge in rats. Low to middle doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a transient and significant, but not relatively potent, increase in the firing rate, followed by a sustained decrease with higher doses. 1-cHex-TIQ increased the firing frequency at low and high doses. In contrast, 1-cHex-N-proTIQ had no effects on spontaneous firing. Although intraperitoneal pretreatment with 1-cHex-TIQ did not inhibit this MPTP-induced decrease in firing, pretreatment with 1-cHex-N-proTIQ significantly depressed this decreased firing in a dose-dependent and long-lasting manner. Selegiline, a monoamine oxidase type B inhibitor that is used as a therapeutic drug for Parkinson's disease, also significantly inhibited the decrease in dopaminergic spontaneous firing induced by MPTP, but the effect was transient. These results suggest that although the decrease in firing induced by 1-cHex-TIQ is clearly more potent compared to that induced by MPTP, its effect is eliminated by adding an N-propargyl functional group. The antagonizing effect of 1-cHex-N-proTIQ on MPTP-induced firing loss may be exerted by a different mechanism than that of selegiline.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Dopamina/metabolismo , Neurônios/efeitos dos fármacos , Substância Negra/citologia , Tetra-Hidroisoquinolinas/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Dopaminérgicos/farmacologia , Interações Medicamentosas , Masculino , Neurotoxinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Tetra-Hidroisoquinolinas/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
Yakugaku Zasshi ; 136(2): 287-96, 2016.
Artigo em Japonês | MEDLINE | ID: mdl-26831807

RESUMO

Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.


Assuntos
Antineoplásicos/efeitos adversos , Canais de Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Compostos Organoplatínicos/efeitos adversos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo , Doença Aguda , Animais , Canais de Cálcio/genética , Gânglios Espinais/metabolismo , Expressão Gênica , Humanos , Hiperalgesia/induzido quimicamente , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/genética , Oxaliplatina , Doenças do Sistema Nervoso Periférico/genética , Ratos , Corno Dorsal da Medula Espinal/metabolismo , Substância P/metabolismo , Canal de Cátion TRPA1 , Canais de Receptores Transientes de Potencial/genética , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Eur J Pharmacol ; 770: 46-51, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26658369

RESUMO

Peripheral neuropathy is a common adverse effect of paclitaxel treatment. The major dose-limiting side effect of paclitaxel is peripheral sensory neuropathy, which is characterized by painful paresthesia of the hands and feet. To analyze the contribution of substance P to the development of paclitaxel-induced mechanical hyperalgesia, substance P expression in the superficial layers of the rat spinal dorsal horn was analyzed after paclitaxel treatment. Behavioral assessment using the von Frey test and the paw thermal test showed that intraperitoneal administration of 2 and 4mg/kg paclitaxel induced mechanical allodynia/hyperalgesia and thermal hyperalgesia 7 and 14 days after treatment. Immunohistochemistry showed that paclitaxel (4mg/kg) treatment significantly increased substance P expression (37.6±3.7% on day 7, 43.6±4.6% on day 14) in the superficial layers of the spinal dorsal horn, whereas calcitonin gene-related peptide (CGRP) expression was unchanged. Moreover, paclitaxel (2 and 4mg/kg) treatment significantly increased substance P release in the spinal cord on day 14. These results suggest that paclitaxel treatment increases release of substance P, but not CGRP in the superficial layers of the spinal dorsal horn and may contribute to paclitaxel-induced painful peripheral neuropathy.


Assuntos
Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Substância P/metabolismo , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
9.
Exp Ther Med ; 10(2): 535-540, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26622350

RESUMO

Guillain-Barré syndrome is a type of acute inflammatory neuropathy that causes ataxia and is associated with the IgG anti-GM1 antibody. However, the pathogenic role of the IgG anti-GM1 antibody and calcium channels in neuromuscular junctions (NMJs) remains unclear. Thus, the aim of the present study was to investigate the effects of the IgG anti-GM1 monoclonal antibody (mAb) on spontaneous muscle action potentials (SMAPs), and the effects of calcium channel blockers, in a rat spinal cord-muscle co-culture system. In addition, the binding of IgG anti-GM1 mAb to calcium channels was investigated in the rat hemidiaphragm. The frequency of SMAPs in the innervated muscle cells was acutely inhibited by the IgG anti-GM1 mAb; however, this effect was blocked by the N-type calcium channel blocker, ω-conotoxin GVIA (30 nM). Furthermore, the P/Q-type calcium channel blocker, ω-agatoxin IVA (10 nM), was found to partially block the IgG anti-GM1 mAb-induced inhibitory effect in the spinal cord-muscle co-culture system. Immunohistochemical analysis of the rat hemidiaphragm indicated that IgG anti-GM1 mAb binding overlapped with anti-Cav2.2 (α1B) antibody binding in the nerve terminal. In addition, IgG anti-GM1 mAb binding partially overlapped with anti-Cav2.1 (α1A) antibody binding. Thus, the results demonstrated that the IgG anti-GM1 mAb binds to calcium channels in the nerve terminals of NMJs. Therefore, the inhibitory effect of IgG anti-GM1 mAb on SMAPs may involve N-type and P/Q-type calcium channels in motor nerve terminals at the NMJ.

10.
Mol Pain ; 11: 69, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26567040

RESUMO

BACKGROUND: Peripheral cold neuropathic pain is a serious side effect of oxaliplatin treatment. However, the mechanism of oxaliplatin-induced cold hyperalgesia is unknown. In the present study, we investigated the effects of oxaliplatin on transient receptor potential ankyrin 1 (TRPA1) in dorsal root ganglion (DRG) neurons of rats. RESULTS: Behavioral assessment using the acetone spray test showed that 3 and 6 mg/kg oxaliplatin (i.p.) induced acute cold hypersensitivity after 1, 2, 4, and 7 days. Real-time PCR showed that oxaliplatin (6 mg/kg) significantly increased TRPA1 mRNA expression in DRGs at days 1, 2, and 4. Western blotting revealed that oxaliplatin significantly increased TRPA1 protein expression in DRGs at days 2, 4, and 7. Moreover, in situ hybridization histochemistry revealed that most TRPA1 mRNA-labeled neurons in the DRGs were small in size. Oxaliplatin significantly increased co-localization of TRPA1 expression and isolectin B4 binding in DRG neurons. Oxaliplatin induced a significant increase in the percent of TRPA1 mRNA-positive small neurons in DRGs at days 1, 2, and 4. In addition, we found that intrathecal administration of TRPA1 antisense, but not TRPA1 mismatched oligodeoxynucleotides, knocked down TRPA1 expression and decreased oxaliplatin-induced cold hyperalgesia. Double labeling showed that p-p38 mitogen-activated protein kinase (MAPK) was co-expressed in TRPA1 mRNA-labeled neurons at day 2 after oxaliplatin administration. Intrathecal administration of the p38 MAPK inhibitor, SB203580, significantly decreased oxaliplatin-induced acute cold hypersensitivity. CONCLUSIONS: Together, these results demonstrate that TRPA1 expression via activation of p38 MAPK in DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia.


Assuntos
Síndromes Periódicas Associadas à Criopirina/induzido quimicamente , Gânglios Espinais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Doença Aguda , Animais , Síndromes Periódicas Associadas à Criopirina/enzimologia , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Gânglios Espinais/enzimologia , Gânglios Espinais/fisiopatologia , Imidazóis/farmacologia , Masculino , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ratos , Canal de Cátion TRPA1 , Proteínas Quinases p38 Ativadas por Mitógeno/genética
11.
Pharmacology ; 95(1-2): 87-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25633935

RESUMO

1,2,3,4-Tetrahydroisoquinoline (TIQ) and its derivatives, 1-methyl-TIQ (1-MeTIQ) and 1-benzyl-TIQ (1-BnTIQ), are endogenously present in the human brain. In this study, we compared the effects of TIQ derivatives on spontaneous nigral dopaminergic discharge in rats treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the low-to-middle dose range (0.01-1 mg/kg), intravenous administration of MPTP induced a transient and potent increase in the firing rate. TIQ (0.01-30 mg/kg) had no effects, and 1-MeTIQ and 1-BnTIQ (0.01-10 mg/kg) produced a weaker increase in the firing frequency immediately after intravenous administration. Pretreatment with 1-MeTIQ (80 mg/kg, i.p.) significantly inhibited the decrease in dopaminergic spontaneous firing induced by a high dose of MPTP. The nigral induction of thiobarbituric acid-reactive substances (TBARS) by MPTP was also significantly suppressed by pretreatment with 1-MeTIQ. These results suggest that the neurotoxicity induced by TIQ derivatives is relatively weak compared to that induced by MPTP. The neuroprotective effect of 1-MeTIQ from MPTP-induced toxicity may be partially due to a decrease in free radicals, as suggested by a decrease in TBARS. This action presumably prevents cell membrane degeneration.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Dopaminérgicos/farmacologia , Neurônios/efeitos dos fármacos , Neurotoxinas/farmacologia , Substância Negra/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Animais , Dopamina/fisiologia , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Ratos Sprague-Dawley , Substância Negra/metabolismo , Substância Negra/fisiologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
12.
Drug Chem Toxicol ; 38(2): 167-73, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24896366

RESUMO

An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10-50 mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72 hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60 min was recorded and summed. We found that at 24 hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.


Assuntos
Histamina/metabolismo , Morfina/administração & dosagem , Prurido/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Analgésicos Opioides/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Relação Dose-Resposta a Droga , Histamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Tempo
13.
Biol Pharm Bull ; 38(1): 134-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25342005

RESUMO

Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate). In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway.


Assuntos
Dopamina/metabolismo , Alucinógenos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Psilocibina/análogos & derivados , Serotonina/metabolismo , Animais , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Psilocibina/farmacologia , Ratos Wistar , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
14.
Neurol Sci ; 35(2): 205-13, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23820959

RESUMO

Guillain-Barré syndrome, which is a variant of acute inflammatory neuropathy, is associated with anti-GM1 antibodies and causes ataxia. We investigated the effects of IgG anti-GM1 monoclonal antibody (IgG anti-GM1 mAb) on spontaneous muscle action potentials in a rat spinal cord-muscle co-culture system and the localization of IgG anti-GM1 mAb binding in the rat hemi-diaphragm. The frequency of spontaneous muscle action potentials in innervated muscle cells was acutely inhibited by IgG anti-GM1 mAb. When cultures were pretreated with GM2 synthase antisense oligodeoxynucleotide, IgG anti-GM1 mAb failed to inhibit spontaneous muscle action potentials, demonstrating the importance of the GM1 epitope in the action of IgG anti-GM1 mAb. Immunohistochemistry of rat hemi-diaphragm showed that IgG anti-GM1 mAb binding overlapped with neurofilament 200 (NF200) antibodies staining, but not α-bungarotoxin (α-BuTx) staining, demonstrating that IgG anti-GM1 mAb was localized at the presynaptic nerve terminal. IgG anti-GM1 mAb binding overlapped with syntaxin antibody and S-100 antibody in the nerve terminal. After collagenase treatment, IgG anti-GM1 mAb and NF200 antibodies did not show staining, but α-BuTx selectively stained the hemi-diaphragm. IgG anti-GM1 mAb binds to the presynaptic nerve terminal of neuromuscular junctions. Therefore, we suggest that the inhibitory effect of IgG anti-GM1 mAb on spontaneous muscle action potentials is related to the GM1 epitope in presynaptic motor nerve terminals at the NMJs.


Assuntos
Potenciais de Ação , Anticorpos Monoclonais/imunologia , Autoanticorpos/imunologia , Gangliosídeo G(M1)/imunologia , Imunoglobulina G/imunologia , Junção Neuromuscular/fisiologia , Animais , Células Cultivadas , Colagenases/metabolismo , Diafragma/efeitos dos fármacos , Diafragma/fisiologia , Técnicas In Vitro , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Proteínas de Neurofilamentos/metabolismo , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Terminações Pré-Sinápticas/fisiologia , Proteínas Qa-SNARE/metabolismo , Ratos , Ratos Wistar , Proteínas S100/metabolismo , Medula Espinal/fisiologia
15.
Pain ; 154(6): 882-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23602343

RESUMO

Peripheral neuropathy is a common adverse effect of paclitaxel treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of paclitaxel-induced thermal hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after paclitaxel treatment. Behavioral assessment using the tail-flick test showed that intraperitoneal administration of 2 and 4 mg/kg paclitaxel induced thermal hyperalgesia after days 7, 14, and 21. Paclitaxel-induced thermal hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Paclitaxel (2 and 4 mg/kg) treatment increased the expression of TRPV1 mRNA and protein in DRG neurons. Immunohistochemistry showed that paclitaxel (4 mg/kg) treatment increased TRPV1 protein expression in small and medium DRG neurons 14 days after treatment. Antibody double labeling revealed that isolectin B4-positive small DRG neurons co-expressed TRPV1. TRPV1 immunostaining was up-regulated in paw skin day 14 after paclitaxel treatment. Moreover, in situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small or medium in size. These results suggest that paclitaxel treatment increases TRPV1 expression in DRG neurons and may contribute to functional peripheral neuropathic pain.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/metabolismo , Paclitaxel/farmacologia , Canais de Cátion TRPV/metabolismo , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Rutênio Vermelho/farmacologia , Canais de Cátion TRPV/genética
16.
Neurol Sci ; 34(10): 1735-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23389808

RESUMO

About 85 % of patients with generalized myasthenia gravis (MG) have anti-nicotinic acetylcholine receptor (nAChR) antibodies in their sera (seropositive MG; SPMG). The other 15 % (seronegative MG; SNMG) are also considered to have antibody-mediated disease, but the nature of the antibodies in SNMG is not fully understood. We investigated the effect of sera from patients with MG on spontaneous muscle action potentials and acetylcholine (ACh)-induced potentials, and we examined the localization of epitopes recognized by SPMG sera or SNMG sera. SPMG sera and SNMG sera inhibited spontaneous muscle action potentials and ACh-induced potentials in the spinal-muscle co-culture system. However, spontaneous muscle action potentials and ACh-induced potentials in the neuromuscular junctions were strongly blocked by SPMG serum, whereas they were weakly blocked by SNMG serum. Both types of sera reacted strongly with the neuromuscular junctions in normal rat muscles, as shown by double immunostaining with serum and α-bungarotoxin. The SPMG epitope remained in the neuromuscular junctions, whereas that of SNMG disappeared after denervation of the sciatic nerve. Therefore, we suggest that the skeletal muscle weakness in SNMG may be due to an interaction with presynaptic neuromuscular transmission and nAChR.


Assuntos
Miastenia Gravis/sangue , Junção Neuromuscular/efeitos dos fármacos , Acetilcolina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Adulto , Idoso , Animais , Anticorpos/farmacologia , Bungarotoxinas/imunologia , Agonistas Colinérgicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Miastenia Gravis/imunologia , Junção Neuromuscular/imunologia , Ratos , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Medula Espinal/citologia , Adulto Jovem
17.
Pharmacol Rep ; 65(5): 1204-12, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24399716

RESUMO

BACKGROUND: Selegiline, a therapeutic drug for Parkinson's disease (PD), structurally resembles the endogenous parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline (TIQ). In the present study, we evaluated the effects of 3-methyl-TIQ (3-MeTIQ) and 3-methyl-N-propargyl-TIQ (3-Me-N-proTIQ), selegiline mimetic TIQ derivatives, for preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism-like symptoms in mice. METHODS: We evaluated the preventative effects of 3-MeTIQ and 3-Me-N-proTIQ on MPTP-induced bradykinesia and depletion of striatal dopamine (DA) and nigral tyrosine hydroxylase (TH)-positive cells. RESULTS: MPTP-induced bradykinesia was not different when mice were pretreated with 3-MeTIQ, except for the high-dose group. However, pretreatment with 3-Me-N-proTIQ significantly prevented the appearance of this akinesic status. MPTP-induced striatal DA and 3,4-dehydroxyphenylacetic acid reduction were significantly prevented by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ, in a dose-dependent manner. On the other hand, levels of serotonin and its metabolite, 5-hydroxyindole acetic acid, in the striatum were increased following treatment with 3-MeTIQ. In addition, the MPTP-induced decrease in TH-positive cells in the substantia nigra was significantly reduced by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ. CONCLUSIONS: These results suggest that not only does 3-Me-N-proTIQ have potential as a candidate compound for disease-modifying therapy for PD, but also the N-propargyl functional group plays an important role in neuroprotection.


Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Hidroxi-Indolacético/metabolismo , Hipocinesia/metabolismo , Hipocinesia/prevenção & controle , Hipocinesia/psicologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Muscle Nerve ; 46(5): 705-10, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23055311

RESUMO

INTRODUCTION: We investigated the localization of a ganglioside, N-acetylgalactosaminyl GD1a (GalNAc-GD1a), in peripheral nerves with an IgG anti-GalNAc-GD1a antibody, which was produced in rabbits immunized with GalNAc-GD1a. METHODS: Teased fibers from ventral and dorsal roots and hemidiaphragm sections of rats were assessed using fluorescent double- and triple-labeling methods. RESULTS: The nodal and paranodal regions of teased fibers from ventral roots were immunostained with IgG anti-GalNAc-GD1a antibodies. After collagenase treatment, no staining was seen with IgG anti-GalNAc-GD1a or anti-NF200 antibodies, whereas α-bungarotoxin selectively stained nerve terminals. In cross-sectional and longitudinal sections of rat hemidiaphragm, IgG anti-GalNAc-GD1a antibodies overlapped with α-BuTx and anti-NF200 antibodies, indicating that GalNAc-GD1a is localized to the nerve terminal. IgG anti-GalNAc-GD1a antibody staining also overlapped with that of AChR clusters and syntaxin-positive presynaptic nerve terminals. CONCLUSION: GalNAc-GD1 is localized in both pre- and postsynaptic nerve terminals of neuromuscular junctions.


Assuntos
Sítios de Ligação de Anticorpos , Diafragma/metabolismo , Gangliosídeos/imunologia , Gangliosídeos/metabolismo , Imunoglobulina G/metabolismo , Junção Neuromuscular/metabolismo , Animais , Diafragma/química , Diafragma/imunologia , Feminino , Junção Neuromuscular/química , Junção Neuromuscular/imunologia , Ligação Proteica/imunologia , Coelhos , Ratos , Ratos Wistar
19.
J Pharmacol Sci ; 120(3): 187-95, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23090716

RESUMO

Peripheral neuropathic pain is a serious side effect of paclitaxel treatment. However, the mechanism of this paclitaxel-induced neuropathic pain is unknown. In this study, we investigated the effects of paclitaxel on the voltage-dependent calcium channel (VDCC) current in rat dorsal root ganglion (DRG) neurons using the whole-cell patch clamp technique. Behavioral assessment using von Frey filament stimuli showed that 2 and 4 mg/kg paclitaxel treatment induced mechanical allodynia/hyperalgesia. Paclitaxel-induced mechanical hyperalgesia was significantly inhibited by gabapentin (100 mg/kg). Using the patch clamp method, we observed that paclitaxel (4 mg/kg) treatment significantly increased the VDCC current in small- and medium-diameter DRG neurons. Moreover, paclitaxel-induced increase in the VDCC current in medium-diameter DRG neurons was completely inhibited by 10 and 100 µM gabapentin. Similar effects in small-diameter DRG neurons were only seen with 100 µM gabapentin. Western blotting revealed that paclitaxel increased protein levels of the VDCC subunit α2δ-1 (Ca(v)α2δ-1) in DRG neurons. Immunohistochemistry showed that paclitaxel treatment increased Ca(v)α2δ-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca(v)α2δ-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Gânglios Espinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Paclitaxel/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Agonistas dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L , Tamanho Celular , Células Cultivadas , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Paclitaxel/efeitos adversos , Ratos , Ratos Wistar
20.
Biol Pharm Bull ; 35(1): 127-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22223349

RESUMO

Cardanol (ginkgol) extracted from Ginkgo biloba leaves and cashew nutshell liquid enhances the growth of NSC-34 immortalized motor neuron-like cells and, when chronically administered to young rats, improves working memory-related learning ability as assessed by eight-arm radial maze tasks. These findings suggest that cardanol is one of the components in Ginkgo biloba leaves that improves cognitive learning ability.


Assuntos
Anacardium/química , Ginkgo biloba/química , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Memória de Curto Prazo/efeitos dos fármacos , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Animais , Masculino , Nozes , Fenóis/administração & dosagem , Fenóis/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos , Ratos Wistar
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