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1.
Braz J Med Biol Res ; 53(11): e10263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32965323

RESUMO

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.


Assuntos
Doenças do Sistema Nervoso Periférico , Amifostina/uso terapêutico , Animais , Antineoplásicos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle
2.
PLoS One ; 15(7): e0236115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697811

RESUMO

BACKGROUND: Anti-GD2 therapy with dinutuximab is effective in improving the survival of high-risk neuroblastoma patients in remission and after relapse. However, allodynia is the major dose-limiting side effect, hindering its use for neuroblastoma patients at higher doses and for other GD2-expressing malignancies. As polyamines can enhance neuronal sensitization, including development of allodynia and other forms of pathological pain, we hypothesized that polyamine depletion might prove an effective strategy for relief of anti-GD2 induced allodynia. METHOD: Sprague-Dawley rats were allowed to drink water containing various concentrations of difluoromethylornithine (DFMO) for several days prior to behavioral testing. Anti-GD2 (14G2a) was injected into the tail vein of lightly sedated animals and basal mechanical hindpaw withdrawal threshold assessed by von Frey filaments. Endpoint serum DFMO and polyamines, assessed 24h after 14G2a injection, were measured by HPLC and mass spectrometry. RESULTS: An i.v. injection of 14G2a causes increased paw sensitivity to light touch in this model, a response that closely mimics patient allodynia. Animals allowed to drink water containing 1% DFMO exhibited a significant reduction of 14G2a-induced pain sensitivity (allodynia). Increasing the dosage of the immunotherapeutic increased the magnitude (intensity and duration) of the pain behavior. Administration of DFMO attenuated the enhanced sensitivity. Consistent with the known actions of DFMO on ornithine decarboxylase (ODC), serum putrescene and spermidine levels were significantly reduced by DFMO, though the decrease in endpoint polyamine levels did not directly correlate with the behavioral changes. CONCLUSIONS: Our results demonstrate that DFMO is an effective agent for reducing anti-GD2 -induced allodynia. Using DFMO in conjunction with dinutuximab may allow for dose escalation in neuroblastoma patients. The reduction in pain may be sufficient to allow new patient populations to utilize this therapy given the more acceptable side effect profile. Thus, DFMO may be an important adjunct to anti-GD2 immunotherapy in addition to a role as a potential anti-cancer therapeutic.


Assuntos
Anticorpos Monoclonais/toxicidade , Antineoplásicos/toxicidade , Eflornitina/farmacologia , Gangliosídeos/imunologia , Hiperalgesia/tratamento farmacológico , Inibidores da Ornitina Descarboxilase/farmacologia , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Masculino , Poliaminas/sangue , Ratos , Ratos Sprague-Dawley
3.
Psychopharmacology (Berl) ; 237(7): 2139-2149, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388618

RESUMO

BACKGROUND: HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation. METHODS: We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund's Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia. RESULTS: Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation. CONCLUSIONS: Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Medição da Dor/efeitos dos fármacos , Animais , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/métodos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
4.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
5.
Life Sci ; 254: 117777, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407839

RESUMO

AIM: Inflammatory cascade and oxidative stress play a central role in diabetic peripheral neuropathy via activation of inflammatory cytokines. Escin has potent antioxidant and anti-inflammatory properties. Hence, the present study was conducted to evaluate the effect of escin on diabetic peripheral neuropathy in streptozotocin (STZ) induced diabetes in rats. MAIN METHODS: Diabetes was induced in rats with streptozotocin (55 mg/kg). The animals with blood glucose above 250 mg/dl were randomized in different groups. Animals were treated with escin at a dose of 5, 10 and 20 mg/kg after six weeks of diabetes induction for the next four weeks. After completion of treatment, various parameters like glucose, thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocities were evaluated. Oxidative stress parameters like malondialdehyde, catalase, reduced glutathione and superoxide dismutase were performed in sciatic nerves. Histopathology study of sciatic nerves was also studied. KEY FINDINGS: Escin treatment significantly reduced plasma glucose, thermal hyperalgesia, mechanical hyperalgesia and mechanical allodynia as compared to diabetic animals. The motor nerve conduction velocity and sensory nerve conduction velocities were significantly improved in diabetic animals treated with escin. Escin significantly normalized oxidative stress parameters. Escin treatment also prevented progression of neuronal damage by reducing demyelination, leukocytic infiltration in sciatic nerves as compared to diabetic animals. SIGNIFICANCE: From the results of study it can be concluded that escin can be a useful option for management of diabetic peripheral neuropathy.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Escina/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Escina/metabolismo , Hiperalgesia/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo
6.
An Acad Bras Cienc ; 92(1): e20180793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401835

RESUMO

The therapeutic effects from Citrus reticulata on painful inflammatory ailments are associated to its flavonoids constituent and phytochemical studies with Citrus genus affirm that the peels have important amounts of it. These bioactive compounds have been a considerable therapeutic source and evaluate potential application of the peel extract is significant. This research aims to investigate the influence of ethanolic crude extract from the peels of Citrus reticulata and its possible mechanism of action in different animal models of pain. The extract reduced hyperalgesia in the second phase of formalin test (vehicle: 501.5 ± 40.0 s; C. reticulata extract 300 mg/kg: 161.8 ± 41.1 s), in the carrageenan model (vehicle at 4th h: 82.5 ± 9.6 %; C. reticulata extract 300 mg/kg at 4th h: 47.5 ± 6.5 %) and in Complete Freund's Adjuvant model (vehicle: 501.5 ± 40.0 s; C. reticulata extract 300 mg/kg: 161.8 ± 41.1 s). The possible contribution of opioidergic and adenosinergic systems in the anti-hyperalgesic effect of C. reticulata extract was observed after treatment, with non-selective antagonists for both systems, which produced reversal effects. In conclusion, these properties of C. reticulata extract suggest a potential therapeutic benefit in treating painful conditions.


Assuntos
Analgésicos/farmacologia , Citrus/química , Hiperalgesia/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Avaliação Pré-Clínica de Medicamentos , Etanol , Masculino , Camundongos , Medição da Dor , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico
7.
Sci Rep ; 10(1): 6569, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300146

RESUMO

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aß fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.


Assuntos
Síndrome de Ehlers-Danlos/complicações , Hiperalgesia/complicações , Tenascina/deficiência , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Formaldeído , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Dor/complicações , Dor/patologia , Dor/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologia , Tenascina/genética , Tenascina/metabolismo
8.
Biochem Pharmacol ; 175: 113903, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156658

RESUMO

As recently described, the administration of extremely low doses (pg/kg) of CCL4 (Macrophage inflammatory protein 1ß, MIP-1ß) can induce antinociceptive effects in mice (García-Domínguez et al., 2019b). We describe here that hydrodynamic delivery of a plasmid containing CCL4 cDNA provokes a biphasic response consisting in an initial thermal hyperalgesic reaction for 8 days followed by analgesia at days 10-12, being both responses blocked after the administration of the CCR5 antagonist DAPTA. Both the luminiscence evoked in liver after the administration of a plasmid containing CCL4 and luciferase cDNAs and the hepatic concentration of CCL4 measured by ELISA were maximal 4 days after plasmid administration and markedly diminished at day 10. A dose-effect curve including a wide dose range of exogenous CCL4 revealed thermal analgesia after the administration of 10-100 pg/kg whereas 1000 times higher doses (30-100 ng/kg) induced, instead, thermal hyperalgesia inhibited by DAPTA. This hyperalgesia was absent in mice with reduced white blood cells after cyclophosphamide treatment, thus supporting the involvement of circulating leukocytes. A multiarray bioluminescent assay revealed increased plasma levels of IL-1α, CCL2, CXCL1, CXCL13, IL-16 and TIMP-1 in mice treated with 100 ng/kg of CCL4. The hyperalgesic response evoked by CCL4 was prevented by IL-1R, CXCR2 or CCR2 antagonists or by the neutralization of CXCL13 or IL-16, but not TIMP-1, with selective antibodies. The administration of the anti-IL-16 antibody was the unique treatment able to convert hyperalgesia evoked by 100 ng/kg of CCL4 in an analgesic effect. The ability of IL-16 to evoke hypernociception was confirmed by studying the response to its exogenous administration (10-30 ng/kg). In summary, the present results demonstrate that CCL4 induces a dual modulation of nociception and describe some mechanisms involved in the hyperalgesic response evoked by this chemokine.


Assuntos
Quimiocina CCL4/administração & dosagem , Técnicas de Transferência de Genes , Temperatura Alta/efeitos adversos , Hiperalgesia/tratamento farmacológico , Nociceptividade/fisiologia , Animais , Quimiocina CCL4/genética , Relação Dose-Resposta a Droga , Hiperalgesia/genética , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos
9.
Pharmacol Rep ; 72(2): 305-313, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112363

RESUMO

BACKGROUND: Chronic use of morphine treatment for neuropathic pain leads to morphine-induced analgesic tolerance. Crocin contained in Crocus sativus L., exerts anti-inflammatory and analgesic effects. This study examined the effects of crocin on morphine tolerance and serum BDNF levels on neuropathic pain induced by chronic constriction injury (CCI) in rats. METHODS: CCI model of neuropathic pain was done in male Wistar rats (200-250 g). Rats were treated with crocin (15 or 30 mg/kg, intraperitoneally) alone or simultaneously with morphine (10 mg/kg, subcutaneously) during or after induction of CCI. Pain behavioral responses including mechanical allodynia and thermal hyperalgesia were measured from days of 15-27 after CCI. Then, rats were evaluated for serum BDNF levels on days 14 and/or 27. RESULTS: We found that morphine tolerance developed after the induction of neuropathic pain. The injection of crocin (15 and 30 mg/kg) was able to enhance analgesic effect of morphine by reduction of mechanical allodynia on days 15-27 post-surgery in CCI rats. While preemptive administration of crocin at a lower dose (15 mg/kg) maintained the analgesic effect of morphine. Morphine injection and/or co-administration with crocin (15, 30 mg/kg) decreased serum BDNF levels in CCI rats. CONCLUSION: These findings indicate that crocin may have a therapeutic effect to maintain morphine analgesic efficacy and also to prevent the development of morphine tolerance in neuropathic pain, but probably not through BDNF.


Assuntos
Analgésicos Opioides/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/sangue , Carotenoides/uso terapêutico , Tolerância a Medicamentos , Morfina/uso terapêutico , Neuralgia/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Animais , Carotenoides/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Masculino , Morfina/administração & dosagem , Neuralgia/sangue , Limiar da Dor/efeitos dos fármacos , Ratos Wistar
10.
J Anesth ; 34(3): 373-381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32189128

RESUMO

PURPOSE: Antiepileptic drugs are used not only for the treatment of epilepsy but also for that of neuropathic pain. However, their action mechanisms have not always been well explained. Stiripentol, an effective antiepileptic drug indicated as a therapeutic for Dravet syndrome, was recently shown to act as an inhibitor of lactate dehydrogenase in astrocytes. In this present study, we examined the effect of stiripentol on neuropathic pain in L5 spinal nerve-transected mice. METHODS: We carried out behavioral tests using calibrated von Frey filaments and the immunohistochemistry of glial fibrillary acidic protein, an astrocyte marker, in L5 spinal nerve-transected mice after intrathecal administration of drugs. RESULTS: Like other anticonvulsants such as gabapentin and carbamazepine, stiripentol alleviated mechanical hyperalgesia induced by L5 spinal nerve transection in a dose-dependent manner, when intrathecally administered to mice 7, 14, and 28 days after L5 spinal nerve transection. Likewise, α-cyano-4-hydroxycinnamic acid, a broad inhibitor of monocarboxylate transporters, diminished mechanical hyperalgesia induced by L5 spinal nerve transection. Simultaneous administration of L-lactate negated the analgesic effect elicited by stiripentol, carbamazepine or α-cyano-4-hydroxycinnamic acid, but not that by gabapentin. None of the anticonvulsants affected the immunoreactivity of glial fibrillary acidic protein. CONCLUSIONS: This present study demonstrated that stiripentol was effective against neuropathic pain and suggested that the astrocyte-neuron lactate shuttle was involved in such pain.


Assuntos
Neuralgia , Nervos Espinhais , Animais , Dioxolanos , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Camundongos , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Medula Espinal
11.
BMC Complement Med Ther ; 20(1): 83, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171311

RESUMO

BACKGROUND: Recent studies pointed up that curcumin produces an anti-nociceptive effect in inflammatory and neuropathic pain. However, the possible mechanisms of action that underline the anti-allodynic effect induced by curcumin are not yet established. The purpose of this study was to determine the possible anti-allodynic effect of curcumin in rats with L5-L6 spinal nerve ligation (SNL). Furthermore, we study the possible participation of the NO-cyclic GMP-ATP-sensitive K+ channels pathway in the anti-allodynic effect induced by curcumin. METHODS: Tactile allodynia was measured using von Frey filaments by the up-down method in female Wistar rats subjected to SNL model of neuropathic pain. RESULTS: Intrathecal and oral administration of curcumin prevented, in a dose-dependent fashion, SNL-induced tactile allodynia. The anti-allodynic effect induced by curcumin was prevented by the intrathecal administration of L-NAME (100 µg/rat, a non-selective nitric oxide synthase inhibitor), ODQ (10 µg/rat, an inhibitor of guanylate-cyclase), and glibenclamide (50 µg/rat, channel blocker of ATP-sensitive K+ channels). CONCLUSIONS: These data suggest that the anti-allodynic effect induced by curcumin is mediated, at least in part, by the NO-cyclic GMP-ATP-sensitive K+ channels pathway in the SNL model of neuropathic pain in rats.


Assuntos
Analgésicos/farmacologia , Curcumina/farmacologia , GMP Cíclico/metabolismo , Hiperalgesia/tratamento farmacológico , Canais KATP/metabolismo , Óxido Nítrico/metabolismo , Animais , Feminino , Ratos , Ratos Wistar
12.
Eur J Pharmacol ; 872: 172972, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32006559

RESUMO

Cisplatin is used as a first line therapy in treating cancers. However, its use is often accompanied with the development of peripheral neuropathy. 6-Methoxyflavanone (6-MeOF) is a positive allosteric modulator at GABAA receptors and is known for attenuating diabetes-induced neuropathic pain. Neuropathy was induced in male Sprague-Dawley rats (150-250 g), via intraperitoneal injection of cisplatin (3 mg/kg) once a week for four consecutive weeks. 6-MeOF (25, 50 and 75 mg/kg, i.p) and gabapentin (75 mg/kg, i.p) were administered 30 min before each cisplatin injection. Static and dynamic allodynia were assessed using von Frey filaments and cotton buds. The anti-inflammatory activity was analyzed with plethysmometer. Body weights were also measured each week. The binding affinity of 6-MeOF with chloride channel, Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) was studied using docking approach. The in vitro COX-1 and COX-2 inhibitory effect of 6-MeOF was conducted with COX colorimetric assay. Administration of cisplatin for four consecutive weeks induced static (decreased paw withdrawal threshold; PWT) and dynamic allodynia (decreased paw withdrawal latency; PWL). Co-administration of 6-MeOF for four weeks significantly attenuated the cisplatin-induced expression of nocifensive behaviors observed as significant increase in PWT and PWL. Moreover, it also prevented the body weight loss induced by cisplatin administration. In silico studies depicted a good interaction of 6-MeOF with chloride ion channels and COX-1 and COX-2 enzymes. The in vitro study confirmed the inhibitory activity of 6-MeOF for COX-1 and COX-2. 6-MeOF may be effective in attenuating cisplatin-induced allodynia, probably through interaction with GABAergic receptors and reducing inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Cisplatino/efeitos adversos , Flavanonas/farmacologia , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptores de GABA-A/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/imunologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Flavanonas/química , Flavanonas/uso terapêutico , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico , Hiperalgesia/imunologia , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/imunologia , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/diagnóstico , Neuralgia/imunologia , Ratos , Receptores de GABA-A/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
13.
Pharmacol Rep ; 72(1): 96-103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016857

RESUMO

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 & dosagem
14.
Anesthesiology ; 132(4): 867-880, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32011337

RESUMO

BACKGROUND: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. METHODS: In male Wistar rats (n = 5 to 8 per group) with Freund's complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. RESULTS: In rats with Freund's complete adjuvant-induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). CONCLUSIONS: Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors.


Assuntos
Citocromo P-450 CYP11B2/biossíntese , Hiperalgesia/metabolismo , Medição da Dor/métodos , Células Receptoras Sensoriais/metabolismo , Adjuvantes Imunológicos/toxicidade , Aldosterona/biossíntese , Animais , Adjuvante de Freund/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Medição da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Wistar , Células Receptoras Sensoriais/efeitos dos fármacos
15.
Molecules ; 25(2)2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968549

RESUMO

Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2-/-) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2-/- mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.


Assuntos
Lesões da Córnea/tratamento farmacológico , Dronabinol/análogos & derivados , Hiperalgesia/tratamento farmacológico , Indóis/administração & dosagem , Inflamação/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Cauterização , Lesões da Córnea/complicações , Lesões da Córnea/etiologia , Modelos Animais de Doenças , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Sinergismo Farmacológico , Técnicas de Inativação de Genes , Hiperalgesia/metabolismo , Indóis/farmacologia , Inflamação/etiologia , Inflamação/metabolismo , Ligantes , Camundongos , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/genética , Transdução de Sinais
16.
Psychopharmacology (Berl) ; 237(4): 1131-1145, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912189

RESUMO

RATIONALE: Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. OBJECTIVES: The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. METHODS: Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. RESULTS: Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. CONCLUSIONS: Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; ß2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Reboxetina/uso terapêutico , Receptores Opioides delta/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/induzido quimicamente , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/sangue , Neuralgia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Reboxetina/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Estreptozocina/toxicidade
17.
Immunology ; 159(4): 413-428, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31919846

RESUMO

A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up-regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin-1ß (IL-1ß), IL-6 and IL-18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.


Assuntos
Analgésicos/farmacologia , Buprenorfina/farmacologia , Hiperalgesia/tratamento farmacológico , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Receptores CCR1/imunologia , Xantenos/farmacologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Gânglios Espinais/fisiopatologia , Regulação da Expressão Gênica , Hiperalgesia/genética , Hiperalgesia/imunologia , Hiperalgesia/fisiopatologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Neuralgia/genética , Neuralgia/imunologia , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Peroxidase/genética , Peroxidase/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Ratos , Ratos Wistar , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/genética , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Transdução de Sinais
18.
BMC Vet Res ; 16(1): 13, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931804

RESUMO

BACKGROUND: Leishmaniasis is a emergent disease characterized by different clinical manifestations in both humans and dogs. Predominant clinical features of cutaneous leishmaniasis are ulcerative painless skin lesions. Several data reported that pain is associated with human and dog leishmaniasis, out with areas of painless ulcerative lesions per se. Actually, current medications used for leishmaniasis management are characterized by several side effects and, in addition, some cases of the disease are refractory to the treatment. On this background it is mandatory the identification of new and safe candidates for designing less toxic and low-cost remedies. Therefore, the search for new leishmanicidal compounds is indispensable. METHODS: In the present paper we investigated the effect of orally N-acetyl-L-cysteine (NAC) supplementation at dose of 200 mg/Kg for 10 weeks, in subcutaneous Leishmania (L). amazonensis infected BALB/c mice. And evaluating the effect of NAC on inflammatory response such as TNF-α, IL-6, IL-1ß levels, and on thermal and mechanical hyperalgesia. RESULTS: In the present paper we showed how NAC supplementation affected parameters of oxidative stress (GSH, MDA, SOD), inflammation such as cytokines levels (IL-1ß, IL-6, TNFα) and mast cell activation and consequently on induced pain, during leishmaniosis in BALB\c mice. CONCLUSIONS: The findings of our study provided the scientific data demonstrating that L. amazonensis infection induces inflammation and pain in BALB/c mice that are reversed by administration of NAC.


Assuntos
Acetilcisteína/farmacologia , Inflamação/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Animais , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/patologia , Masculino , Mastocitose/tratamento farmacológico , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos
19.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
20.
Phytomedicine ; 67: 153166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31955133

RESUMO

BACKGROUND: Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. PURPOSE: This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. RESULTS: Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1ß), inflammatory proteins (TNF-α, IL-1ß, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. CONCLUSION: Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1ß-dependent NF-κB activation.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Iridoides/farmacologia , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Células de Schwann/efeitos dos fármacos , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Dor Crônica/patologia , Constrição , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Interleucina-1beta/metabolismo , Masculino , Neuralgia/metabolismo , Neuralgia/patologia , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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