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1.
PLoS One ; 15(2): e0226289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32015563

RESUMO

Calcium binding proteins are expressed throughout the central and peripheral nervous system and disruption of their activity has major consequences in a wide array of cellular processes, including transmission of nociceptive signals that are processed at the level of the spinal cord. We previously reported that the calcium binding protein, hippocalcin-like 4 (Hpcal4), is heavily expressed in interneurons of the superficial dorsal horn, and that its expression is significantly downregulated in a TR4 mutant mouse model that exhibits major pain and itch deficits due to loss of a subpopulation of excitatory interneurons. That finding suggested that Hpcal4 may be a contributor to the behavioral phenotype of the TR4 mutant mouse. To address this question, here we investigated the behavioral consequences of global deletion of Hpcal4 in a battery of acute and persistent pain and itch tests. Unexpectedly, with the exception of a mild reduction in acute baseline thermal responses, Hpcal4-deficient mice exhibit no major deficits in pain or itch responses, under normal conditions or in the setting of tissue or nerve injury. Taken together, our results indicate that the neural calcium sensor Hpcal4 likely makes a limited contribution to pain and itch processing.


Assuntos
Neurocalcina/metabolismo , Dor/metabolismo , Prurido/metabolismo , Animais , Escala de Avaliação Comportamental , Comportamento Animal , Cloroquina/administração & dosagem , Cloroquina/farmacologia , Técnicas de Inativação de Genes , Histamina/administração & dosagem , Histamina/farmacologia , Temperatura Alta , Interneurônios/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurocalcina/genética , Prurido/induzido quimicamente , Nervo Isquiático/lesões , Corno Dorsal da Medula Espinal/metabolismo
2.
J Ethnopharmacol ; 248: 112277, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31606533

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Knee osteoarthritis (OA) cause pain and edema, as well as unbalance between the production of reactive oxygen species and antioxidant activity. These problems interfere with the articular function, leading to a significant loss of life quality. Sida tuberculata R.E.Fr. is an herbaceous plant belonging to the Malvaceae family found in southern Brazil. This plant has traditionally been consumed as an aqueous extract and popularly used in the treatment of many diseases, with antioxidant and antimicrobial activity, reducing pain and inflammation. AIM OF THE STUDY: To verify the effects of S. tuberculata extract obtained from leaves on oxidative, toxic and nociceptive parameters induced by knee OA in rats. MATERIALS AND METHODS: Aqueous extracts of S. tuberculata were evaluated under phytochemical analyses. Knee Osteoarthritis was induced in rats with monosodium iodoacetate (1.5 mg/50 µl) and treated with S. tuberculata extract. The animals were treated orally with 3 doses of S. tuberculata extract (STE): 1.5, 5 and 15 mg/ml, for 14 days. For biochemical analyses, the following tests were performed: lipid peroxidation, carbonylated protein content, superoxide dismutase activity, non-protein thiol levels and myeloperoxidase activity. For the evaluation of pain and edema we verify mechanical and thermal hyperalgesia, spontaneous pain observation and measurement of knee edema with a caliper. For histological evaluations, the animal knee joints were removed. For toxicity evaluation, the levels of aspartate aminotransferase, alanine aminotransferase and urea, as well as the relative weight of the organs were analyzed. RESULTS: The S. tuberculata phytochemical analyses showed the majority peak corresponding to 20-hydroxyecdysone (20HE). The plant extract decreased damages related to oxidative stress in the blood serum (lipid peroxidation and carbonyl content) Overall, the STE 5 mg Group presented the greater statistical significance, in the blood serum samples, in relation to the other groups, being the most relevant result. The S. tuberculata groups presented pain decrease, lower neutrophil activity in the knee, and increased blood serum activity. The animals of S. tuberculata groups showed a decrease in mechanical hyperalgesia. The animals treated also presented lower scores for spontaneous pain. It was observed that the dose of 5 mg presented, once again, more expressive results, since the animals of this group had a higher frequency (greater number of days) with significant decrease of pain. In the histological analysis, in the STE 5 mg group, the articular cartilage lesions were observed at an intermediate point between the damage found in the MIA and Diclofenac groups. Besides that, the STE did not show significant changes in oxidative stress damage in liver and kidney samples. Blood serum samples did not indicate significant differences in liver and renal function. As well as, there were no differences in mean relative body weights in relation to control groups (Salina and MIA). CONCLUSION: S. tuberculata reduced the damage due to oxidative stress and pain caused by knee osteoarthritis in rats. In addition, the extract presented no toxicity. Our results suggest that S. tuberculata seems to have a therapeutic potential in the osteoarthritis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Malvaceae , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Edema/patologia , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Estresse Oxidativo/efeitos dos fármacos , Dor/metabolismo , Peroxidase/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar , Superóxido Dismutase/metabolismo
3.
BMC Pharmacol Toxicol ; 20(1): 85, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856925

RESUMO

BACKGROUND: Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents. METHODS: KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models. RESULTS: KEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5-10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats. CONCLUSIONS: KEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.


Assuntos
Analgésicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Ketamina/análogos & derivados , Ketamina/farmacologia , Dor/tratamento farmacológico , Analgésicos/efeitos adversos , Animais , Ésteres/química , Feminino , Hipnóticos e Sedativos/efeitos adversos , Ketamina/efeitos adversos , Masculino , Dor/metabolismo , Dor/psicologia , Medição da Dor , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Reflexo de Endireitamento/efeitos dos fármacos
4.
Life Sci ; 239: 117083, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759043

RESUMO

AIMS: The present study aims to evaluate the analgesic effect of ginsenoside Rg3 in different mouse pain models. MAIN METHODS: Formalin-, carrageenan- and S180 tumor cells induced mouse pain models were built in the study. The licking and biting time and PEG2 contents in the inflammatory sites were measured. The excitatory and inhibitory amino acids in the brains were determined by pre-column derivation FLD-HPLC method. KEY FINDING: We have found that ginsenoside Rg3 treated the pain phases and decreased the PGE2 in formalin and carrageenan induced models, respectively. It significantly increased the contents of EAAs (Asp and Glu) in the brains of S180 tumor inducing pain mice, meanwhile, the IAAs (Gly, Tau and GABA) decreased. SIGNIFICANCE: Our results revealed that ginsenoside Rg3 acted central and peripheral analgesic effect and regulated the inflammatory factors and pain-related amino acids. It could re-balance the abnormal EAAs/IAAs value when the pain occurred. The analgesic mechanism and the clinical application of ginsenoside Rg3 need be evaluated furtherly.


Assuntos
Ginsenosídeos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Aminoácidos/uso terapêutico , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ginsenosídeos/metabolismo , Camundongos , Neovascularização Patológica/tratamento farmacológico
5.
Gen Physiol Biophys ; 38(5): 407-416, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31595882

RESUMO

The P2X7 receptor (P2X7R) plays an important role in inflammatory and neuropathic pain. Our recent study indicated that activation of P2X7R in microglial cells of spinal cord contributes to the inflammatory pain induced by BmK I, the major active compound from Buthus martensi Karsch (BmK). In the present study, we further investigated whether P2X7R in satellite glial cells (SGCs) of dorsal root ganglion (DRG) is involved in the BmK I-induced pain in rats. The results found that the expression of P2X7R in SGCs was increased in the ipsilateral side of L4-L5 DRGs after intraplantar injection of BmK I. Moreover, the expression of an inflammatory cytokine IL-1ß was increased in DRG after BmK I injection. Systemic administration of an inhibitor of P2X7R (A-438079) significantly inhibited both spontaneous and evoked nociceptive behaviors induced by BmK I. These results suggest that the P2X7R in SGCs of DRG might contribute to pain induced by toxins that sensitize peripheral sensory nerves.


Assuntos
Gânglios Espinais/patologia , Dor/induzido quimicamente , Dor/patologia , Receptores Purinérgicos P2X7/metabolismo , Células Satélites Perineuronais/metabolismo , Venenos de Escorpião , Animais , Dor/metabolismo , Ratos
6.
Life Sci ; 237: 116926, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31614148

RESUMO

Sex-related differences in pain and opioids has been the focus of many researches. It is demonstrated that women experience greater clinical pain, lower pain threshold and tolerance, more sensitivity and distress to experimentally induced pain compared to men. Sex differences in response to opioid treatment revealed inconsistent results. However, the etiology of these disparities is not fully elucidated. It is, therefore, conceivable now that this literature merits to be revisited comprehensively. Possible multifaceted factors seem to be associated. These include neuroanatomical, hormonal, neuroimmunological, psychological, social and cultural aspects and comorbidities. This review aims at providing an overview of the substantial literature documenting the sex differences in pain and analgesic response to opioids from animal and human studies within the context of the modulatory effects of the aforementioned factors. A detailed and critical discussion of the cellular and molecular signaling pathways underlying the modulatory actions of gonadal hormones in the sexual dimorphism in pain processing and opioid analgesia is extensively presented. It is indicated that sexual dimorphic activation of certain brain regions contributes to differential pain sensitivity between females and males. Plausible crosstalk between sex hormones and neuroimmunological signaling pertinent to toll-like and purinergic receptors is uncovered as causal cues underlying sexually dimorphic pain and opioid analgesia. Conceivably, a thorough understanding of these factors may aid in sex-related advancement in pain therapeutic management.


Assuntos
Analgésicos Opioides/administração & dosagem , Hormônios Gonadais/metabolismo , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Animais , Feminino , Humanos , Masculino , Nociceptividade/fisiologia , Dor/metabolismo , Caracteres Sexuais
7.
Life Sci ; 239: 116961, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654745

RESUMO

Neuropathic pain (NP) is a difficult condition to treat because of the modest efficacy of available drugs. New treatments are required. In the study we aimed to investigate the effects of the essential oil from Lippia grata alone or complexed in ß-cyclodextrin (LG or LG-ßCD) on persistent inflammatory and neuropathic pain in a mouse model. We also investigated Ca2+ currents in rat dorsal root ganglion (DRG) neurons. Male Swiss mice were treated with LG or LG/ß-CD (24 mg/kg, i.g.) and their effect was evaluated using an acute inflammatory pleurisy model and nociception triggered by intraplantar injection of an agonist of the TRPs channels. We also tested their effect in chronic pain models: injection of Freund's Complete Adjuvant and partial sciatic nerve ligation (PSNL). In the pleurisy model, LG reduced the number of leukocytes and the levels of TNF-α and IL-1ß. It also inhibited cinnamaldehyde and menthol-induced nociceptive behavior. The pain threshold in mechanical and thermal hyperalgesia was increased and paw edema was decreased in models of inflammatory and neuropathic pain. PSNL increased inflammatory protein contents and LG and LG-ßCD restored the protein contents of TNF-α, NF-κB, and PKA, but not IL-1ß and IL-10. LG inhibited voltage gated Ca2+ channels from DRG neurons. Our results suggested that LG or LG-ßCD produce anti-hyperalgesic effect in chronic pain models through reductions in TNF-α levels and PKA, and inhibited voltage-gated calcium channels and may be innovative therapeutic agents for the management of NP.


Assuntos
Hiperalgesia/tratamento farmacológico , Lippia/metabolismo , beta-Ciclodextrinas/farmacologia , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , beta-Ciclodextrinas/metabolismo
8.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510021

RESUMO

Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous system (ENS), located in the wall of the gastrointestinal (GI) tract. It regulates most of the functions of the stomach and intestine and it is characterized by complex organization and a high degree of independence from the central nervous system. SOM has been described in the ENS of numerous mammal species and its main functions in the GI tract are connected with the inhibition of the intestinal motility and secretory activity. Moreover, SOM participates in sensory and pain stimuli conduction, modulation of the release of other neuronal factors, and regulation of blood flow in the intestinal vessels. This peptide is also involved in the pathological processes in the GI tract and is known as an anti-inflammatory agent. This paper, which focuses primarily on the distribution of SOM in the ENS and extrinsic intestinal innervation in various mammalian species, is a review of studies concerning this issue published from 1973 to the present.


Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Entérico/metabolismo , Trato Gastrointestinal/metabolismo , Mamíferos/metabolismo , Somatostatina/metabolismo , Animais , Motilidade Gastrointestinal , Humanos , Dor/metabolismo , Dor/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia
9.
Eur J Med Chem ; 182: 111634, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472474

RESUMO

In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CHO , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Dor/metabolismo , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
10.
Nat Commun ; 10(1): 4140, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515501

RESUMO

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Neuropeptídeos/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Heroína/efeitos adversos , Histona Desacetilase 2/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Núcleo Accumbens/metabolismo , Alcaloides Opiáceos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor/metabolismo , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
11.
Int J Mol Sci ; 20(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31540178

RESUMO

Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.


Assuntos
Canais Iônicos/metabolismo , Dor/etiologia , Dor/metabolismo , Animais , Suscetibilidade a Doenças , Descoberta de Drogas , Humanos , Ativação do Canal Iônico , Canais Iônicos/química , Canais Iônicos/genética , Dor/tratamento farmacológico
13.
PLoS Biol ; 17(8): e3000205, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31404058

RESUMO

Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts and which activity is due to general aspects of sensory stimulation, such as its salience, or the accompanying arousal. The challenge posed by this question rests largely in the fact that pain per se exhibits highly intense but unspecific characteristics. These therefore should be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging (fMRI) and behavioral and autonomic measures to address this longstanding debate in pain research. Subjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in 6 different intensities, 3 of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses [SCRs]) did not differ between the 2 stimulus modalities. Having thus ascertained a comparable amount of stimulation-related but unspecific activation, we analyzed stimulus-response functions (SRFs) after painful stimulation and contrasted them with those of the matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and peri-insular regions that are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to nonpainful heat and, at the same time, showing a steeper SRF for painful heat compared to unpleasant sound. Intriguingly, an area in the posterior parietal operculum emerged, whose response showed a pain preference after satisfying all axiomatic constraints. This result has important implications for the interpretation of functional imaging findings in pain research, because it clearly demonstrates that there are areas where activity following painful stimulation is not due to general attributes or results of sensory stimulation, such as salience or arousal. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.


Assuntos
Limiar da Dor/fisiologia , Lobo Parietal/fisiologia , Lobo Temporal/fisiologia , Adulto , Percepção Auditiva/fisiologia , Encéfalo/fisiopatologia , Mapeamento Encefálico , Feminino , Temperatura Alta , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética/métodos , Masculino , Dor/metabolismo , Dor/fisiopatologia , Estimulação Física
14.
Chin J Nat Med ; 17(6): 413-423, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262454

RESUMO

Isoflavones are widely consumed by people around the world in the form of soy products, dietary supplements and drugs. Many isoflavones or related crude extracts have been reported to exert pain-relief activities, but the mechanism remains unclear. Voltage-gated sodium channels (VGSCs) play important roles in excitability of pain sensing neurons and many of them are important nociceptors. Here, we report that several isoflavones including 3'-methoxydaidzein (3MOD), genistein (GEN) and daidzein (DAI) show abilities to block VGSCs and thus to attenuate chemicals and heat induced acute pain or chronic constriction injury (CCI) induced pain hypersensitivity in mice. Especially, 3MOD shows strong analgesic potential without inducing addiction through inhibiting subtypes NaV1.7, NaV1.8 and NaV1.3 with the IC50 of 181 ± 14, 397 ± 26, and 505 ± 46 nmol·L-1, respectively, providing a promising compound or parent structure for the treatment of pain pathologies. This study reveals a pain-alleviating mechanism of dietary isoflavones and may provide a convenient avenue to alleviate pain.


Assuntos
Analgésicos/administração & dosagem , Isoflavonas/administração & dosagem , Dor/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Canais de Sódio Disparados por Voltagem/metabolismo , Analgésicos/química , Animais , Humanos , Isoflavonas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/genética , Dor/metabolismo , Canais de Sódio Disparados por Voltagem/genética
15.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336748

RESUMO

Receptor-type ion channels are critical for detection of noxious stimuli in primary sensory neurons. Transient receptor potential (TRP) channels mediate pain sensations and promote a variety of neuronal signals that elicit secondary neural functions (such as calcitonin gene-related peptide [CGRP] secretion), which are important for physiological functions throughout the body. In this review, we focus on the involvement of TRP channels in sensing acute pain, inflammatory pain, headache, migraine, pain due to fungal infections, and osteo-inflammation. Furthermore, action potentials mediated via interactions between TRP channels and the chloride channel, anoctamin 1 (ANO1), can also generate strong pain sensations in primary sensory neurons. Thus, we also discuss mechanisms that enhance neuronal excitation and are dependent on ANO1, and consider modulation of pain sensation from the perspective of both cation and anion dynamics.


Assuntos
Anoctamina-1/metabolismo , Proteínas de Neoplasias/metabolismo , Manejo da Dor , Dor/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo , Animais , Anoctamina-1/genética , Humanos , Canais Iônicos/metabolismo , Proteínas de Neoplasias/genética , Dor/etiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais , Canais de Receptores Transientes de Potencial/genética
16.
J Immunol ; 203(2): 485-492, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31152077

RESUMO

Osteoarthritis (OA) is a degenerative joint disease that causes chronic disability among the elderly. Despite recent advances in symptomatic management of OA by pharmacological and surgical approaches, there remains a lack of optimal approaches to manage inflammation in the joints, which causes cartilage degradation and pain. In this study, we investigated the efficacy and underlying mechanisms of nicotine exposure in attenuating joint inflammation, cartilage degradation, and pain in a mouse model of OA. A mouse model of OA was induced by injection of monosodium iodoacetate into the knee joint. Cell culture models were also used to study the efficacy and underlying mechanisms of nicotine treatment in attenuating symptoms of OA. Nicotine treatment reduced mechanical allodynia, cartilage degradation, and the upregulation of matrix metalloproteinase-9 (MMP-9), a hallmark of joint inflammation in OA, in mice treated with monosodium iodoacetate. The effects of nicotine were abolished by the selective α7 nicotinic acetylcholine receptor (nAChR) blocker, methyllycaconitine . In RAW264.7 cells and murine primary bone marrow-derived macrophages, nicotine significantly inhibited MMP-9 production induced by LPS. In addition, nicotine significantly enhanced PI3K/Akt and inhibited NF-κB translocation from the cytosol to the nucleus in an α7-nAChR-dependent manner, suggesting that nicotine acts on α7-nAChRs to inhibit MMP-9 production by macrophages through modulation of the PI3K/Akt-NF-κB pathway. Our results provide novel evidence that nicotine can attenuate joint inflammation and pain in experimental OA via α7-nAChRs. α7-nAChR could thus serve as a highly promising target to manage joint inflammation and pain in OA.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Nicotina/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Biochemistry (Mosc) ; 84(2): 101-118, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31216970

RESUMO

TRPA1 is a cation channel located on the plasma membrane of many types of human and animal cells, including skin sensory neurons and epithelial cells of the intestine, lungs, urinary bladder, etc. TRPA1 is the major chemosensor that also responds to thermal and mechanical stimuli. Substances that activate TRPA1, e.g., allyl isothiocyanates (pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, organosulfur compounds from garlic and onion, tear gas, acrolein and crotonaldehyde from cigarette smoke, etc., cause burning, mechanical and thermal hypersensitivity, cough, eye irritation, sneezing, mucus secretion, and neurogenic inflammation. An increased activity of TRPA1 leads to the emergence of chronic pruritus and allergic dermatitis and is associated with episodic pain syndrome, a hereditary disease characterized by episodes of debilitating pain triggered by stress. TRPA1 is now considered as one of the targets for developing new anti-inflammatory and analgesic drugs. This review summarizes information on the structure, function, and physiological role of this channel, as well as describes known TRPA1 ligands and their significance as therapeutic agents in the treatment of inflammation-associated pain.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inflamação Neurogênica/tratamento farmacológico , Dor/tratamento farmacológico , Canal de Cátion TRPA1/antagonistas & inibidores , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Humanos , Ligantes , Estrutura Molecular , Inflamação Neurogênica/metabolismo , Dor/metabolismo , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/metabolismo
18.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058210

RESUMO

The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.


Assuntos
Ansiedade/metabolismo , Neurônios Dopaminérgicos/metabolismo , Ácido Glutâmico/metabolismo , Dor/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Analgesia/métodos , Animais , Núcleo Dorsal da Rafe/metabolismo , Medo/fisiologia , Masculino , Camundongos Transgênicos
19.
Mar Drugs ; 17(5)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083641

RESUMO

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.


Assuntos
Analgésicos/farmacocinética , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Proteínas Recombinantes de Fusão/farmacocinética , ômega-Conotoxinas/farmacocinética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacocinética , Analgésicos/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Feminino , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Peptídeos/administração & dosagem , Peptídeos/química , Proteína FUS de Ligação a RNA , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/biossíntese , Tremor/tratamento farmacológico , Tremor/metabolismo , ômega-Conotoxinas/administração & dosagem , Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem
20.
Eur J Pharmacol ; 856: 172404, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31132352

RESUMO

The gasotransmitter hydrogen sulfide (H2S) is known to regulate many pathophysiological processes. Preclinical assays have demonstrated that H2S donors exhibit anti-inflammatory and antinociceptive activities, characterized by reduction of inflammatory mediators production, leukocytes recruitment, edema and mechanical allodynia. In the present study, the effects induced by 4-methylbenzenecarbothioamide (4-MBC) in models of pain and inflammation in mice, the mechanisms mediating such effects and the H2S-releasing property of this compound were evaluated. 4-MBC spontaneously released H2S in vitro in the absence of organic thiols. Intraperitoneal (i.p.) administration of 4-MBC (100 or 150 mg/kg) reduced the second phase of the nociceptive response induced by formaldehyde and induced a long lasting inhibitory effect on carrageenan mechanical allodynia. 4-MBC antiallodynic effect was not affected by previous administration of naltrexone or glibenclamide. 4-MBC (50, 100 or 150 mg/kg, i.p.) induced a long lasting inhibitory effect on paw edema induced by carrageenan. The highest dose (150 mg/kg, i.p.) of 4-MBC inhibited tumor necrosis factor-α and CXCL1 production and myeloperoxidase activity induced by carrageenan. Mechanical allodynia and paw edema induced by carrageenan were not inhibited by the 4-MBC oxo analogue (p-toluamide). In summary, 4-MBC, an H2S releasing thiobenzamide, exhibits antinociceptive and anti-inflammatory activities. These activities may be due to reduced cytokine and chemokine production and neutrophil recruitment. The H2S releasing property is likely essential for 4-MBC activity. Our results indicate that 4-MBC may represent a useful pharmacological tool to investigate the biological roles of H2S.


Assuntos
Amidas/farmacologia , Quimiocina CXCL1/biossíntese , Sulfeto de Hidrogênio/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Amidas/uso terapêutico , Animais , Modelos Animais de Doenças , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos
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