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1.
Life Sci ; 245: 117348, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981633

RESUMO

AIMS: Haloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N­(1­benzylpiperidin­4-yl)­4­fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain). MAIN METHODS: LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (1H and 13C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ1R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI. KEY FINDINGS: LMH-2 showed high affinity for σ1R in an in vitro binding assay, with a Ki = 6.0 nM and a high σ1R/σ2R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug. SIGNIFICANCE: LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ1R, suggesting its potential use as an analgesic drug for neuropathic pain.


Assuntos
Analgésicos/síntese química , Benzamidas/síntese química , Haloperidol/análogos & derivados , Nociceptividade/efeitos dos fármacos , Receptores sigma/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Benzamidas/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Wistar
2.
Food Chem Toxicol ; 135: 111053, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31857126

RESUMO

Chronic pain management has several adverse effects and research looking for new and effective pain management drugs posing lower undesirable effects is necessary. Given the above, the pharmacological investigation of medicinal plants significantly contributes to the dissemination of plant-derived therapeutics. The aim of this study was to evaluate the antinociceptive activity of the Psidium brownianum Mart ex DC. leaf essential oil (PBEO) and the participation of the opioid pathway in this effect in mice. Swiss Mus musculus male mice were tested using acute nociception models (acetic acid induced abdominal contortions, formalin, capsaicin and hot plate tests). The possible myorelaxant action of the PBEO was tested using the rotarod test. The essential oil reduced animal nociception in chemical and heat models, with this action being devoid of a myorelaxant effect. Naloxone (2 mg/kg, intraperitoneally - i.p.) partially antagonized the PBEO activity, possibly acting via opioid receptors. The results obtained provide evidence that the traditional Psidium brownianum use may be effective for pain treatment.


Assuntos
Analgésicos/farmacologia , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Psidium/química , Animais , Modelos Animais de Doenças , Dose Letal Mediana , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Teste de Desempenho do Rota-Rod
3.
J Ethnopharmacol ; 247: 112265, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31580941

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hymenaea cangaceira Pinto, Mansano & Azevedo (Fabaceae) is a Brazilian medicinal plant widely known as "Jatobá". In folk medicine, it is used to treat infections, respiratory problems, rheumatism, antitumoral, inflammation and pain, however, no activity has been scientifically validated. AIM OF THE STUDY: This study investigated chemical composition of essential oil from Hymenaea cangaceira (EOHc), antimicrobial, antinociceptive and antioxidant activities besides protection against DNA damage and hemolysis. MATERIAL AND METHODS: The essential oil was obtained by hydrodistillation, and characterized by GC-MS and GC-FID. The evaluation of antimicrobial activity was performed by microdilution method. The evaluation of the antioxidant activity was performed using the radicals DPPH, ABTS, O2- and OH-, and the protection of DNA damage using plasmid pBR322. Different experimental models were used to evaluate the antinociceptive effect (acetic acid and formalin), and evaluate the mechanisms of action involved with pharmacological antagonists (naloxone, atropine and gibenclamide) in mice. The essential oil was evaluated for hemolysis on human erythrocytes. RESULTS: The extraction of EOHc showed a yield of 0.18% on a dry basis, presenting high content of hydrocarbon sesquiterpenes (79.04%), high antioxidant activity and protect DNA from damage, besides presenting antifungal and antibacterial activity against Gram-positive and Gram-negative bacteria in vitro. It was found that the essential oil had no acute toxicity in mice up to 5000 mg/kg oral administration (o.a.), in addition to no hemolysis on human erythrocytes. The reduction of antinociceptive activity was 75%, with the opioid system as the mechanism of action. CONCLUSION: Our results validate the main activities by the traditional use attributed to H. cangaceira for antimicrobial and analgesic activity. In addition, the oil has a potent antioxidant activity, protecting the body against oxidative stress damage, adding new value to an endemic species not known to the industry.


Assuntos
Analgésicos/farmacologia , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Hymenaea/química , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Ácido Acético/toxicidade , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Brasil , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Etanol/química , Etnofarmacologia , Formaldeído/toxicidade , Humanos , Medicina Tradicional/métodos , Camundongos , Testes de Sensibilidade Microbiana , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/química , Óleos Voláteis/uso terapêutico , Dor/induzido quimicamente , Dor/diagnóstico , Dor/tratamento farmacológico , Medição da Dor , Óleos Vegetais/química , Óleos Vegetais/isolamento & purificação , Testes de Toxicidade Aguda
4.
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
5.
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
6.
Endocr Regul ; 53(1): 14-25, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517620

RESUMO

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Nitratos/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nitratos/uso terapêutico , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
7.
Funct Neurol ; 34(2): 119-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556392

RESUMO

We describe the case of a 68-year-old woman with an acute episode of severe low back pain (LBP) resistant to opioids, who had experienced a sacral insufficiency fracture (SIF) two years earlier. At clinical examination, patient reported constant, dull, non-localizable pain at lumbar and sacral level, exacerbated by paravertebral palpation, particularly at L4-L5 and the sacroiliac joint, with a concomitant and remittent neuropathic component, difficult to localize at lumbar and sacral level. The latest magnetic resonance imaging study revealed disc herniations at L3-L4, L4-L5, and L5-S1 levels. The patient was treated with intramuscularparavertebral injections of oxygen-ozone (O2O3) mixture for 4 weeks (once a week), using a O3 concentration of 20 mcg/mL (5 mL in L4-L5 zone and 5 mL in L5-S1 zone, bilaterally). At 1 week after the first injection, the pain (assessed by Numerical Pain Rating Scale and Brief Pain Inventory) was considerably reduced and the patient's health-related quality of life (assessed by Short Form 12-Item Health Survey and European Quality of Life Index) had improved; these findings were confirmed at follow-up 1 month after the last injection. This paradigmatic case of nociplastic pain successfully treated by paravertebral O2O3 therapy might be a starting point for further studies on the effects of this treatment in terms of decreasing pain and improving HRQoL in patients affected by opioid-resistant LBP.


Assuntos
Fraturas de Estresse/complicações , Dor Lombar/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Oxigênio/administração & dosagem , Ozônio/administração & dosagem , Idoso , Feminino , Humanos , Deslocamento do Disco Intervertebral/complicações , Dor Lombar/etiologia , Medição da Dor , Sacro/lesões , Resultado do Tratamento
8.
Rev Bras Anestesiol ; 69(4): 396-402, 2019.
Artigo em Português | MEDLINE | ID: mdl-31399197

RESUMO

BACKGROUND AND OBJECTIVES: Patient self-rating based scales such as Numerical Rating Scale, Visual Analog Scale that is used for postoperative pain assessment may be problematic in geriatric or critically ill patients with communication problems. A method capable of the assessment of pain in objective manner has been searched for years. Analgesia nociception index, which is based on electrocardiographic data reflecting parasympathetic activity, has been proposed for this. In this study we aimed to investigate the effectiveness of analgesia nociception index as a tool for acute postoperative pain assessment. Our hypothesis was that analgesia nociception index may have good correlation with Numerical Rating Scale values. METHODS: A total of 120 patients of American Society of Anesthesiologists (ASA) physical status I and II undergoing any surgical procedure under halogenated-based anesthesia with fentanyl or remifentanil were enrolled for the study. At the 15th minute of arrival to the Postoperative Care Unit the patients' pain was rated on a 0-10 point Numerical Rating Scale. The patients' heart rate, blood pressure, and analgesia nociception index scores were simultaneously measured at that time. The correlation between analgesia nociception index, heart rate, blood pressure and Numerical Rating Scale was examined. RESULTS: The study was completed with 107 patients, of which 46 were males (43%). Mean (SD) analgesia nociception index values were significantly higher in patients with initial Numerical Rating Scale ≤ 3, compared with Numerical Rating Scale> 3 (69.1 [13.4] vs. 58.1 [12.9] respectively, p <0.001). A significant negative linear relationship (r2=-0.312, p=0.001) was observed between analgesia nociception index and Numerical Rating Scale. CONCLUSION: Analgesia nociception index measurements at postoperative period after volatile agent and opioid-based anesthesia correlate well with subjective Numerical Rating Scale scores.


Assuntos
Dor Aguda/diagnóstico , Analgesia/métodos , Medição da Dor/métodos , Dor Pós-Operatória/diagnóstico , Dor Aguda/prevenção & controle , Adulto , Analgésicos Opioides/administração & dosagem , Feminino , Fentanila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Nociceptividade/efeitos dos fármacos , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Remifentanil/administração & dosagem , Adulto Jovem
9.
Chem Biol Interact ; 311: 108790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400342

RESUMO

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interferon gama/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/genética , Edema/tratamento farmacológico , Edema/patologia , Comportamento Exploratório/efeitos dos fármacos , Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Interferon gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Testes de Toxicidade Aguda , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
BMC Complement Altern Med ; 19(1): 214, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412852

RESUMO

BACKGROUND: The present study evaluated the antinociceptive effect of the bark of Artocarpus lacucha, which is used for the treatment of stomachache, headache and boils in the traditional system of medicine. METHODS: The antinociceptive activity was investigated by the tail immersion, hot plate, acetic acid- & formalin-induced nociception and carrageenan-induced paw edema tests using a hydro-methanolic extract of A. lacucha bark. The plant extract was found to contain a substantial amount of phenolic compounds according to the total phenolic and flavonoid content assay. A phenolic metabolite, (+)-catechin, has been isolated using different chromatographic techniques. The compound was characterized with 1D and 2D NMR spectroscopic data. (+)-catechin, isolated from A. lacucha was assessed for antinociceptive effects swiss albino mice. Furthermore, the possible involvement of opioid receptors and ATP-sensitive K+ channel for the effect of the plant extract and (+)-catechin has been justified using naloxone and glibenclamide, respectively. RESULTS: Oral administration (p.o) of the plant extract (50-200 mg/Kg b.w.) resulted in significant thermal pain protection in the hot plate and tail immersion tests. The action of the plant extract was significantly antagonized by naloxone, a non-selective opioid antagonist, in the hot plate and tail immersion tests, which supports the involvement of opioid receptors. Both the plant extract and (+)-catechin, (50-200 mg/Kg b.w., p.o.) significantly diminished the acetic acid- & formalin-induced nociception, and carrageenan-induced paw edema. Glibenclamide, an ATP-sensitive K+ channel blocker, significantly reversed their effect in the acetic acid-induced writhing test which indicates the participation of ATP-sensitive K+ channel system. CONCLUSIONS: The investigation revealed potential central and peripheral antinociceptive effects of A. lacucha bark supports its applications in the traditional system of medicine.


Assuntos
Analgésicos/administração & dosagem , Artocarpus/química , Catequina/administração & dosagem , Edema/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Carragenina/efeitos adversos , Catequina/análise , Catequina/isolamento & purificação , Edema/induzido quimicamente , Humanos , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Extratos Vegetais/química
11.
Anesth Analg ; 129(3): 890-895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31425234

RESUMO

BACKGROUND: As opioid abuse and addiction have developed into a major national health crisis, prescription of opioids for pain management has become more controversial. However, opioids do help some patients by providing pain relief and improving the quality of life. To better understand the addictive properties of opioids under chronic pain conditions, we used a conditioned place preference (CPP) paradigm to examine the rewarding properties of morphine in rats with persistent nociception. METHODS: Spared nerve injury (SNI) model was used to induce persistent nociception in rats. Nociceptive behavior was assessed by von Frey test. CPP test was used to examine the rewarding properties of morphine. RESULTS: Our findings are as follows: (1) SNI rats did not show a difference compared with sham rats in magnitude of morphine-induced CPP 1 day after last morphine injection (2-way analysis of variance; for SNI versus sham, F[1,42] = 0.014, P = .91; and 95% confidence intervals for difference of means, -5.9 [-58 to 46], 0.76 [-51 to 53], and 0.90 [-51 to 53] for 2.5, 5, and 10 mg/kg, respectively); (2) increasing morphine dosage (2.5, 5, and 10 mg/kg) did not further increase the magnitude of CPP in both sham and SNI rats (for dosage: F[2,42] = 0.94, P = .40); and (3) morphine-induced CPP persisted in sham rats but extinguished in SNI rats when tested at 8 days after last morphine injection (for sham versus SNI: Bonferroni correction, P < .006 for both 5 and 10 mg/kg doses; and 95% confidence intervals for difference of means, 80.3 [19.7-141] and 87.0 [26.3-148] for 5 and 10 mg/kg, respectively). CONCLUSIONS: Our data provide new evidence supporting the notion that the brain's reward circuitry changes in the context of persistent pain. This observational study suggests that future investigation into the neurobiology of opioid reward requires consideration of the circumstances in which opioid analgesics are administered.


Assuntos
Analgésicos Opioides/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Morfina/administração & dosagem , Nociceptividade/efeitos dos fármacos , Animais , Condicionamento Operante/fisiologia , Masculino , Nociceptividade/fisiologia , Ratos , Ratos Sprague-Dawley
12.
Neurol Res ; 41(11): 972-979, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31296147

RESUMO

Objective: Bone cancer pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Transient receptor potential vanilloid subfamily member 1 (TRPV1), a new target of the analgesics, activated by heat, protons and capsaicin and the hot component of pepper. However, little is known of the anti-nociceptive effects of TRPV1 in cancer-induced bone pain. RNA interference (RNAi) has proven to be a powerful technique to study the function of genes by producing knock-down phenotypes. The aim of this study is to investigate the potential role of TRPV1 in rat model of bone cancer pain. Methods: Bone cancer pain animal model was created by tumor cell implantation (TCI). An AAV-mediated siRNA against TRPV1 was intrathecally delivered into the rats. Animal behaviors were measured using a set of mechanical or electronic von Frey apparatus and hot plate. mRNA and protein expression were examined by using qPCR and western blot methods. Results: Mechanical threshold and paw withdrawal latency in response to thermal stimulation were significantly elevated in rats with intrathecal administration of AAV-mediated siRNA against TRPV1. Moreover, class I histone deacetylases (HDACs), which plays a critical role in the neuro-inflammation response, and TNFα in the spinal cord were also significantly suppressed upon knockdown of TRPV1 by AAV-mediated siRNA against TRPV1 in rat spinal cord. Conclusions: Knockdown of TRPV1 effectively ameliorated mechanical allodynia and thermal hyperalgesia induced by TCI. Our data demonstrated that modulate the expression of TRPV1 in the spinal cord could be a potential therapeutic approach for bone cancer pain.


Assuntos
Dor do Câncer/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Canais de Cátion TRPV/genética , Analgésicos Opioides/uso terapêutico , Animais , Dor do Câncer/genética , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Masculino , Interferência de RNA/fisiologia , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Medula Espinal/patologia
13.
BMC Vet Res ; 15(1): 258, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340857

RESUMO

BACKGROUND: Heart rate variability (HRV) provides information about autonomic nervous system (ANS) activity and is therefore a possible tool with which to assess anaesthetic depth. The aim of the present study was to evaluate the effects of isoflurane, remifentanil and dexmedetomidine on HRV before and after nociceptive stimulation at different anaesthetic depths. Seven healthy domestic short-hair cats were used, and each cat was anaesthetized three times - group I with isoflurane alone, group IR with isoflurane and a constant rate infusion (CRI) of remifentanil (18 µg/kg/h), and group ID with isoflurane and a CRI of dexmedetomidine (3 µg/kg/h). Minimum alveolar concentration (MAC) values were determined via electrical supramaximal nociceptive stimulation for each treatment group. Nociceptive stimulation was repeated at 3 different MAC multiples (0.75, 1.0 and 1.5 MAC), and electrocardiographic recordings were performed for 3 min before and after stimulation. Only the 1 min epochs were used for further statistical analysis. Electrocardiographic data were exported for offline HRV analysis. RESULTS: The mean isoflurane MAC ± standard deviation (SD) was 1.83 ± 0.22 vol% in group I, 1.65 ± 0.13 vol% in group IR and 0.82 ± 0.20 vol% in group ID. Nociception was indicated by several HRV parameters, however, with high variability between treatments. The best correlation with MAC was found for the SD of heart rate (STD HR) in group I (rs = - 0.76, p = 0.0001, r2 = 0.46). STD HR was also able to distinguish 0.75 MAC from 1.5 MAC and 1.0 MAC from 1.5 MAC in group I, as well as 0.75 MAC from 1.5 MAC in group ID. CONCLUSIONS: The choice of anaesthetic protocol influences the HRV parameters in cats. Frequency domain parameters respond to nociception at lower MAC levels. The STD HR has the potential to provide additional information for the assessment of anaesthetic depth in isoflurane-anaesthetized cats. The utility of HRV analysis for the assessment of anaesthetic depth in cats is still questionable.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos Opioides/administração & dosagem , Anestésicos Inalatórios/administração & dosagem , Dexmedetomidina/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Isoflurano/administração & dosagem , Remifentanil/administração & dosagem , Anestesia por Inalação/veterinária , Animais , Gatos , Estimulação Elétrica , Eletrocardiografia/veterinária , Feminino , Masculino , Nociceptividade/efeitos dos fármacos
14.
Curr Opin Anaesthesiol ; 32(5): 623-628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31356363

RESUMO

PURPOSE OF REVIEW: The medicinal use of cannabis has recently become the focus of much medical, as well as political, attention. This reality of growing use but limited evidence creates unique dilemmas for the prescribing clinician. The purpose of this review is to explore current evidence and gaps in knowledge and offer some practical considerations. RECENT FINDINGS: There is robust preclinical data regarding the relevance of the endocannabinoid system to many pain-relevant processes. However, evidence to support cannabis-based medicines clinical use is still lacking. The best evidence to date is in managing neuropathic pain, although whether effects are clinically significant remains undetermined. However, the safety profile of cannabinoids seems favorable, especially by comparison to other medications used for pain control. SUMMARY: The endocannabinoid system is undoubtedly a new and exciting pharmaceutical target for chronic pain management, but transition from preclinical to clinical studies has so far proved difficult. Although it is reasonable to consider cannabinoids for otherwise unresponsive pain, care should be taken in frail clinical populations. As this has become a socioeconomic and political issue in which agendas often take precedence over due diligence, there is a pressing need for unbiased empirical data and high quality evidence to better inform prescribers and patients.


Assuntos
Dor Crônica/tratamento farmacológico , Maconha Medicinal/administração & dosagem , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Dor Crônica/patologia , Endocanabinoides/metabolismo , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/tendências , Humanos , Maconha Medicinal/efeitos adversos , Maconha Medicinal/economia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Manejo da Dor/efeitos adversos , Manejo da Dor/tendências , Política , Fatores Socioeconômicos , Resultado do Tratamento
15.
Pharmacol Biochem Behav ; 184: 172741, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31336109

RESUMO

RATIONALE: Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE: To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS: Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS: Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.


Assuntos
Canabidiol/administração & dosagem , Canabidiol/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Administração por Inalação , Animais , Temperatura Corporal/efeitos dos fármacos , Canabidiol/sangue , Cannabis/química , Estudos de Coortes , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Hipotermia/induzido quimicamente , Masculino , Modelos Animais , Nicotina/administração & dosagem , Nicotina/farmacologia , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/sangue , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo
16.
Int J Occup Med Environ Health ; 32(4): 465-474, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31303648

RESUMO

OBJECTIVES: The aim of this study, conducted at the Military Institute of Hygiene and Epidemiology in Warsaw in 2017, was to evaluate the effects of a single (15 min) and repeated (5 times for 15 min) radio-frequency radiation (RFR) exposure of 1800 MHz frequency on the analgesic efficacy of morphine in healthy rats and rats with complete Freund's adjuvant (CFA) induced inflammation. MATERIAL AND METHODS: Rats were injected intraperitoneally with morphine (MF) in the dose of 8 mg/kg or drug vehicle 15 min before RFR exposure. The authors used the plantar analgesia meter and the radiant heat paw-withdrawal test to assess the pain threshold. RESULTS: A single RFR exposure slightly influenced paw withdrawal latency (PWL) in healthy rats in the single exposure baseline group, and influenced PWL, 30 and 60 min after morphine or vehicle injection, in the repeated exposure group. There were differences between the sham-exposed groups (vehicle), 30, 60 and 90 min after injection, both in the single and repeated RFR-exposure groups. The antinociceptive effect of morphine in healthy rats was slightly decreased by RFR exposure at 60 and 90 min, both in the single and repeated exposure groups. The PWL was slightly decreased, both in the single and repeated exposure groups with inflammation (CFA and CFA/MF), at 30, 60 and 90 min, and PWL was increased in the sham-exposed groups (CFA and CFA/MF), both in the single and repeated exposure groups, at 30, 60 and 90 min. The antinociceptive effect of morphine in healthy rats was significantly increased by RFR exposure at 30 min after drug injection in the single exposure group, and increased at 30 and 60 min in the repeated exposure group. CONCLUSIONS: The authors observed a minor influence of RFR exposure on the antinociceptive effects of morphine in healthy rats after repeated exposures and a statistically significant influence of repeated exposure on morphine mediated antinociceptive effects in the inflammation group. Int J Occup Med Environ Health. 2019;32(4):465-74.


Assuntos
Analgésicos/farmacologia , Analgésicos/efeitos da radiação , Morfina/farmacologia , Morfina/efeitos da radiação , Ondas de Rádio , Animais , Adjuvante de Freund/administração & dosagem , Inflamação/induzido quimicamente , Masculino , Nociceptividade/efeitos dos fármacos , Nociceptividade/efeitos da radiação , Dor , Ratos Wistar
17.
Eur J Pharmacol ; 858: 172460, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31228448

RESUMO

Contact dermatitis is a very common inflammatory reaction in the skin, causing not only aesthetic problems but also loss functionality at work. The molecular mechanisms of contact dermatitis induced by chemical irritants are still unclear. Considering that transient receptor potential channels (TRP) may induce neurogenic inflammation and the exacerbation of inflammatory responses, here we investigated the role of transient receptor potential channel ankyrin type-1 (TRPA1) in skin inflammation evoked by chemical irritants. Ear oedema and nociceptive responses elicited by the topical application of xylene and toluene were measured in Swiss mice, wild type and TRPA1 knockout (Trpa1-/-) C57BL/6 mice. Histological analyses were performed in mice subjected to the ear oedema assay. Topical application of xylene and toluene in the mouse ear induced an edematogenic response (0.113 ±â€¯0.008 mm and 0.067 ±â€¯0.011 mm), compared to vehicle (0.008 ±â€¯0.008 mm), assessed by ear thickness measurements and histological analyses. These responses were prevented by topical pretreatment with a selective TRPA1 antagonist, HC-030031 (% inhibition: xylene 36.8 ±â€¯9.4% and toluene 50.7 ±â€¯11.0%), and by the genetic deletion of TRPA1 ((% inhibition: xylene 66.6 ±â€¯16.7% and toluene 75 ±â€¯0%). In addition, the topical application of xylene and toluene to the mouse paw elicited nociceptive responses, which were significantly reduced by oral treatment with HC-030031 ((% of inhibition: 84.9 ±â€¯1.3% and 27.1 ±â€¯8.0%, respectively); nociceptive responses were almost completely abolished in Trpa1-/-mice. Our data suggest that the activation of TRPA1 could be involved in some of the symptoms of irritant-mediated contact dermatitis, such as oedema, pain and neurogenic inflammation.


Assuntos
Pele/efeitos dos fármacos , Canal de Cátion TRPA1/metabolismo , Tolueno/farmacologia , Xilenos/farmacologia , Animais , Edema/induzido quimicamente , Edema/genética , Edema/metabolismo , Edema/patologia , Técnicas de Inativação de Genes , Inflamação/induzido quimicamente , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/deficiência , Canal de Cátion TRPA1/genética , Volatilização
18.
Biomed Pharmacother ; 117: 109123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31234026

RESUMO

Chrysanthemum trifurcatum is common to Mediterranean countries and widely-used in traditional medicine. Due to the scarcity of data about the pharmacological properties of C. trifurcatum, this present study was designed to determine the effects of C. trifurcatumethanolic extract (CEE) for its anti-nociceptive, anti-epileptic, anti-inflammatory, and hepatoprotective activities in mice and rat models. We demonstrate that CEE contains alkaloids, carbohydrates, and flavonoids, and in a dose-dependent (300 and 500 mg/kg) manner exhibited significant reductions in paracetamol (PCM; 500 mg/kg)-induced increased serum AST, ALT and ALP levels, similar to as seen by silymarin (25 mg/kg). Additionally, CEE (300 mg/kg) elicited inhibition in acetic acid-induced abdominal writhes, delayed latency time to paw's licking in hot plate tests, exerted an anti-convulsant effect by prolonging the onset of clonic and tonic convulsions, and reduced pentylenetetrazole (PTZ; 80 mg/kg)-induced mortality. Moreover, CEE (500 mg/kg) exhibited a prominent reduction in carrageenan-induced paw edema. These studies indicate that CEE possesses profound central and peripheral analgesic, anti-convulsant, anti-inflammatory, and hepatoprotective activities.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Anticonvulsivantes/farmacologia , Asteraceae/química , Fígado/patologia , Substâncias Protetoras/farmacologia , Animais , Carragenina , Feminino , Fígado/efeitos dos fármacos , Camundongos , Nociceptividade/efeitos dos fármacos , Compostos Fitoquímicos/análise , Ratos Wistar , Tramadol/farmacologia , Ácido Valproico/farmacologia
19.
PLoS One ; 14(6): e0218619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237895

RESUMO

(-)-Incarvillateine (INCA) is a natural product that has garnered attention due to its purported analgesic effects and historical use as a pain reliever in China. α-Truxillic acid monoesters (TAMEs) constitute a class of inhibitors targeting fatty acid binding protein 5 (FABP5), whose inhibition produces analgesia in animal models. The structural similarity between INCA and TAMEs motivated us to assess whether INCA exerts its antinociceptive effects via FABP inhibition. We found that, in contrast to TAMEs, INCA did not exhibit meaningful binding affinities toward four human FABP isoforms (FABP3, FABP4, FABP5 and FABP7) in vitro. INCA-TAME, a putative monoester metabolite of INCA that closely resembles TAMEs also lacked affinity for FABPs. Administration of INCA to mice produced potent antinociceptive effects while INCA-TAME was without effect. Surprisingly, INCA also potently suppressed locomotor activity at the same dose that produces antinociception. The motor suppressive effects of INCA were reversed by the adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine. Collectively, our results indicate that INCA and INCA-TAME do not inhibit FABPs and that INCA exerts potent antinociceptive and motor suppressive effects at equivalent doses. Therefore, the observed antinociceptive effects of INCA should be interpreted with caution.


Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Locomoção/efeitos dos fármacos , Monoterpenos/farmacologia , Nociceptividade/efeitos dos fármacos , Receptores A2 de Adenosina/metabolismo , Agonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Camundongos , Ligação Proteica , Teobromina/análogos & derivados , Teobromina/farmacologia
20.
Eur J Pharmacol ; 858: 172497, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31238066

RESUMO

Metformin, an AMP-activated protein kinase (AMPK) activator, is an oral hypoglycemic drug widely used to treat patients with type 2 diabetes. As AMPK plays a role in the nociceptive processing, investigating the effects induced by metformin in experimental models of pain is warranted. In the present study, we further evaluated the effects induced by metformin in models of nociceptive and neuropathic pain and investigated mechanisms that could mediate such effects. Metformin was administered per os (p.o.) in mice. Nociceptive response induced by heat (hot-plate) and mechanical allodynia induced by chronic constriction injury (CCI) were used as pain models. Naltrexone (intraperitoneal) and glibenclamide (p.o.) were used to investigate mechanisms mediating metformin effects. A single administration of metformin (500 or 1000 mg/kg) inhibited the nociceptive response in the hot-plate model. Single and repeated administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia induced by CCI. Metformin (250, 500 or 1000 mg/kg) did not affect the time mice spent in the rota-rod apparatus. The activity of metformin (1000 mg/kg) in both pain models was attenuated by naltrexone (10 mg/kg), but not by glibenclamide. Concluding, metformin exhibited activity in models of nociceptive and neuropathic pain. In the model of neuropathic pain, preventive and therapeutic effects were observed. Activation of opioidergic pathways partially mediates metformin antinociceptive activity. Altogether, the results indicate that metformin should be further investigated aiming its repositioning in the treatment of patients with different painful conditions.


Assuntos
Analgésicos/farmacologia , Metformina/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Glibureto/farmacologia , Hiperalgesia/tratamento farmacológico , Metformina/uso terapêutico , Camundongos , Naltrexona/farmacologia , Neuralgia/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos
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