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1.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3830-3836, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602960

RESUMO

The peeled root,stem or twig of Syringa pinnatifolia is a representative Mongolian folk medicine with the effects of antidepression and pain relief. It has been used for the treatments of heart tingling,heart palpitations,upset,insomnia and other symptoms. Inspired by Mongolian medical theory and clinical practices,this study evaluated the analgesic effect of S. pinnatifolia ethanol extract( T) through three analgesic models including acetic acid writhing test,formalin test,and hot plate test,and the sedative effect of T was evaluated by locomotor activity and synergistic sleeping experiments,and furthermore the effects of T on the GABAergic nervous system were investigated by ELISA,immunohistochemistry,Western blot,and PCR methods. The results showed that T can significantly reduce the number of writhing,the time of paw licking and extend the thermal threshold of mice,suggesting the analgesic effect of T.T also can indicate its sedative effect by reducing the number of activities,decreasing latency of sleeping and extending sleeping time of mice. ELISA results showed that T can increase the content of GABA/Glu in rat cortex,hippocampus,and hypothalamus,and the most significant increase in hypothalamus. The immunohistochemistry and Western blot results showed that T can up-regulate the expression of GAD67 protein in hypothalamus,and the PCR results showed that T can up-regulate the expression of GABAA Rα1,α2,α3,α5,ß1-3,γ1-3 genes,suggesting a sedative effect through the GABAergic nervous system. In conclusion,this study shed insight into the theoretical basis and clinical application of S. pinnatifolia,and also provides inspiration for subsequent development and application.


Assuntos
Analgésicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Syringa/química , Animais , Medicina Tradicional da Mongólia , Camundongos , Dor , Ratos
2.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2980-2986, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602843

RESUMO

Pain is one of the problems that seriously affect people's quality of life for thousands of years. The causes of pain are complex and varied,and long-term pain can also lead to depression. It has become a research hotspot to develop analgesic preparations with significant drug effects and small side effects. Recent studies have shown that certain alkaloid monomers have analgesic targets such as γ-aminobutyric acid,cannabinoids,and capsaicin. If their preparation is applied to the analgesic field,they can make up for the defects such as strong addiction and side effects of traditional opioid and non-steroidal analgesic drugs,but there is no relevant literature to summarize the research results in this field. This article first introduces the mechanism of pain production and the target of analgesia. Based on this,the application status of alkaloid monomer analgesic preparations approved by China Food and Drug Administration( CFDA)( number varieties,type of dosage form,drug description,analgesic mechanism and advantages) was analyzed,and the research dynamics of alkaloid monomer analgesic preparations( new formulation and new technology) were reviewed. Finally,some problems in this field were pointed out,such as imperfect medication information,inadequate transformation of research results,and too few kinds of analgesic components in developed alkaloids. The development direction was also pointed out for the above problems,with a view to provide reference for further development and in-depth research.


Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Dor/tratamento farmacológico , Analgesia , China , Humanos , Qualidade de Vida
3.
Br J Anaesth ; 123(5): 592-600, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31492526

RESUMO

BACKGROUND: Previous work on the electroencephalographic (EEG) effects of anaesthetic doses of ketamine has identified a characteristic signature of increased high frequency (beta-gamma) and theta waves alternating with episodic slow waves. It is unclear which EEG parameter is optimal for pharmacokinetic-pharmacodynamic modelling of the hypnotic actions of ketamine, or which EEG parameter is most closely linked to loss of behavioural responsiveness. METHODS: We re-analysed previously published 128-channel scalp EEG data from 15 subjects who had received a 1.5 mg kg-1 bolus i.v. dose of ketamine. We applied standard sigmoid pharmacokinetic-pharmacodynamic models to the drug-induced changes in slow wave activity, theta, and beta-gamma EEG power; and examined the morphology of the slow waves in the time domain for Fz, F3, T3, P3, and Pz average-referenced channels. RESULTS: Hypnotic doses of ketamine i.v. induced medio-frontal EEG slow waves, and loss of behavioural response when the estimated brain concentration was 1.64 (0.17) µg ml-1. Recovery of responsiveness occurred at 1.06 (0.21) µg.ml-1 after slow wave activity had markedly diminished. Pharmacokinetic-pharmacodynamic modelling fitted best to the slow wave activity and theta power (almost half the beta-gamma channels could not be modelled). Slow wave effect-site equilibration half-time (23 [4] s), and offset, was faster than for theta (47 [22] s). CONCLUSIONS: Changes in EEG slow wave activity after a hypnotic dose of ketamine could be fitted by a standard sigmoid dose-response model. Their onset, but not their offset, was consistently associated with loss of behavioural response in our small study group.


Assuntos
Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Ketamina/farmacologia , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Valores de Referência , Adulto Jovem
4.
Anticancer Res ; 39(9): 4721-4728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519571

RESUMO

BACKGROUND/AIM: Recent research has identified the transcription factors NFATc2 and Sp1 as key regulators in the carcinogenesis of pancreatic carcinoma. This study aimed to examine the effect of clinically achievable dosages of analgesics including ketamine, s-ketamine, metamizole, and paracetamol as well as that of sufentanil, ropicavaine, and lidocaine on pancreatic carcinoma cells and the expression of NFATc2 and Sp1. MATERIALS AND METHODS: The effects of analgesics on the expression of NFATc2 and Sp1 were investigated with immunoblotting. Cell proliferation was measured with the ELISA BrdU assay. RESULTS: In PaTu8988t pancreatic carcinoma cells, 48 h stimulation with ketamine and s-ketamine significantly inhibited proliferation and decreased expression of NFATc2 in the nucleus. The addition of metamizole and lidocaine reduced proliferation of PaTu8988t cells after 48 h. CONCLUSION: New treatment concepts target specific signaling and transcription pathways. The extent to which drugs influence these mechanisms in pancreatic carcinoma cells needs to be investigated in future studies.


Assuntos
Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fator de Transcrição Sp1/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/patologia , Transcrição Genética
5.
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
6.
Br J Anaesth ; 123(3): 335-349, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303268

RESUMO

Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Dor Crônica/tratamento farmacológico , Lidocaína/farmacologia , Terapia de Alvo Molecular/métodos , Dor Aguda/metabolismo , Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/metabolismo , Humanos , Canais Iônicos/efeitos dos fármacos , Lidocaína/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos
7.
Planta Med ; 85(11-12): 1016-1023, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31212319

RESUMO

Nectarine (Prunus persica var. nucipersica) is a worldwide appreciated edible subspecies, with a high nutritional value and benefits on human health due to its phenolic content. Despite the large consumption of the fruit, the potential use of its kernel is poorly studied. Herein, the potential pharmacological activities and the phenolic constituents of an alcoholic extract of kernel nectarine fruits were investigated. Administering nectarine kernel extract (50 and 100 mg/kg, respectively) in rats reduced paw edema after carrageenan injection by 11 and 47% in 1 h, 24 and 33% in 2 h, and 23 and 32% in 4 h, when compared to the controls. At the higher dose (100 mg/kg), nectarine kernel extract increased the reaction time in the hot-plate model and produced a significant decrease in the rectal temperature of the pyretic rats, while both doses produced 52 and 59% of writhing inhibition compared to the control group. Total polyphenolic (55.91 ± 5.78 mg/g) and flavonoid (29.89 ± 0.55 mg/g) content indicated that the extract is a promising source of these constituents. HPLC-ESI-MS/MS analysis demonstrated the presence of flavonoids, such as naringenin and apigenin glycosides. The cyanogenic glycosides amigdalin and prunasin were also detected. These results highlight the anti-inflammatory, analgesic, and antipyretic activities of nectarine kernel alcoholic extract, together with significant phenolic content, promoting its exploitation as a source of bioactive molecules.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antipiréticos/farmacologia , Nozes/química , Extratos Vegetais/farmacologia , Prunus persica/química , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Antipiréticos/isolamento & purificação , Colostro/imunologia , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar
8.
Dokl Biochem Biophys ; 485(1): 123-125, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201630

RESUMO

Previously, we synthesized a dimeric dipeptide mimetic of the brain-derived neurotrophic factor (BDNF) loop 4, GSB-106, which, similarly to BDNF, activated TrkB, PI3K/AKT, and MAPK/ERK. When administered systemically, it exhibited neuroprotective, antidepressant, and antidiabetic activities and stimulated neurogenesis and synaptogenesis. In this study, we established that GSB-106 also exhibits the analgesic activity, typical for BDNF, which was revealed in rats in hot plate and tail flick tests 0.5-48 h after intraperitoneal injection at doses of 0.1 and 1 mg/kg.


Assuntos
Analgésicos , Fator Neurotrófico Derivado do Encéfalo , Dipeptídeos , Peptidomiméticos , Analgésicos/química , Analgésicos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Humanos , Masculino , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Estrutura Secundária de Proteína , Ratos
9.
Life Sci ; 231: 116523, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31152811

RESUMO

Tagetes lucida Cav. is an ancient medicinal plant used to treat different ailments involving neurological diseases and pain. However, scientific studies to validate their medicinal properties as analgesic have not been described. The aim of this study was to evaluate the T. lucida antinociceptive response using pain models. Bioactive compounds and a possible mechanism of action were also explored. Dose-response effects of an ethanol crude extract were investigated in the writhing and formalin tests in mice and rats, respectively. The extract was fractionated to isolate active fractions and bioactive compounds (quercetagetin 7­O­ß­d­glucoside and 6,7­dimethoxycoumarin) using the formalin test. The antinociceptive effects were compared to the reference drugs (tramadol 10 mg/kg, diclofenac 50 mg/kg, and/or ketorolac 1 mg/kg, i.p.). The ethanol extract was explored in the presence of naloxone (3 mg/kg, i.p. a non-selective opioid receptor antagonist) and WAY100635 (0.5 mg/kg, s.c., a selective 5-HT1A receptor antagonist) to screen their participation as possible inhibitory mechanisms involved in the antinociceptive response of T. lucida. The ethanol crude extract, fractions, and pure compounds caused a significant antinociceptive response resembling the effect of the reference drugs. Both opioid and 5-HT1A receptors participated in the analgesic -like activity of the extract, which did not produce gastric damage. On the contrary, the gastric damage produced as an adverse effect of the analgesic ketorolac was prevented when combined with the extract. In conclusion, these preliminary data provide evidence and give support to the properties attributed to T. lucida in the traditional medicine to alleviate pain.


Assuntos
Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Tagetes/metabolismo , Analgésicos/farmacologia , Animais , Curcumina/análogos & derivados , Curcumina/farmacologia , Feminino , Flavonas/farmacologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Modelos Animais , Naloxona/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/efeitos dos fármacos
10.
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
11.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 37-42, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078150

RESUMO

Inflammation and insomnia are two types of symptoms very likely occur in life, seriously perplexing people's work and life. How to alleviate these symptoms is an urgent medical problem. Lucidone D (LUC) is a terpene from the ethanol extract of Ganoderma lucidum fruiting body. Triterpenoids are also the main pharmacological components of Ganoderma lucidum. In recent years, people pay more and more attention to its anti-inflammatory effect. In this study, LPS induced RAW264.7 macrophage inflammatory response model was used to evaluate the anti-inflammatory activity of LUC. The results showed that LUC could significantly inhibit the production of inflammatory mediators NO, which may play a role by down-regulating the expression level of iNOS and COX-2 proteins. Meanwhile, the production of TNF-α and IL-6 was significantly inhibited. These results indicate that LUC has obvious anti-inflammatory activity. Writhing and sedation tests in ICR male mice showed that LUC showed significant analgesic and sedative effects. In conclusion, these results suggest the anti-inflammatory, analgesic and sedative effects of LUC in vitro and in vivo.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Hipnóticos e Sedativos/farmacologia , Reishi/química , Terpenos/farmacologia , Analgésicos/química , Animais , Anti-Inflamatórios/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/biossíntese , Hipnóticos e Sedativos/química , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Pentobarbital , Células RAW 264.7 , Latência do Sono/efeitos dos fármacos , Terpenos/química
12.
Oxid Med Cell Longev ; 2019: 1346878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049124

RESUMO

2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico, in vitro, and in vivo. At 30 min prior to the start of in vivo pharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-α and IL-1ß. In vitro antioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals. In silico docking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-α and IL-1ß reduction activity, corroborating its antinociceptive effect.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Interleucina-1beta/metabolismo , Fenóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Masculino , Camundongos , Simulação de Acoplamento Molecular , Peritonite/tratamento farmacológico , Peritonite/metabolismo , Peritonite/patologia , Fenóis/química , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo
13.
Yonsei Med J ; 60(6): 491-499, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31124331

RESUMO

With the rapid development of diagnostic and therapeutic procedures performed outside the operating room (OR), the need for appropriate sedation care has emerged in importance to ensure the safety and comfort of patients and clinicians. The preparation and administration of sedatives and sedation care outside the OR require careful attention, proper monitoring systems, and clinically useful sedation guidelines. This literature review addresses proper monitoring and selection of sedatives for diagnostic and interventional procedures outside the OR. As the depth of sedation increases, respiratory depression and cardiovascular suppression become serious, necessitating careful surveillance using appropriate monitoring equipment.


Assuntos
Sedação Consciente/métodos , Salas Cirúrgicas , Analgésicos/farmacologia , Humanos , Hipnóticos e Sedativos/farmacologia , Monitorização Fisiológica
14.
Handb Exp Pharmacol ; 254: 165-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119465

RESUMO

Since the discovery of the NOP receptor and N/OFQ as the endogenous ligand, evidence has appeared demonstrating the involvement of this receptor system in pain. This was not surprising for members of the opioid receptor and peptide families, particularly since both the receptor and N/OFQ are highly expressed in brain regions involved in pain, spinal cord, and dorsal root ganglia. What has been surprising is the complicated picture that has emerged from 25 years of research. The original finding that N/OFQ decreased tail flick and hotplate latency, when administered i.c.v., led to the hypothesis that NOP receptor antagonists could have analgesic activity without abuse liability. However, as data accumulated, it became clear that not only the potency but the activity per se was different when N/OFQ or small molecule NOP agonists were administered in the brain versus the spinal cord and it also depended upon the pain assay used. When administered systemically, NOP receptor agonists are generally ineffective in attenuating heat pain but are antinociceptive in an acute inflammatory pain model. Most antagonists administered systemically have no antinociceptive activity of their own, even though selective peptide NOP antagonists have potent antinociceptive activity when administered i.c.v. Chronic pain models provide different results as well, as small molecule NOP receptor agonists have potent anti-allodynic and anti-hyperalgesic activity after systemic administration. A considerable number of electrophysiological and anatomical experiments, in particular with NOP-eGFP mice, have been conducted in an attempt to explain the complicated profile resulting from NOP receptor modulation, to examine receptor plasticity, and to elucidate mechanisms by which selective NOP agonists, bifunctional NOP/mu agonists, or NOP receptor antagonists modulate acute and chronic pain.


Assuntos
Analgesia , Analgésicos/farmacologia , Peptídeos Opioides/farmacologia , Receptores Opioides , Analgésicos/uso terapêutico , Animais , Hiperalgesia , Camundongos , Peptídeos Opioides/química , Peptídeos Opioides/metabolismo , Manejo da Dor , Receptores Opioides/química , Receptores Opioides/metabolismo
15.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067750

RESUMO

The ATP-sensitive K+ channel (KATP) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of KATP channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different KATP channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-KATP channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype KATP channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.


Assuntos
Analgésicos/farmacologia , Diazóxido/farmacologia , Hiperalgesia/tratamento farmacológico , Nervos Espinhais/efeitos dos fármacos , Receptores Sulfonilureia/agonistas , Analgésicos/uso terapêutico , Animais , Diazóxido/uso terapêutico , Potenciais Evocados , Feminino , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Nervos Espinhais/metabolismo , Nervos Espinhais/fisiopatologia , Receptores Sulfonilureia/genética , Receptores Sulfonilureia/metabolismo , Tato
16.
Mar Drugs ; 17(5)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060282

RESUMO

Oxaliplatin is a third-generation platinum drug and is widely used as a first-line therapy for the treatment of colorectal cancer (CRC). However, a large number of patients receiving oxaliplatin develop dose-limiting painful neuropathy. Here, we report that αO-conotoxin GeXIVA[1,2], a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype, can relieve and reverse oxaliplatin-induced mechanical and cold allodynia after single and repeated intramuscular (IM) injections in rats. Treatments were started at 4 days post oxaliplatin injection when neuropathic pain emerged and continued for 8 and 16 days. Cold score and mechanical paw withdrawal threshold (PWT) were detected by the acetone test and von Frey test respectively. GeXIVA[1,2] significantly relieved mechanical and cold allodynia in oxaliplatin-treated rats after a single injection. After repeated treatments, GeXIVA[1,2] produced a cumulative analgesic effect without tolerance and promoted recovery from neuropathic pain. Moreover, the long lasting analgesic effect of GeXIVA[1,2] on mechanical allodynia continued until day 10 after the termination of the 16-day repeated treatment procedure. On the contrary, GeXIVA[1,2] did not affect acute mechanical and thermal pain behaviors in normal rats after repeated injections detected by the von Frey test and tail flick test. GeXIVA[1,2] had no influence on rat hind limb grip strength and body weight after repeated treatments. These results indicate that αO-conotoxin GeXIVA[1,2] could provide a novel strategy to treat chemotherapy-induced neuropathic pain.


Assuntos
Analgésicos/farmacologia , Conotoxinas/farmacologia , Neuralgia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Oxaliplatina/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/induzido quimicamente , Oxaliplatina/administração & dosagem , Ratos , Ratos Sprague-Dawley
17.
J Chromatogr A ; 1603: 338-347, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31056272

RESUMO

Supercritical fluid chromatography (SFC) holds the potential to become an orthogonal method to HPLC/UHPLC in xenobiotic metabolism studies, due to its outstanding capacity to simultaneously separate highly similar (as HPLC) and physicochemically different analytes (problematic using HPLC). Paucity of guideline-conform validation, however, has been a major obstacle to clinical application of SFC, even in cases where biotransformation yields chemically dissimilar metabolites that require more than one HPLC method for comprehensive analysis. Here, a method based on supercritical fluid chromatography coupled to single quadrupole MS detection was developed to simultaneously quantify the divisive analgesic flupirtine and its acidic and basic metabolites, represented by 4-fluorohippuric acid (4-FHA) and the active metabolite D-13223 respectively, using custom-made synthetic internal standards. Experimental data on the fundamental retention mechanisms under supercritical conditions, indicating the importance of halogen and π-π-bonding for specific retention on polysaccharide-based stationary-phases, is discussed. Compared to previous HPLC methods, the novel method offers higher versatility in terms of the target metabolite range (addressing both acidic and basic metabolites within a singular method), faster analysis (7.5 min), and compliance with green chemistry principles. Validation was performed according to EMA criteria on bioanalytical method validation, demonstrating selectivity, carry-over, calibration curve parameters (LLOQ, range, and linearity), within- and between-run accuracy and precision, dilution integrity, matrix effect and stability. For proof-of-concept, the SFC method was applied to clinical samples of human urine obtained after single intravenous (100 mg), single oral (100 mg), and repeated oral administration (400 mg). Flupirtine, D-13223, and 4-FHA could be quantified, shedding light on the extent of oxidative flupirtine metabolism in humans in the context of the unresolved biotoxification that has led to the withdrawal of specific neuronal KV7 openers.


Assuntos
Ácidos/química , Aminopiridinas/análise , Cromatografia com Fluido Supercrítico/métodos , Metaboloma , Adulto , Aminopiridinas/farmacologia , Aminopiridinas/urina , Analgésicos/farmacologia , Analgésicos/urina , Calibragem , Europa (Continente) , Feminino , Humanos , Limite de Detecção , Masculino , Reprodutibilidade dos Testes , Solventes , Temperatura Ambiente , Adulto Jovem
18.
Life Sci ; 228: 176-188, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059688

RESUMO

AIM: Inflammatory algesia and pyresia are common pathological consequences of physiological defense. Phenacetin introduced as effective analgesic anti-pyretic agent, was proscribed from therapeutic use because of associated systemic toxicity. The aim of the study was to evaluate the potency of 1,2,3-triazole conjugation in reducing toxicity and increasing efficacy of the phenacetin nucleus. MAIN METHODS: The amide bond implicated as the cause of phenacetin toxicity was bioisosterically replaced with 1,2,3-triazoles to yield a series of PhTCs(PhTC1, PhTC2 and PhTC3). The toxicology of the synthesized conjugates in reference to phenacetin was evaluated in accordance with OECD test guidelines 420, 425 and 407. For the purpose of evaluating anti-inflammatory potency carrageenan induced paw edema and croton oil induced ear edema models were evaluated. Anti-nociceptive efficacy was assessed using Eddy's hot plate and acetic acid induced writhing experimental models. For anti-pyretic efficacy, the conjugates were submitted to Brewer's yeast antipyretic assay. KEY FINDINGS: Toxicological examination of PhTCs in comparison to phenacetin revealed that, phenacetin treatment caused considerable nephrotoxicity and hepatotoxicity in experimental models PhTCs were devoid of such toxic manifestations. Results of pharmacological assays showed that the entire series of PhTCs possessed better anti-inflammatory, anti-nociceptive and anti-pyretic potential than phenacetin. Furthermore it was revealed that the pharmacological profile of PhTC1 with triazole substitution at para position of the phenol ring exhibited potency even better than that exhibited by the reference standards. CONCLUSION: Bioisosteric replacement of amide bond by 1,2,3-triazole in the phenacetin moiety yields conjugates with superior efficacy and diminished toxicity, thus opening neo avenues in treatment of inflammatory syndromes.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Fenacetina/análogos & derivados , Fenacetina/farmacologia , Triazóis/química , Triazóis/farmacologia , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Fenacetina/toxicidade , Ratos Wistar , Triazóis/toxicidade
19.
Eur J Med Chem ; 174: 226-235, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042618

RESUMO

A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards σ1 and σ2 receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best Ki values (Ki σ1 = 1.27, 2.30, and 0.78 and Ki σ2 = 7.9, 3.8, and 7.61 nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess σ2 receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ1 receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ1/σ2 agonist, compound 24 a σ1 antagonist/σ2 agonist, whereas compound 22 might act as σ1 antagonist/σ2 partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ1/σ2 receptor ligands, especially 22 and 24, is proposed.


Assuntos
Analgésicos/uso terapêutico , Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Humanos , Ligantes , Células MCF-7 , Camundongos , Estrutura Molecular
20.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052248

RESUMO

Incarvillea compacta Maxim is a traditional Tibetan plant widely used to treat rheumatic pain and bruises. We conducted qualitative analyses by liquid chromatography-mass spectrometry and quantitative analyses of the total phenols, flavonoids, and alkaloids content of different extracts of I. compacta Maxim. Antioxidant and analgesic activity were analyzed. The results showed that the methanol extract had the highest content of the various ingredients. A total of 25 constituents were identified, of which compounds 1-23 were found for the first time in this plant. The water extract had the highest capacity to clear free radicals in the antioxidant test. The water extract had dose-dependent analgesic effects in the first and second phase in a formalin test. The latency of pain from a hot-plate test was augmented by the water extract when the dose was greater than or equal to 30 g/kg. The water extract significantly decreased the amount of writhing in a dose-dependent manner compared with the control group in the acetic acid-induced writhing test. These results showed that I. compacta Maxim is a new antioxidant and analgesic agent, and this study provides information on its ingredients for further study.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bignoniaceae/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Cromatografia Líquida , Flavonoides/química , Flavonoides/farmacologia , Espectrometria de Massas , Estrutura Molecular , Fenóis , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solventes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tibet
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