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1.
Nat Commun ; 13(1): 4150, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35851064

RESUMO

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of ß-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.


Assuntos
Analgesia , Depressão , Adenosina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Purinérgicos P1
2.
Neuropharmacology ; 198: 108755, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34416268

RESUMO

Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect of this control is modulation of neuronal activity through cholinergic signaling. Nociceptive neurons in the dorsal horn express both nicotinic and muscarinic cholinergic receptors and activation of these receptors reduces pain in humans, while inhibition leads to nociceptive hypersensitivity. At a cellular level, acetylcholine (ACh) has diverse effects on excitability which is dependent on the receptor and neuronal subtypes involved. In the present study we sought to characterize the electrophysiological responses of specific subsets of lamina II interneurons from rat and marmoset spinal cord. Neurons were grouped by morphology and by action potential firing properties. Whole-cell voltage-clamp recordings from lamina II dorsal horn neurons of adult rats showed that bath applied acetylcholine increased, decreased or had no effect on spontaneous synaptic current activity in a cell-type specific manner. ACh modulated inhibitory synaptic activity in 80% of neurons, whereas excitatory synaptic activity was affected in less than 50% of neurons. In whole-cell current clamp recordings, brief somatic application of ACh induced cell-type specific responses in 79% of rat lamina II neurons, which included: depolarization and action potential firing, subthreshold membrane depolarization, biphasic responses characterized by transient depolarization followed by hyperpolarization and membrane hyperpolarization alone. Similar responses were seen in marmoset lamina II neurons and the properties of each neuron group were consistent across species. ACh-induced hyperpolarization was blocked by the muscarinic antagonist atropine and all forms of acetylcholine-induced depolarization were blocked by the nicotinic antagonist mecamylamine. The cholinergic system plays an important role in regulating nociception and this study contributes to our understanding of how circuit activity is controlled by ACh at a cellular level in primate and rodent spinal cord.


Assuntos
Acetilcolina/farmacologia , Rede Nervosa/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Atropina/farmacologia , Callithrix , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Camundongos , Antagonistas Muscarínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Nociceptividade/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
3.
J Med Chem ; 64(6): 3222-3233, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33724033

RESUMO

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.


Assuntos
Alcinos/uso terapêutico , Analgésicos/uso terapêutico , Conotoxinas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Alcinos/química , Analgésicos/química , Animais , Células Cultivadas , Conotoxinas/química , Caramujo Conus/química , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Hiperalgesia/fisiopatologia , Masculino , Modelos Moleculares , Neuralgia/fisiopatologia , Ratos Sprague-Dawley , Xenopus
4.
Mol Metab ; 34: 54-71, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32180560

RESUMO

OBJECTIVES: Nutrient sensing by hypothalamic neurons is critical for the regulation of food intake and energy expenditure. We aimed to identify long- and medium-chain fatty acid species transported into the brain, their effects on energy balance, and the mechanisms by which they regulate activity of hypothalamic neurons. METHODS: Simultaneous blood and cerebrospinal fluid (CSF) sampling was undertaken in rats and metabolic analyses using radiolabeled fatty acid tracers were performed on mice. Electrophysiological recording techniques were used to investigate signaling mechanisms underlying fatty acid-induced changes in activity of pro-opiomelanocortin (POMC) neurons. RESULTS: Medium-chain fatty acid (MCFA) octanoic acid (C8:0), unlike long-chain fatty acids, was rapidly transported into the hypothalamus of mice and almost exclusively oxidized, causing rapid, transient reductions in food intake and increased energy expenditure. Octanoic acid differentially regulates the excitability of POMC neurons, activating these neurons directly via GPR40 and inducing inhibition via an indirect non-synaptic, purine, and adenosine receptor-dependent mechanism. CONCLUSIONS: MCFA octanoic acid is a central signaling nutrient that targets POMC neurons via distinct direct and indirect signal transduction pathways to instigate changes in energy status. These results could explain the beneficial health effects that accompany MCFA consumption.


Assuntos
Caprilatos/metabolismo , Metabolismo Energético , Neurônios/metabolismo , Animais , Masculino , Ratos , Ratos Wistar
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(2): 322-327, 2017 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28446269

RESUMO

OBJECTIVE: To explore the expression of death-associated protein kinase 1(DAPK1) in chronic lymphocytic leukemia(CLL). METHODS: The DAPK1 expression was studied by means of MEC1 cells and B lymphocytes from blood samples of the patients with CLL. The quantitative detection of mRNA and Western blot were used to detecte the expression of DAPK1 and autophagy-related genes at both mRNA and protein levels. RESULTS: mRNA quantitative detection and Western blot displayed that the DAPK1 expression in the patients with CLL was silenced. So, the expression of DAPK1 and autophagy related genes in MEC1 cells was not significantly different, no matter the cells were treated with or without INF-γ. CONCLUSION: Scilencing of DAPK1 expression in CLL results in abnormality of autophagy behavior, thus leading to the occurence of disease.


Assuntos
Proteínas Quinases Associadas com Morte Celular/genética , Leucemia Linfocítica Crônica de Células B/genética , Linfócitos B , Humanos , RNA Mensageiro
6.
Curr Protoc Pharmacol ; 66: 11.15.1-11.15.26, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25181009

RESUMO

Neuropathic pain develops following nerve injury, and is a chronic pain syndrome that can persist long after repair of a wound or removal of the neurological insult. This condition remains poorly treated, not least because of a lack of mechanism-based therapeutics. Clinically, neuropathic pain is characterized by three major symptoms: thermal or mechanical allodynia (pain sensation in response to previously non-noxious stimuli); hyperalgesia (enhanced pain sensation to noxious stimulation); and spontaneous, ongoing pain. These clinical symptoms can be modeled in rodent neuropathic pain models using behavioral and electrophysiological readouts. This unit describes techniques designed to record pathophysiological electrical activity associated with neuropathic pain at the level of the periphery, in single fibers of primary sensory neurons, and from wide dynamic range (WDR) neurons of the dorsal horn of the spinal cord. These techniques can be employed in both naïve animals and in animal models of neuropathy to investigate fundamental mechanisms contributing to the neuropathic pain state and the site, mode, and mechanism of action of putative analgesics.


Assuntos
Modelos Animais de Doenças , Neuralgia/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Técnicas Eletrofisiológicas Cardíacas , Fenômenos Eletrofisiológicos/fisiologia , Masculino , Nervos Periféricos/fisiopatologia , Nervos Periféricos/cirurgia , Células do Corno Posterior/fisiologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/fisiopatologia
7.
Curr Protoc Pharmacol ; 64: 11.11.1-17, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26344209

RESUMO

Understanding the physiology, pharmacology, and plasticity associated with synaptic function is a key goal of neuroscience research and is fundamental to identifying the processes involved in the development and manifestation of neurological disease. A diverse range of electrophysiological methodologies are used to study synaptic function. Described in this unit is a technique for recording electrical activity from a single component of the central nervous system that is used to investigate pre- and post-synaptic elements of synaptic function. A strength of this technique is that it can be used on live animals, although the effect of anesthesia must be taken into consideration when interpreting the results. This methodology can be employed not only in naïve animals for studying normal physiological synaptic function, but also in a variety of disease models, including transgenic animals, to examine dysfunctional synaptic plasticity associated with neurological pathologies.


Assuntos
Região CA1 Hipocampal/fisiologia , Sinapses/fisiologia , Animais , Eletrodos , Fenômenos Eletrofisiológicos , Ratos , Transmissão Sináptica/fisiologia
8.
J Pharmacol Exp Ther ; 345(3): 502-11, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23520265

RESUMO

Inhibition of d-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury. In addition, SUN was efficacious against complete Freund's adjuvant-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates of increase in brain and plasma d-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically evoked responses of central spinal cord dorsal horn neurons and compared these with spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. After intravenous administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.


Assuntos
D-Aminoácido Oxidase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neuralgia/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Aminas/farmacologia , Analgésicos/farmacologia , Anestesia , Animais , Comportamento Animal/efeitos dos fármacos , Constrição Patológica/patologia , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Adjuvante de Freund , Furanos/farmacologia , Gabapentina , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Hiperalgesia/psicologia , Ligadura , Masculino , Estimulação Física , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Serina/farmacocinética , Nervos Espinhais/fisiologia , Ácido gama-Aminobutírico/farmacologia
9.
J Formos Med Assoc ; 109(6): 438-45, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20610145

RESUMO

BACKGROUND/PURPOSE: Rats display behavioral signs of neuropathic pain lasting for months in the chronic constriction injury (CCI) model. During intrathecal anesthesia, the administered drugs mainly diffuse directly into the superficial neurons in the spinal dorsal horn. This study aimed to investigate the effect of bath application of norepinephrine on whole cell patch clamp recordings from spinal cord slices of CCI rats with allodynia. METHODS: An assessment of paw withdrawal threshold in response to mechanical stimulation was performed on the operated side on the day before surgery and was repeated after recovery from anesthesia and on the 7(th) and 14(th) days after surgery. Spinal cord slice preparations containing dorsal horn neurons were obtained from both sham-operated rats and CCI rats (after the 14(th) postoperative day behavior test). RESULTS: Compared with normal controls, CCI rats had significantly lower levels of both hyperpolarization and spike threshold in single action potentials recorded from lamina I and II neurons of the spinal dorsal horn. In contrast, a series of action potential recordings showed that the percentage of spiking neurons of the spinal dorsal horn of CCI rats were significantly higher than those of normal controls. The CCI-induced reduction in hyperpolarization, as well as the increased numbers of spinal dorsal horn spiking neurons could be significantly reduced by norepinephrine application. The norepinephrine-induced increased hyperpolarization and input resistance could be abolished by the application of an alpha(2)-adrenoceptor antagonist (idazoxan; 200 nM). CONCLUSION: The results suggest that chronic nerve injury may induce neuropathic pain by increasing the excitability of spinal dorsal horn neurons. This excitability can be reduced by norepinephrine.


Assuntos
Norepinefrina/farmacologia , Células do Corno Posterior/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Idazoxano/farmacologia , Masculino , Ratos , Ratos Wistar , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/fisiopatologia
10.
Pain ; 128(1-2): 78-87, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17055166

RESUMO

There are several lines of evidence to suggest that cyclooxygenase-2 (COX-2) plays an important role in the generation and maintenance of neuropathic pain states following peripheral nerve injury. However, COX-2 inhibitors are generally ineffective in reversing mechanical allodynia and hyperalgesia in models of neuropathic hypersensitivity. Here, we have investigated the effects of GW406381, a novel COX-2 inhibitor, on mechanical allodynia, hyperalgesia and generation of spontaneous ectopic discharge in rats following chronic constriction injury (CCI) of the sciatic nerve and compared it with rofecoxib. GW406381 (5mg/kg, 5 days of treatment) significantly reversed the CCI-induced decrease in paw withdrawal thresholds (PWTs), assessed using both von Frey hair and paw pressure tests, whereas an equi-effective dose of rofecoxib (5mg/kg, 5 days of treatment) in inflammatory pain models was ineffective. In rats treated with GW406381, the proportion of fibres showing spontaneous activity was significantly lower (15.58%) than that in the vehicle (32.67%)- and rofecoxib (39.66%)-treated rats. Ibuprofen, a non-selective COX inhibitor, at 5mg/kg, orally dosed three times a day for 5 days did not significantly affect the PWTs in CCI rats. In naïve rats, GW406381 did not significantly change the PWTs. These results illustrate that COX-2 may indeed play an important role in the maintenance of neuropathic pain following nerve injury, but that only certain COX-2 inhibitors, such as GW406381, are effective in this paradigm. Whilst the mechanisms underlying this differential effect of GW406381 are not clear, differences in drug/enzyme kinetic interactions may be a key contributing factor.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Hidrocarbonetos Aromáticos/administração & dosagem , Hiperalgesia/fisiopatologia , Síndromes de Compressão Nervosa/fisiopatologia , Nitrogênio/administração & dosagem , Nervo Sural/lesões , Nervo Sural/fisiopatologia , Animais , Doença Crônica , Constrição Patológica/tratamento farmacológico , Constrição Patológica/fisiopatologia , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Lactonas/administração & dosagem , Masculino , Síndromes de Compressão Nervosa/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Pirazóis , Piridazinas , Ratos , Ratos Sprague-Dawley , Sulfonas/administração & dosagem , Nervo Sural/efeitos dos fármacos
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