Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Neurobiol ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33411247

RESUMO

Somatostatin (SST) and its analogues like octreotide (OCT) have analgesic effect on a variety of pain through peripheral SST receptors (SSTRs). However, the precise molecular mechanisms have not yet been fully elucidated. This research aimed to identify possible antinociceptive mechanisms, showing functional links of the SSTR2 and acid-sensing ion channels (ASICs). Herein, we reported that OCT inhibited the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. OCT concentration-dependently decreased the peak amplitude of acid-evoked inward currents, which were mediated by ASICs. OCT shifted concentration-response curve to protons downwards, with a decrease of 36.53 ± 5.28% in the maximal current response to pH 4.5 in the presence of OCT. OCT inhibited ASIC-mediated currents through SSTR2, since the inhibition was blocked by Cyn 154806, a specific SSTR2 antagonist. The OCT inhibition of ASIC-mediated currents was mimicked by H-89, a membrane-permeable inhibitor of PKA, and reversed by internal treatment of an adenylyl cyclase activator forskolin or 8-Br-cAMP. OCT also decreased the number of action potentials induced by acid stimuli through SSTR2. Finally, peripheral administration of 20 µM OCT, but not 2 µM OCT, significantly relieved nociceptive responses to intraplantar injection of acetic acid in rats. This occurred through local activation of SSTR2 in the injected hindpaw and was reversed following co-application of Cyn 154806. Our results indicate that activation SSTR2 by OCT can inhibit the activity of ASICs via an intracellular cAMP and PKA signaling pathway in rat DRG neurons. These observations demonstrate a cross-talk between ASICs and SSTR2 in peripheral sensory neurons, which was a novel peripheral analgesic mechanism of SST and its analogues.

2.
Neuropharmacology ; 181: 108356, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069757

RESUMO

Endothelin-1 (ET-1), an endogenous vasoconstrictor, has been known as a pro-nociceptive agent involved in multitude of pain. ET-1 acts on endothelin receptors on vascular endothelial cells, sensitizes release of ATP, which then acts on P2X3 receptors on nociceptors and results in mechanical hyperalgesia. Both endothelin receptors and P2X3 receptors are present in primary sensory neuron, where it remains unclear whether there is an interaction between them. Herein, we reported that ET-1 potentiated the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. ET-1 concentration-dependently increased α,ß-methylene-ATP (α,ß-meATP)-evoked inward currents, which were mediated by P2X3 receptors. ET-1 shifted the α,ß-meATP concentration-response curve upwards, with an increase of 34.38 ± 4.72% in the maximal current response to α,ß-meATP in the presence of ET-1. ET-1 potentiation of α,ß-meATP-evoked currents was voltage-independent. ET-1 potentiated P2X3 receptor-mediated currents through endothelin-A receptors (ETAR), but not endothelin-B receptors (ETBR). ET-1 potentiation was supressed by blockade of intracellular G-protein or protein kinase C (PKC) signaling. Moreover, there is a synergistic effect on mechanical allodynia induced by intraplantar injection of ET-1 and α,ß-meATP in rats. Pharmacological blockade of P2X3 receptors also alleviated ET-1-induced mechanical allodynia. These results suggested that ET-1 sensitized P2X3 receptors in primary sensory neurons via an ETAR and PKC signaling pathway. Our data provide evidence that cutaneous ET-1 induced mechanical allodynia not only by increasing the release of ATP from vascular endothelial cells, but also by sensitizing P2X3 receptors on nociceptive DRG neurons.

3.
Acta Pharmacol Sin ; 41(8): 1049-1057, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32107467

RESUMO

Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid-sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1-100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration-response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETAR), but not endothelin-B receptor (ETBR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETAR. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETAR and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.

4.
Neuropharmacology ; 165: 107816, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31874168

RESUMO

Contactin-associated protein-like 2 (CNTNAP2 or CASPR2) is a neuronal transmembrane protein of the neurexin superfamily that is involved in many neurological diseases, such as autism and pain hypersensitivity. We recently found that Cntnap2-/- mice showed elevated Akt-mTOR activity in the brain, and suppression of the Akt-mTOR pathway rescued the social deficit in Cntnap2-/- mice. In this study, we found that the dorsal root ganglion (DRG) from Cntnap2-/- mice also showed hyperactive Akt-mTOR signaling. Treatment with the Akt inhibitor LY94002 or the mTOR inhibitor rapamycin attenuated pain-related hypersensitivity to noxious mechanical stimuli, heat, and inflammatory substances. Further, suppression of mTOR signaling by rapamycin decreased DRG neuronal hyperexcitability. We further indicated that treatment with the FDA-approved drug metformin normalized the hyperactive Akt-mTOR signaling, and attenuated pain-related hypersensitivity in Cntnap2-/- mice. Our results thus identified hyperactive Akt-mTOR signaling pathway as a promising therapeutic target for pain-related hypersensitivity in patients with dysfunction of CNTNAP2.

5.
Brain Res ; 1724: 146442, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513790

RESUMO

Prostaglandin E2 (PGE2) and proton are typical inflammatory mediators. They play a major role in pain processing and hypersensitivity through activating their cognate receptors expressed in terminals of nociceptive sensory neurons. However, it remains unclear whether there is an interaction between PGE2 receptors and proton-activated acid-sensing ion channels (ASICs). Herein, we show that PGE2 enhanced the functional activity of ASICs in rat dorsal root ganglion (DRG) neurons through EP1 and EP4 receptors. In the present study, PGE2 concentration-dependently increased ASIC currents in DRG neurons. It shifted the proton concentration-response curve upwards, without change in the apparent affinity of proton for ASICs. Moreover, PGE2 enhancement of ASIC currents was partially blocked by EP1 or EP4 receptor antagonist. PGE2 failed to enhance ASIC currents when simultaneous blockade of both EP1 and EP4 receptors. PGE2 enhancement was partially suppressed after inhibition of intracellular PKC or PKA signaling, and completely disappeared after concurrent blockade of both PKC and PKA signaling. PGE2 increased significantly the expression levels of p-PKCε and p-PKA in DRG cells. PGE2 also enhanced proton-evoked action potentials in rat DRG neurons. Finally, peripherally administration of PGE2 dose-dependently exacerbated acid-induced nocifensive behaviors in rats through EP1 and EP4 receptors. Our results indicate that PGE2 enhanced the electrophysiological activity of ASICs in DRG neurons and contributed to acidosis-evoked pain, which revealed a novel peripheral mechanism underlying PGE2 involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Gânglios Espinais/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Canais Iônicos Sensíveis a Ácido/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Dinoprostona/metabolismo , Dinoprostona/fisiologia , Hiperalgesia/metabolismo , Masculino , Neurônios/metabolismo , Nociceptores/metabolismo , Dor/fisiopatologia , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP2/fisiologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
6.
J Neurosci Res ; 97(10): 1298-1305, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31240740

RESUMO

Transforming growth factor-ß1 (TGF-ß1) is an important member of multifunctional growth factor superfamily. It has been implicated in pain signaling, but little is known about the underlying mechanisms. Herein, we report that TGF-ß1 can exert a sustained enhancing effect on the functional activity of acid-sensing ion channels (ASICs) in rat dorsal root ganglia (DRG) neurons. Pre-application of TGF-ß1 increased the amplitude of proton-gated currents in a dose-dependent manner. Enhancement of ASIC currents lasted for more than 30 min although TGF-ß1 was treated once only. This sustained enhancement by TGF-ß1 could be blocked by extracellular treatment of selective TGF-ß receptor I antagonist SD-208, and abolished by blockade of intracellular several non-Smad-signaling pathways. TGF-ß1 also sustainedly enhanced proton-evoked spikes in rat DRG neurons. Moreover, peripheral pre-treatment with TGF-ß1 dose-dependently exacerbated nociceptive behaviors evoked by intraplantar injection of acetic acid through TGF-ß receptor I in rats. These results suggested that TGF-ß1 potentiated ASIC-mediated electrophysiological activity and nociceptive behaviors, which revealed a novel mechanism underlying TGF-ß1 implicated in peripheral pain signaling by sensitizing ASICs.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Nociceptividade/fisiologia , Dor Nociceptiva/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Gânglios Espinais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
7.
Neurosci Lett ; 684: 200-204, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30114476

RESUMO

Sex differences occur in nociceptive pain, and estrogens are involved in the sex differences. Our previous study shows sex differences exist in acidosis-induced nociception in rats, with females being more sensitive than males to acetic acid. However, the mechanisms underlying the sex differences remain unclear. We report here17ß-estradiol (E2) up-regulates expression of acid-sensing ion channel 3 (ASIC3), which can mediate the acidosis-induced events. The recombinant plasmid of pCDNA3.1-ASIC3-GFP and pCDNA3.1-estrogen receptor α (ERα) were cotransfected to 293 T cells by lipid transfection method. And western blot assays showed expression of ASIC3. We found that E2 markedly increases ASIC3 protein expression in a dose- and time- dependent manner in 293 T cells expressing ASIC3 and ERα. The up-regulating effect of E2 on ASIC3 protein expression is almost completely blocked by the addition of MPP, a specific ERα antagonist. We also observed that sex differences occur in ASIC3 expression in rat dorsal root ganglia (DRG) and in acetic acid-induced nociceptive responses. ASIC3 protein expression in female rat DRG is higher than those in male rat DRG. And female rats are more sensitive to acetic acid-induced nociception than males. ASIC3 protein expression in DRG decreases significantly after ovariectomy, but not after orchiectomy. These results suggest that E2 up-regulates ASIC3 expression through ERα, which may contribute to sex differences in acetic acid-induced nociception.


Assuntos
Canais Iônicos Sensíveis a Ácido/biossíntese , Estradiol/farmacologia , Estrogênios/farmacologia , Caracteres Sexuais , Regulação para Cima/fisiologia , Canais Iônicos Sensíveis a Ácido/genética , Animais , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Expressão Gênica , Células HEK293 , Humanos , Masculino , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
8.
Oncotarget ; 8(54): 93051-93062, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190977

RESUMO

Peroxisome proliferator-activated receptor-α (PPAR-α), a lipid activated transcription factor of nuclear hormone receptor superfamily, can relieve pain through a rapid-response mechanism. However, little is known about the underlying mechanism. Herein, we report that PPAR-α activation acutely inhibits the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglion (DRG) neurons. Pre-application of PPAR-α agonist GW7647 for 2 min decreased the amplitude of proton-gated currents mediated by ASICs in a concentration-dependent manner. GW7647 shifted the concentration-response curve for proton downwards, with a decrease of 36.9 ± 2.3% in the maximal current response to proton. GW7647 inhibition of proton-gated currents can be blocked by GW6471, a selective PPAR-α antagonist. Moreover, PPAR-α activation decreased the number of acidosis-evoked action potentials in rat DRG neurons. Finally, peripheral administration of GW7647 dose-dependently relieved nociceptive responses to injection of acetic acid in rats. These results indicated that activation of peripheral PPAR-α acutely inhibited functional activity of ASICs in a non-genomic manner, which revealed a novel mechanism underlying rapid analgesia through peripheral PPAR-α.

9.
J Neuroinflammation ; 14(1): 150, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754162

RESUMO

BACKGROUND: Tissue acidosis and inflammatory mediators play critical roles in pain. Pro-inflammatory agents trypsin and tryptase cleave and activate proteinase-activated receptor 2 (PAR2) expressed on sensory nerves, which is involved in peripheral mechanisms of inflammation and pain. Extracellular acidosis activates acid-sensing ion channel 3 (ASIC3) to trigger pain sensation. Here, we show that a functional interaction of PAR2 and ASIC3 could contribute to acidosis-induced nociception. METHODS: Electrophysiological experiments were performed on both rat DRG neurons and Chinese hamster ovary (CHO) cells expressing ASIC3 and PAR2. Nociceptive behavior was induced by acetic acid in rats. RESULTS: PAR2-AP, PAR2-activating peptide, concentration-dependently increased the ASIC3 currents in CHO cells transfected with ASIC3 and PAR2. The proton concentration-response relationship was not changed, but that the maximal response increased 58.7 ± 3.8% after pretreatment of PAR2-AP. PAR2 mediated the potentiation of ASIC3 currents via an intracellular cascade. PAR2-AP potentiation of ASIC3 currents disappeared after inhibition of intracellular G protein, PLC, PKC, or PKA signaling. Moreover, PAR2 activation increased proton-evoked currents and spikes mediated by ASIC3 in rat dorsal root ganglion neurons. Finally, peripheral administration of PAR2-AP dose-dependently exacerbated acidosis-induced nocifensive behaviors in rats. CONCLUSIONS: These results indicated that PAR2 signaling sensitized ASIC3, which may contribute to acidosis-induced nociception. These represent a novel peripheral mechanism underlying PAR2 involvement in hyperalgesia by sensitizing ASIC3 in primary sensory neurons.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/complicações , Nociceptividade/fisiologia , Dor/induzido quimicamente , Receptor PAR-2/metabolismo , Transdução de Sinais/fisiologia , Canais Iônicos Sensíveis a Ácido/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Células CHO , Células Cultivadas , Cricetulus , Modelos Animais de Doenças , Gânglios Espinais/citologia , Concentração de Íons de Hidrogênio , Masculino , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Oligopeptídeos/farmacologia , Técnicas de Patch-Clamp , Ratos , Receptor PAR-2/genética , Transdução de Sinais/efeitos dos fármacos
10.
Pharmacol Res ; 107: 19-26, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26946972

RESUMO

Glutamate activates peripheral group I metabotropic glutamate receptors (mGluRs) and contributes to inflammatory pain. However, it is still not clear the mechanisms are involved in group I mGluR-mediated peripheral sensitization. Herein, we report that group I mGluRs signaling sensitizes acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons and contributes to acidosis-evoked pain. DHPG, a selective group I mGluR agonist, can potentiate the functional activity of ASICs, which mediated the proton-induced events. DHPG concentration-dependently increased proton-gated currents in DRG neurons. It shifted the proton concentration-response curve upwards, with a 47.3±7.0% increase of the maximal current response to proton. Group I mGluRs, especially mGluR5, mediated the potentiation of DHPG via an intracellular cascade. DHPG potentiation of proton-gated currents disappeared after inhibition of intracellular Gq/11 proteins, PLCß, PKC or PICK1 signaling. Moreover, DHPG enhanced proton-evoked membrane excitability of rat DRG neurons and increased the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, peripherally administration of DHPG dose-dependently exacerbated nociceptive responses to intraplantar injection of acetic acid in rats. Potentiation of ASIC activity by group I mGluR signaling in rat DRG neurons revealed a novel peripheral mechanism underlying group I mGluRs involvement in hyperalgesia.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Gânglios Espinais/fisiologia , Neurônios/fisiologia , Dor/fisiopatologia , Receptores de Glutamato Metabotrópico/fisiologia , Ácido Acético , Acidose/complicações , Acidose/fisiopatologia , Animais , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Neurônios/efeitos dos fármacos , Dor/induzido quimicamente , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Tetrodotoxina/farmacologia
11.
Neuropharmacology ; 103: 174-82, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26188144

RESUMO

Prolactin (PRL) is a polypeptide hormone produced and released from the pituitary and extrapituitary tissues. It regulates activity of nociceptors and causes hyperalgesia in pain conditions, but little is known the molecular mechanism. We report here that PRL can exert a potentiating effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons. First, PRL dose-dependently increased the amplitude of ASIC currents with an EC50 of (5.89 ± 0.28) × 10(-8) M. PRL potentiation of ASIC currents was also pH dependent. Second, PRL potentiation of ASIC currents was blocked by Δ1-9-G129R-hPRL, a PRL receptor antagonist, and removed by intracellular dialysis of either protein kinase C inhibitor GF109203X, protein interacting with C-kinase 1(PICK1) inhibitor FSC-231, or PI3K inhibitor AS605240. Third, PRL altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Four, PRL exacerbated nociceptive responses to injection of acetic acid in female rats. Finally, PRL displayed a stronger effect on ASIC mediated-currents and nociceptive behavior in intact female rats than OVX female and male rats and thus modulation of PRL may be gender-dependent. These results suggest that PRL up-regulates the activity of ASICs and enhances ASIC mediated nociceptive responses in female rats, which reveal a novel peripheral mechanism underlying PRL involvement in hyperalgesia.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Gânglios Espinais/fisiologia , Prolactina/fisiologia , Células Receptoras Sensoriais/fisiologia , Ácido Acético/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Prolactina/análogos & derivados , Prolactina/farmacologia , Prótons , Ratos , Ratos Sprague-Dawley , Receptores da Prolactina/antagonistas & inibidores , Receptores da Prolactina/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Purinergic Signal ; 12(1): 69-78, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26538146

RESUMO

Peripheral purinergic signaling plays an important role in nociception. Increasing evidence suggests that metabotropic P2Y receptors are also involved, but little is known about the underlying mechanism. Herein, we report that selective P2Y receptor agonist uridine 5'-triphosphate (UTP) can exert an enhancing effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglia (DRG) neurons. First, UTP dose-dependently increased the amplitude of ASIC currents. UTP also shifted the concentration-response curve for proton upwards, with a 56.6 ± 6.4% increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine 5'-triphosphate (ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2Y receptor antagonist suramin and by inhibition of intracellular G protein, phospholipase C (PLC), protein kinase C (PKC), or protein interacting with C-kinase 1 (PICK1) signaling. Third, UTP altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, UTP dose-dependently exacerbated nociceptive responses to injection of acetic acid in rats. These results suggest that UTP enhanced ASIC-mediated currents and nociceptive responses, which reveal a novel peripheral mechanism underlying UTP-sensitive P2Y2 receptor involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.


Assuntos
Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Agonistas do Receptor Purinérgico P2Y/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Uridina Trifosfato/farmacologia , Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/fisiopatologia , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/farmacologia , Animais , Relação Dose-Resposta a Droga , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Dor/psicologia , Medição da Dor/efeitos dos fármacos , Prótons , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Uridina Trifosfato/antagonistas & inibidores
13.
Eur J Pharmacol ; 767: 24-9, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26435025

RESUMO

Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP-ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of α,ß-methylene ATP (α,ß-meATP). Third, PK2 concentration-dependently potentiated α,ß-meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of α,ß-meATP-induced mechanical allodynia and α,ß-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by α,ß-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Hormônios Gastrointestinais/farmacologia , Hiperalgesia/induzido quimicamente , Neuropeptídeos/farmacologia , Trifosfato de Adenosina/efeitos adversos , Trifosfato de Adenosina/farmacologia , Animais , Sinergismo Farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Hormônios Gastrointestinais/antagonistas & inibidores , Hiperalgesia/fisiopatologia , Indóis/farmacologia , Masculino , Maleimidas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neuropeptídeos/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores de Peptídeos/antagonistas & inibidores , Receptores Purinérgicos P2X3/efeitos dos fármacos , Receptores Purinérgicos P2X3/fisiologia
14.
Endocrinology ; 156(12): 4660-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26441237

RESUMO

Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17ß-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERß agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.


Assuntos
Ácido Acético/farmacologia , Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Percepção da Dor/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitrilos/farmacologia , Nociceptores/metabolismo , Técnicas de Patch-Clamp , Fenóis/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo , Fatores Sexuais
15.
Neurosci Lett ; 593: 61-5, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25782631

RESUMO

Arginine vasopressin (AVP) plays a regulatory role in nociception. Intrathecal administration of AVP displays an antinociceptive effect. However, little is understood about the mechanism underlying spinal AVP analgesia. Here, we have found that spinal AVP dose dependently reduced the second, but not first, phase of formalin-induced spontaneous nociception in mice. The AVP analgesia was completely blocked by intrathecal injected SR 49059, a vasopressin-1A (V1A) receptor antagonist. However, spinal AVP failed to exert its antinociceptive effect on the second phase formalin-induced spontaneous nociception in V1A receptor knock-out (V1A-/-) mice. The AVP analgesia was also reversed by bicuculline, a GABAA receptor antagonist. Moreover, AVP potentiated GABA-activated currents in dorsal root ganglion neurons from wild-type littermates, but not from V1A-/- mice. Our results may reveal a novel spinal mechanism of AVP analgesia by enhancing the GABAA receptor function in the spinal cord through V1A receptors.


Assuntos
Arginina Vasopressina/metabolismo , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/psicologia , Receptores de GABA-A/metabolismo , Receptores de Vasopressinas/metabolismo , Medula Espinal/metabolismo , Analgésicos/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Arginina Vasopressina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Gânglios Espinais/fisiopatologia , Injeções Espinhais , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Medição da Dor , Receptores de Vasopressinas/genética , Medula Espinal/efeitos dos fármacos
16.
J Neurosci Res ; 93(2): 333-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25395088

RESUMO

Levo-tetrahydropalmatine (l-THP), a main bioactive Chinese herbal constituent from the genera Stephania and Corydalis, has been in use in clinical practice for years in China as a traditional analgesic agent. However, the mechanism underlying the analgesic action of l-THP is poorly understood. This study shows that l-THP can exert an inhibitory effect on the functional activity of native acid-sensing ion channels (ASICs), which are believed to mediate pain caused by extracellular acidification. l-THP dose dependently decreased the amplitude of proton-gated currents mediated by ASICs in rat dorsal root ganglion (DRG) neurons. l-THP shifted the proton concentration-response curve downward, with a decrease of 40.93% ± 8.45% in the maximum current response to protons, with no significant change in the pH0.5 value. Moreover, l-THP can alter the membrane excitability of rat DRG neurons to acid stimuli. It significantly decreased the number of action potentials and the amplitude of the depolarization induced by an extracellular pH drop. Finally, peripherally administered l-THP inhibited the nociceptive response to intraplantar injection of acetic acid in rats. These results indicate that l-THP can inhibit the functional activity of ASICs in dissociated primary sensory neurons and relieve acidosis-evoked pain in vivo, which for the first time provides a novel peripheral mechanism underlying the analgesic action of l-THP.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Alcaloides de Berberina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Gânglios Espinais/citologia , Neurônios/efeitos dos fármacos , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Concentração de Íons de Hidrogênio , Masculino , Potenciais da Membrana/efeitos dos fármacos , Dor/induzido quimicamente , Dor/prevenção & controle , Medição da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Prótons/efeitos adversos , Ratos , Ratos Sprague-Dawley
17.
J Circadian Rhythms ; 13: 2, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27103928

RESUMO

The mammalian circadian clock is composed of single-cell oscillators. Neurochemical and electrical signaling among these oscillators is important for the normal expression of circadian rhythms. Prokineticin 2 (PK2), encoding a cysteine-rich secreted protein, has been shown to be a critical signaling molecule for the regulation of circadian rhythms. PK2 expression in the suprachiasmatic nucleus (SCN) is highly rhythmic, peaking during the day and being essentially absent during the night. Mice with disrupted PK2 gene or its receptor PKR2 display greatly reduced rhythmicity of broad circadian parameters such as locomotor activity, body temperature and sleep/wake patterns. PK2 has been shown to increase the firing rate of SCN neurons, with unknown molecular mechanisms. Here we report that TRPV2, an ion channel belonging to the family of TRP, is co-expressed with PKR2 in the SCN neurons. Further, TRPV2 protein, but not TRPV2 mRNA, was shown to oscillate in the SCN in a PK2-dependent manner. Functional studies revealed that TRPV2 enhanced signaling of PKR2 in calcium mobilization or ion current conductance, likely via the increased trafficking of TRPV2 to the cell surface. Taken together, these results indicate that TRPV2 is likely part of the downstream signaling of PK2 in the regulation of the circadian rhythms.

18.
Sheng Li Xue Bao ; 66(6): 647-57, 2014 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-25516513

RESUMO

A growing number of studies have shown that arginine vasopressin (AVP) plays an analgesia role in the modulation of nociception. Previous studies have focused on the central mechanisms of AVP analgesia. The aim of the present study was to find out whether peripheral mechanisms are also involved. The effect of AVP on GABA-activated currents (IGABA) and GABAA receptor function in freshly isolated dorsal root ganglion (DRG) neurons of rats were studied using whole cell patch clamp technique. The result showed that, IGABA were potentiated by pre-treatment with AVP (1 × 10⁻¹°-1 × 10⁻5 mol/L) in a concentration-dependent manner. Meanwhile, the GABA concentration-response curve was shifted upwards, with an increase of (49.1 ± 4.0)% in the maximal current response but with no significant change in the EC50 values. These results indicate that the enhancing effect is non-competitive. In addition, the effects of AVP on IGABA might be voltage-independent. This potentiation of IGABA induced by AVP was almost completely blocked by the V1a receptor antagonist SR49059 (3 × 10⁻6 mol/L). Also it could be removed by intracellular dialysis of either GDP-ß-S (5 × 10⁻4mol/L), a non-hydrolyzable GDP analog, or GF109203X (2 × 10⁻6 mol/L), a selective protein kinase C (PKC) inhibitor, with the re-patch clamp. These results suggest that AVP up-regulates the function of the GABAA receptor via G protein-coupled receptors and PKC-dependent signal pathways in rat DRG neurons, and this potentiation may underlie the analgesia induced by AVP.


Assuntos
Arginina Vasopressina/farmacologia , Gânglios Espinais/citologia , Neurônios/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Guanosina Difosfato/análogos & derivados , Guanosina Difosfato/farmacologia , Indóis , Maleimidas , Potenciais da Membrana , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Transdução de Sinais , Tionucleotídeos/farmacologia
19.
Neurosci Lett ; 567: 35-9, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24680850

RESUMO

Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet. Recently, it is demonstrated to have potent antinociceptive effect. However, little is understood about the mechanism underlying CGA analgesia. Here, we have found that CGA can exert an inhibitory effect on the functional activity of native acid-sensing ion channels (ASICs) in rat dorsal root ganglion (DRG) neurons. First, CGA decreased the peak amplitude of proton-gated currents mediated by ASICs in a concentration-dependent manner. Second, CGA shifted the proton concentration-response curve downward, with a decrease of 41.76 ± 8.65% in the maximum current response to protons but with no significant change in the pH0.5 value. Third, CGA altered acidosis-evoked membrane excitability of rat DRG neurons and caused a significant decrease in the amplitude of the depolarization and the number of action potentials induced by acid stimuli. Finally, peripheral administered CGA attenuated nociceptive response to intraplantar injection of acetic acid in rats. ASICs are distributed in peripheral sensory neurons and participate in nociception. Our findings CGA inhibition of native ASICs indicated that CGA may exert analgesic action by modulating ASICs in the primary afferent neurons, which revealed a novel cellular and molecular mechanism underlying CGA analgesia.


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/fisiologia , Analgésicos/farmacologia , Ácido Clorogênico/farmacologia , Gânglios Espinais/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Ácido Acético , Potenciais de Ação , Animais , Membrana Celular/fisiologia , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Ativação do Canal Iônico , Masculino , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor/induzido quimicamente , Dor/fisiopatologia , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Células Receptoras Sensoriais/fisiologia
20.
Eur J Pharmacol ; 731: 50-7, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24642360

RESUMO

Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are believed to mediate pain caused by extracellular acidification. Gastrodin is a main bioactive constituent of the traditional herbal Gastrodia elata Blume, which has been widely used in Oriental countries for centuries. As an analgesic, gastrodin has been used clinically to treat pain such as migraine and headache. However, the mechanisms underlying analgesic action of gastrodin are still poorly understood. Here, we have found that gastrodin inhibited the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Gastrodin dose-dependently inhibited proton-gated currents mediated by ASICs. Gastrodin shifted the proton concentration-response curve downwards, with a decrease of 36.92 ± 6.23% in the maximum current response but with no significant change in the pH0.5 value. Moreover, gastrodin altered acid-evoked membrane excitability of rat DRG neurons and caused a significant decrease in the amplitude of the depolarization and the number of action potentials induced by acid stimuli. Finally, peripheral applied gastrodin relieved pain evoked by intraplantar injection of acetic acid in rats. Our results indicate that gastrodin can inhibit the activity of ASICs in the primary sensory neurons, which provided a novel mechanism underlying analgesic action of gastrodin.


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/metabolismo , Álcoois Benzílicos/farmacologia , Gânglios Espinais/citologia , Glucosídeos/farmacologia , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Formaldeído/farmacologia , Masculino , Nociceptividade/efeitos dos fármacos , Prótons , Ratos , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...