DORES NEUROPÁTICAS E CANAIS IÔNICOS
Com o aprofundamento dos estudos dos mecanismos das dores agudas e crônicas e do processo de sensitização, temos contato com a importância dos aspectos bioquímicos dos canais iônicos. Novas pesquisas avançam na busca de novas drogas que possam agir nestes processos celulares e, aos poucos, percebemos o grande desafio das novas gerações na busca do controle das dores neuropáticas centrais e periféricas, entre elas as lombalgias, as ciatalgias, as cervicalgias, etc.
Não podemos continuar a tratar as dores com "panos mornos", ou seja, com processos empíricos e inespecíficos, sejam eles por terapias físicas ou químicas de ordem geral. Precisamos avançar com maior rigor científico e devemos ter uma boa interação laboratório-clínica, para a mais rápida adoção de protocolos eficazes.
É neste contexto que a equipe do Centro Médico da Coluna Vertebral tem participado dos grandes eventos mundiais sobre o tema DOR. Já estivemos várias vezes na Europa para congressos das federadas européias da IASP, no Congresso NeuPsig e estaremos em poucos meses na Alemanha, para o importante congresso de Hamburgo. É a oportunidade de ter acesso às novas drogas e protocolos clínicos em uso, para rápida disponibilização à nossa clientela.
Foi através da participação em congressos e de diversas vistas técnicas aos maiores serviçoes de tratamento de dor musculoesquelética da Europoa, que desenvolvemos o protocolo clínico-intervencionistas da Neuroporação, já apresentado oficialmente à comunidade médica brasileira no último Congresso de Cirurgia Espinhal, como uma arma de alta resolutividade para os casos até agora sem solução, com uma eficácia superior a todos os métodos em uso corrente, na especialidade da coluna vertebral.
Aproveitem a leitura e façam dela o início de um caminho de busca de um mais efetivo alívio para nossos paciente.
Dr Henrique da Mota
Recomendamos, ainda, a leitura do seguinte artigo: Contribution of Ion Channels in Pain Sensation
Não podemos continuar a tratar as dores com "panos mornos", ou seja, com processos empíricos e inespecíficos, sejam eles por terapias físicas ou químicas de ordem geral. Precisamos avançar com maior rigor científico e devemos ter uma boa interação laboratório-clínica, para a mais rápida adoção de protocolos eficazes.
É neste contexto que a equipe do Centro Médico da Coluna Vertebral tem participado dos grandes eventos mundiais sobre o tema DOR. Já estivemos várias vezes na Europa para congressos das federadas européias da IASP, no Congresso NeuPsig e estaremos em poucos meses na Alemanha, para o importante congresso de Hamburgo. É a oportunidade de ter acesso às novas drogas e protocolos clínicos em uso, para rápida disponibilização à nossa clientela.
Foi através da participação em congressos e de diversas vistas técnicas aos maiores serviçoes de tratamento de dor musculoesquelética da Europoa, que desenvolvemos o protocolo clínico-intervencionistas da Neuroporação, já apresentado oficialmente à comunidade médica brasileira no último Congresso de Cirurgia Espinhal, como uma arma de alta resolutividade para os casos até agora sem solução, com uma eficácia superior a todos os métodos em uso corrente, na especialidade da coluna vertebral.
Aproveitem a leitura e façam dela o início de um caminho de busca de um mais efetivo alívio para nossos paciente.
Dr Henrique da Mota
Recomendamos, ainda, a leitura do seguinte artigo: Contribution of Ion Channels in Pain Sensation
What are ion channels?
Ion channels are transmembrane pores which allow the passage of ions (charged particles) into and out of a cell down the electrochemical gradient. There are hundreds of different ion channels and they are distinguished based upon their ion selectivity, gating mechanism, and sequence similarity. Ion channels can be voltage-gated, ligand-gated, pH-gated, or mechanically gated. These gating criteria along with a combination of sequence similarity and ion selectivity further subdivides ion channels into several subtypes:
Voltage-gated potassium channels
Voltage-gated K channels are activated by membrane depolarization. As with all voltage-gated ion channels, depolarization results in a conformational change in the S4 voltage sensor which contains positively charged amino acids. This conformational change triggers additional conformational changes leading to channel opening. Upon depolarization, these channels open, allowing the efflux of potassium from the cell, down its electrochemical gradient. They function in the heart and brain to repolarize the membrane potential and to terminate an action potential. A-type potassium currents are quickly inactivating potassium currents (eg, Kv4.2 and Kv1.4) and are important in the initial notch of repolarization in cardiac cells and the fast-spiking behavior of some neurons. Slowly inactivating channels provide more prolonged repolarization effects (eg, Kv1.5, Kv3.1, Kv2.1). hERG (human ether-a-go-go) channels are unusual voltage-gated potassium channels in that they are inwardly rectifying due to accelerated inactivation at positive voltages. hERG channels play a role in long-QT syndrome and block of hERG can precipitate torsades de pointe which may lead to fatal ventricular fibrillation. Screening of drugs for effects on hERG is now required of all investigational compounds.
Other potassium channels
Other potassium channels include the inwardly rectifying potassium channels which are not voltage-gated, but allow influx of potassium ions upon hyperpolarization which dislodges magnesium from a binding site in the pore. Calcium activated potassium channels are activated both by voltage and by intracellular calcium. Two-pore domain potassium channels have a double-barrelled pore and are gated by different mechanisms including oxygen, pH, stretch, and G-proteins.
Voltage-gated calcium channels
Opening of voltage-gated calcium channels results in influx of calcium ions into the cell. This influx of calcium plays an important role in excitation-contraction coupling in cardiac and skeletal muscle fibers. The reversal potential for calcium is extremely positive, so calcium current is almost always inward, resulting in an action potential plateau in many excitable cells. These channels are the target of calcium channel blocker subtype of antihypertensive drugs. The alpha-1 subunit forms the ion conducting pore, with several modulating auxiliary subunits. Major subtypes of voltage-gated calcium channels include L-type (Cav1.1, Cav1.2, Cav1.3, Cav1.4), T-type (Cav3.1, Cav3.2, Cav3.3), N-type (Cav2.2), P-type (Cav2.1), and R-type (Cav2.3).
Voltage-gated sodium channels
These channels are responsible for action potential creation and propagation. These channels open and inactivate very rapidly, allowing the influx of sodium down its concentration gradient. Like calcium, the reversal potential of sodium is very positive and sodium current is always inward. The alpha subunit form the ion conducting pore and beta subunits modulate channel activity.
Chloride channels
These channels are important for setting the resting membrane potential and the maintenance of cell volume. Chloride channels vary greatly in structure, gating mechanism, and physiological function.
Transient receptor potential channels
These channels are also known as TRP channels. These channels are very diverse in their physiological function. TRP channels also vary greatly in their selectivity for calcium and gating mechanism. TRP channels are subdivided into 6 subfamilies based upon homology: vanilloid (TRPV), classical (TRPC), melastatin (TRPM), mucolipins (TRPML), ankyrin transmembrane protein-1 (TRPA), and polycystins (TRPP).
Cyclic nucleotide gated channels
This superfamily of ion channels is subdivided into the cyclic nucleotide gated channels (CNG) and hyperpolarization-activated cyclic nucleotide gated channels (HCN). CNG channels are activated by the binding of intracellular cAMP or cGMP. They are permeable to cations such as K+ and Na+. HCN channels are opened by hyperpolarization, and are also sensitive to cAMP and cGMP which alter the voltage-sensitivity of channel opening. HCN channels function as pacemaking channels in the heart SA node and in some neurons.
Ligand-gated channels
Ligand-gated ion channels open in response to binding of specific ligands to extracellular sites. They are also known as ionotropic receptors. Examples of these channels include the [[nicotinic acetylcholine receptor]], glutamate-gated receptors, GABA-A receptors,ATP-gated P2X receptors, and the 5HT3 serotonin receptor.
Ion channels are transmembrane pores which allow the passage of ions (charged particles) into and out of a cell down the electrochemical gradient. There are hundreds of different ion channels and they are distinguished based upon their ion selectivity, gating mechanism, and sequence similarity. Ion channels can be voltage-gated, ligand-gated, pH-gated, or mechanically gated. These gating criteria along with a combination of sequence similarity and ion selectivity further subdivides ion channels into several subtypes:
Voltage-gated potassium channels
Voltage-gated K channels are activated by membrane depolarization. As with all voltage-gated ion channels, depolarization results in a conformational change in the S4 voltage sensor which contains positively charged amino acids. This conformational change triggers additional conformational changes leading to channel opening. Upon depolarization, these channels open, allowing the efflux of potassium from the cell, down its electrochemical gradient. They function in the heart and brain to repolarize the membrane potential and to terminate an action potential. A-type potassium currents are quickly inactivating potassium currents (eg, Kv4.2 and Kv1.4) and are important in the initial notch of repolarization in cardiac cells and the fast-spiking behavior of some neurons. Slowly inactivating channels provide more prolonged repolarization effects (eg, Kv1.5, Kv3.1, Kv2.1). hERG (human ether-a-go-go) channels are unusual voltage-gated potassium channels in that they are inwardly rectifying due to accelerated inactivation at positive voltages. hERG channels play a role in long-QT syndrome and block of hERG can precipitate torsades de pointe which may lead to fatal ventricular fibrillation. Screening of drugs for effects on hERG is now required of all investigational compounds.
Other potassium channels
Other potassium channels include the inwardly rectifying potassium channels which are not voltage-gated, but allow influx of potassium ions upon hyperpolarization which dislodges magnesium from a binding site in the pore. Calcium activated potassium channels are activated both by voltage and by intracellular calcium. Two-pore domain potassium channels have a double-barrelled pore and are gated by different mechanisms including oxygen, pH, stretch, and G-proteins.
Voltage-gated calcium channels
Opening of voltage-gated calcium channels results in influx of calcium ions into the cell. This influx of calcium plays an important role in excitation-contraction coupling in cardiac and skeletal muscle fibers. The reversal potential for calcium is extremely positive, so calcium current is almost always inward, resulting in an action potential plateau in many excitable cells. These channels are the target of calcium channel blocker subtype of antihypertensive drugs. The alpha-1 subunit forms the ion conducting pore, with several modulating auxiliary subunits. Major subtypes of voltage-gated calcium channels include L-type (Cav1.1, Cav1.2, Cav1.3, Cav1.4), T-type (Cav3.1, Cav3.2, Cav3.3), N-type (Cav2.2), P-type (Cav2.1), and R-type (Cav2.3).
Voltage-gated sodium channels
These channels are responsible for action potential creation and propagation. These channels open and inactivate very rapidly, allowing the influx of sodium down its concentration gradient. Like calcium, the reversal potential of sodium is very positive and sodium current is always inward. The alpha subunit form the ion conducting pore and beta subunits modulate channel activity.
Chloride channels
These channels are important for setting the resting membrane potential and the maintenance of cell volume. Chloride channels vary greatly in structure, gating mechanism, and physiological function.
Transient receptor potential channels
These channels are also known as TRP channels. These channels are very diverse in their physiological function. TRP channels also vary greatly in their selectivity for calcium and gating mechanism. TRP channels are subdivided into 6 subfamilies based upon homology: vanilloid (TRPV), classical (TRPC), melastatin (TRPM), mucolipins (TRPML), ankyrin transmembrane protein-1 (TRPA), and polycystins (TRPP).
Cyclic nucleotide gated channels
This superfamily of ion channels is subdivided into the cyclic nucleotide gated channels (CNG) and hyperpolarization-activated cyclic nucleotide gated channels (HCN). CNG channels are activated by the binding of intracellular cAMP or cGMP. They are permeable to cations such as K+ and Na+. HCN channels are opened by hyperpolarization, and are also sensitive to cAMP and cGMP which alter the voltage-sensitivity of channel opening. HCN channels function as pacemaking channels in the heart SA node and in some neurons.
Ligand-gated channels
Ligand-gated ion channels open in response to binding of specific ligands to extracellular sites. They are also known as ionotropic receptors. Examples of these channels include the [[nicotinic acetylcholine receptor]], glutamate-gated receptors, GABA-A receptors,ATP-gated P2X receptors, and the 5HT3 serotonin receptor.
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