The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Diana Conte Camerino - One of the best experts on this subject based on the ideXlab platform.
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Involvement of voltage-gated sodium channels blockade in the analgesic effects of Orphenadrine.
PAIN, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Christelle Gaudioso, Patrick Delmas, Diana Conte CamerinoAbstract:Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that Orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that Orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that Orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant Orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of Orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
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use dependent block of voltage gated sodium channels by Orphenadrine through binding at the local anesthetic receptor
Biophysical Journal, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Diana Conte CamerinoAbstract:Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether Orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that Orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that Orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of Orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by Orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of Orphenadrine (Supported by Telethon-Italy grant GGP04140).
Jean François Desaphy - One of the best experts on this subject based on the ideXlab platform.
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Involvement of voltage-gated sodium channels blockade in the analgesic effects of Orphenadrine.
PAIN, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Christelle Gaudioso, Patrick Delmas, Diana Conte CamerinoAbstract:Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that Orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that Orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that Orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant Orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of Orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
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use dependent block of voltage gated sodium channels by Orphenadrine through binding at the local anesthetic receptor
Biophysical Journal, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Diana Conte CamerinoAbstract:Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether Orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that Orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that Orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of Orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by Orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of Orphenadrine (Supported by Telethon-Italy grant GGP04140).
Michela De Bellis - One of the best experts on this subject based on the ideXlab platform.
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Involvement of voltage-gated sodium channels blockade in the analgesic effects of Orphenadrine.
PAIN, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Christelle Gaudioso, Patrick Delmas, Diana Conte CamerinoAbstract:Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that Orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that Orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that Orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant Orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of Orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
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use dependent block of voltage gated sodium channels by Orphenadrine through binding at the local anesthetic receptor
Biophysical Journal, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Diana Conte CamerinoAbstract:Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether Orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that Orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that Orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of Orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by Orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of Orphenadrine (Supported by Telethon-Italy grant GGP04140).
Antonella Dipalma - One of the best experts on this subject based on the ideXlab platform.
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Involvement of voltage-gated sodium channels blockade in the analgesic effects of Orphenadrine.
PAIN, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Christelle Gaudioso, Patrick Delmas, Diana Conte CamerinoAbstract:Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that Orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that Orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that Orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant Orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of Orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
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use dependent block of voltage gated sodium channels by Orphenadrine through binding at the local anesthetic receptor
Biophysical Journal, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Diana Conte CamerinoAbstract:Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether Orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that Orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that Orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of Orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by Orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of Orphenadrine (Supported by Telethon-Italy grant GGP04140).
Teresa Costanza - One of the best experts on this subject based on the ideXlab platform.
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Involvement of voltage-gated sodium channels blockade in the analgesic effects of Orphenadrine.
PAIN, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Christelle Gaudioso, Patrick Delmas, Diana Conte CamerinoAbstract:Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that Orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that Orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that Orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant Orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of Orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
-
use dependent block of voltage gated sodium channels by Orphenadrine through binding at the local anesthetic receptor
Biophysical Journal, 2009Co-Authors: Jean François Desaphy, Alfred L George, Antonella Dipalma, Michela De Bellis, Teresa Costanza, Diana Conte CamerinoAbstract:Orphenadrine is most often used against muscle spasm and rigidity, and pain of various etiologies. The drug may act on multiple targets, including muscarinic, histaminic, and NMDA receptors. Its structure recalls that of local anesthetics, with an aromatic hydrophobic moiety linked to a protonable tertiary ammine terminal. Thus we wondered whether Orphenadrine may also block voltage-gated sodium channels. We tested the drug on whole-cell sodium currents recorded using patch-clamp in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels. The results indicate that Orphenadrine inhibits sodium channels in a concentration, voltage and frequency dependent manner. Introducing the F1586C mutation in hNav1.4 reduced two-fold the tonic block at the holding potential (hp) of -120 mV and almost zeroed the use-dependent block at 10 Hz, indicating that Orphenadrine binds to the same receptor as the local anesthetics. Channel state-dependent affinities of Orphenadrine were calculated using specific protocols. At the hp of -180 mV, the entire population of channels are closed and ready to open in response to depolarization. Thus determination of tonic block at this hp allows the determination of drug affinity for resting channels, which was 160 μM. The affinity for inactivated sodium channels (KI) was calculated according to the modulated receptor hypothesis, which forecasts that the apparent affinity measured at a particular hp depends on the proportion of resting and inactivated channels at this hp. The calculated KI value was 2.2 μM. Use-dependent reduction of sodium currents at the hp of -100 mV was enhanced by Orphenadrine at 0.1 μM, a clinically relevant concentration. This study suggests that blockade of sodium channels may contribute to clinical efficacy of Orphenadrine (Supported by Telethon-Italy grant GGP04140).