Free radical signalling underlies inhibition of CaV3.2 T‐type calcium channels by nitrous oxide in the pain pathway
Non‐technical summary Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T‐type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal...
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| Published in | The Journal of physiology Vol. 589; no. 1; pp. 135 - 148 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford, UK
Blackwell Publishing Ltd
01.01.2011
Wiley Subscription Services, Inc Blackwell Science Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-3751 1469-7793 1469-7793 |
| DOI | 10.1113/jphysiol.2010.196220 |
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| Abstract | Non‐technical summary
Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T‐type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T‐currents. Mice that are treated with EUK‐134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works.
Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low‐voltage‐activated (T‐type) calcium channels in pain pathways. Using site‐directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal‐catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin‐induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK‐134, diminished pain responses to formalin in wild‐type mice, but EUK‐134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing.
Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T‐type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T‐currents. Mice that are treated with EUK‐134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. |
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| AbstractList | Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing.Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing. Non‐technical summary Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T‐type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T‐currents. Mice that are treated with EUK‐134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low‐voltage‐activated (T‐type) calcium channels in pain pathways. Using site‐directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal‐catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin‐induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK‐134, diminished pain responses to formalin in wild‐type mice, but EUK‐134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing. Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T‐type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T‐currents. Mice that are treated with EUK‐134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. Non-technical summary Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T-type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T-currents. Mice that are treated with EUK-134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing. Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T-type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T-currents. Mice that are treated with EUK-134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. Nitrous oxide (N 2 O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of Ca V 3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of Ca V 3.2 participates in a critical metal binding site, which may in turn interact with N 2 O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of Ca V 3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N 2 O inhibition of Ca V 3.2 channels is attenuated when H 2 O 2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N 2 O and iron. Ensuing in vivo studies indicate that mice lacking Ca V 3.2 channels display decreased analgesia to N 2 O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N 2 O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N 2 O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N 2 O and ion channels, furthering our understanding of this widely used analgesic in pain processing. Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing. NON-TECHNICAL SUMMARY: Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly inhibits T-type calcium channels through free radical reactions. These reactions depend on a histidine residue on the channel that binds metal ions. If we prevent this histidine from binding metals, N2O cannot inhibit T-currents. Mice that are treated with EUK-134 to remove free radicals show little pain relief after N2O administration. This report provides new information on how N2O interacts with ion channels, helping our understanding of how this popular pain reliever works. Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing. |
| Author | Bojadzic, Damir Lee, JeongHan Leach, Emily Todorovic, Slobodan M. Salajegheh, Reza DiGruccio, Michael R. Orestes, Peihan Nelson, Michael T. |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21059758$$D View this record in MEDLINE/PubMed |
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| Snippet | Non‐technical summary
Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly... Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we... Non-technical summary Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly... NON-TECHNICAL SUMMARY: Nitrous oxide (N2O) has long been used as a pain reliever, but little is known of its targets in the body. We show that N2O indirectly... Nitrous oxide (N 2 O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we... |
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| StartPage | 135 |
| SubjectTerms | Adrenochrome - metabolism Analgesics Analgesics, Non-Narcotic - pharmacology Animals Calcium Calcium Channel Blockers - pharmacology Calcium Channels, T-Type - drug effects Calcium Channels, T-Type - metabolism Catalase - metabolism Chelating Agents - pharmacology Deferoxamine - pharmacology Disease Models, Animal Female Free radicals Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism HEK293 Cells Histidine Humans Hydrogen Peroxide - metabolism Male Membrane Potentials Mice Mice, Inbred C57BL Mice, Knockout Mutagenesis, Site-Directed Neuroscience Nitrous oxide Nitrous Oxide - pharmacology Organometallic Compounds - pharmacology Oxidation-Reduction Pain - metabolism Pain - prevention & control Pain management Pentetic Acid - pharmacology Rats Rats, Sprague-Dawley Reactive Oxygen Species - metabolism Salicylates - pharmacology Signal Transduction - drug effects Time Factors Transfection |
| Title | Free radical signalling underlies inhibition of CaV3.2 T‐type calcium channels by nitrous oxide in the pain pathway |
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