TREK‐1, a K+ channel involved in polymodal pain perception

The TREK‐1 channel is a temperature‐sensitive, osmosensitive and mechano‐gated K+ channel with a regulation by Gs and Gq coupled receptors. This paper demonstrates that TREK‐1 qualifies as one of the molecular sensors involved in pain perception. TREK‐1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin‐activated nonselective ion channel. Mice with a disrupted TREK‐1 gene are more sensitive to painful heat sensations near the threshold between anoxious warmth and painful heat. This phenotype is associated with the primary sensory neuron, as polymodal C‐fibers were found to be more sensitive to heat in single fiber experiments. Knockout animals are more sensitive to low threshold mechanical stimuli and display an increased thermal and mechanical hyperalgesia in conditions of inflammation. They display a largely decreased pain response induced by osmotic changes particularly in prostaglandin E2‐sensitized animals. TREK‐1 appears as an important ion channel for polymodal pain perception and as an attractive target for the development of new analgesics.

[1]  M. Stebbing,et al.  Comparison of the effects of phorbol dibutyrate and low-frequency stimulation of synaptic inputs on the excitability of myenteric AH neurons , 2003, Pflügers Archiv.

[2]  F. Franciolini,et al.  Histamine activates a background, arachidonic acid-sensitive K channel in embryonic chick dorsal root ganglion neurons , 2004, Neuroscience.

[3]  A. Patel,et al.  Lipid and mechano-gated 2P domain K(+) channels. , 2001, Current opinion in cell biology.

[4]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[5]  M. Tominaga,et al.  Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins , 2005, Molecular pain.

[6]  M. Flonta,et al.  Cold transduction by inhibition of a background potassium conductance in rat primary sensory neurones , 2001, Neuroscience Letters.

[7]  M. Lazdunski,et al.  Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels , 2003, The EMBO journal.

[8]  J. Levine,et al.  Hypotonicity Induces TRPV4-Mediated Nociception in Rat , 2003, Neuron.

[9]  S. Ferreira,et al.  Rat knee-joint carrageenin incapacitation test: an objective screen for central and peripheral analgesics , 1992, Pain.

[10]  Janssen Pa,et al.  The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water induced tail withdrawl reflex in rats. , 1963 .

[11]  John N. Wood,et al.  Distinct Mechanosensitive Properties of Capsaicin-Sensitive and -Insensitive Sensory Neurons , 2002, The Journal of Neuroscience.

[12]  J. Boorman,et al.  Voltage-gated sodium channels and pain pathways. , 2004, Journal of neurobiology.

[13]  L. Dekker,et al.  Specific Involvement of PKC-ε in Sensitization of the Neuronal Response to Painful Heat , 1999, Neuron.

[14]  Bernd Nilius,et al.  The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels , 2004, Nature.

[15]  Gary J. Bennett,et al.  A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man , 1988, Pain.

[16]  G. Bennett,et al.  Neuropathic pain sensations are differentially sensitive to dextrorphan , 1994, Neuroreport.

[17]  F. Porreca,et al.  Methodological refinements to the mouse paw formalin test. An animal model of tonic pain. , 1988, Journal of pharmacological methods.

[18]  M. Lazdunski,et al.  Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. , 1996, The EMBO journal.

[19]  M. Lazdunski,et al.  Axonal transport of TREK and TRAAK potassium channels in rat sciatic nerves , 2000, Neuroreport.

[20]  M. Lazdunski,et al.  TREK‐1, a K+ channel involved in neuroprotection and general anesthesia , 2004, The EMBO journal.

[21]  D. Julius,et al.  A Modular PIP2 Binding Site as a Determinant of Capsaicin Receptor Sensitivity , 2003, Science.

[22]  J. Zgombick,et al.  Multiple subtypes of serotonin receptors are expressed in rat sensory neurons in culture. , 1998, The Journal of pharmacology and experimental therapeutics.

[23]  A. Basbaum,et al.  Molecular mechanisms of nociception , 2001, Nature.

[24]  A. Patel,et al.  Mechano- or Acid Stimulation, Two Interactive Modes of Activation of the TREK-1 Potassium Channel* , 1999, The Journal of Biological Chemistry.

[25]  J. Levine,et al.  TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator , 2005, Pain.

[26]  A. Basbaum,et al.  The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli , 1998, Neuron.

[27]  E. Mccleskey,et al.  Ion channels of nociception. , 2020, Annual review of physiology.

[28]  H O Handwerker,et al.  Responsiveness and functional attributes of electrically localized terminals of cutaneous C-fibers in vivo and in vitro. , 1992, Journal of neurophysiology.

[29]  M. Pangalos,et al.  Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. , 2001, Brain research. Molecular brain research.

[30]  David M Tobin,et al.  Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Lazdunski,et al.  TREK‐1 is a heat‐activated background K+ channel , 2000, The EMBO journal.

[32]  G. Czirják,et al.  TASK-3 dominates the background potassium conductance in rat adrenal glomerulosa cells. , 2002, Molecular endocrinology.

[33]  P. Reeh,et al.  Sensory receptors in mammalian skin in an in vitro preparation , 1986, Neuroscience Letters.

[34]  R. Cadmus,et al.  A Method for Evaluating both Non-Narcotic and Narcotic Analgesics , 1957, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[35]  Makoto Tominaga,et al.  Heat-Evoked Activation of the Ion Channel, TRPV4 , 2002, The Journal of Neuroscience.

[36]  B. Nilius,et al.  The TRPV4 channel: structure-function relationship and promiscuous gating behaviour , 2003, Pflügers Archiv.

[37]  D. Bayliss,et al.  CNS Distribution of Members of the Two-Pore-Domain (KCNK) Potassium Channel Family , 2001, The Journal of Neuroscience.

[38]  Olivier Poirot,et al.  Silencing of the Cav3.2 T‐type calcium channel gene in sensory neurons demonstrates its major role in nociception , 2005, The EMBO journal.

[39]  C. Woolf,et al.  Neuropathic pain: aetiology, symptoms, mechanisms, and management , 1999, The Lancet.

[40]  H. Handwerker,et al.  Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin , 1988, Brain Research.

[41]  M. Lazdunski,et al.  A mammalian two pore domain mechano‐gated S‐like K+ channel , 1998, The EMBO journal.

[42]  J. Friedman,et al.  Abnormal osmotic regulation in trpv4-/- mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Caterina,et al.  Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses , 2004, The Journal of Neuroscience.

[44]  C. Niemegeers,et al.  The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water induced tail withdrawl reflex in rats. , 1963, Arzneimittel-Forschung.

[45]  L. O. Randall,et al.  A method for measurement of analgesic activity on inflamed tissue. , 1957, Archives internationales de pharmacodynamie et de therapie.

[46]  Antti Pertovaara,et al.  Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy , 1999, Pain.

[47]  D. Bayliss,et al.  Sequential Phosphorylation Mediates Receptor- and Kinase-induced Inhibition of TREK-1 Background Potassium Channels* , 2005, Journal of Biological Chemistry.

[48]  Donghee Kim,et al.  TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. , 2006, American journal of physiology. Cell physiology.

[49]  D. Julius,et al.  A capsaicin-receptor homologue with a high threshold for noxious heat , 1999, Nature.

[50]  L. Dekker,et al.  Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. , 1999, Neuron.

[51]  C. Belmonte,et al.  Specificity of cold thermotransduction is determined by differential ionic channel expression , 2002, Nature Neuroscience.

[52]  D. Simone,et al.  Influence of thermode size for detecting heat pain dysfunction in a capsaicin model of epidermal nerve fiber loss , 2001, Pain.

[53]  Donghee Kim,et al.  Thermosensitivity of the two‐pore domain K+ channels TREK‐2 and TRAAK , 2005, The Journal of physiology.