Ion Channels and Pain.PDF

See online version for glossary,acknowledgments,and references.366 Cell 134,July 25,2008 2008 Elsevier Inc.DOI 10.1016/j.cell.2008.07.006SnapShot:Ion Channels and PainPatrick DelmasUniversit de la Mditerrane,CNRS,Marseille,FranceChannel CharacteristicsExpression Evidence from Animal Models Role in HumansNav1.3TTX-sensitive,voltage-gated sodium channel Embryonic DRG and TG neurons,spinal cord,and thalamus;upregulated in DRG and dorsal horn neurons following nerve injuryLoss of function attenuates pain-related behaviorNa+channel blockers including local anesthetics,anticonvulsants,anti-arrhythmic,and TCAs relieve pain associated with neuropathy,diabetes,osteoarthritis,and surgery.Mutations in the Nav1.7 gene(scn9a)cause erythromelalgia and paroxysmal extreme pain disorder;loss of function of Nav1.7 results in pain insensitivity.Nav1.7TTX-sensitive,voltage-gated sodium channelMost adult DRG and TG neurons;upregulated in small DRG and TG neurons postinflammationLoss of function reduces mechanical and thermal hypersensitivity;the Nav1.7/Nav1.8 blocker CDA54 reduces neuropathic pain in nerve injury modelsNav1.8TTX-resistant,voltage-gated sodium channelSmall and medium DRG and TG neurons;upregulated in small DRG neurons after inflammation;down-regulated in small DRG neurons in nerve injury modelsDecrease in sensitivity to noxious thermal and mechanical stimuli in knockout mouse;Nav1.8 blocker A-803467 reduces mechanical allodynia and thermal hyperalgesiaNav1.9TTX-resistant,voltage-gated sodium channelSmall and medium DRG and TG neurons;silent noci-ceptors;upregulated function in DRGs postinflammationLoss of function reduces mechanical and thermal hypersensitivity associated with inflammatory painPossible involvement in chronic and inflammatory painCav2.2High-threshold,voltage-gated calcium channel Small and medium DRG neurons,brainstem,thalamus;increased expression in the dorsal horn of the spinal cord in neuropathic pain models;upregulated in DRGs following nerve injury and tissue inflammationLoss of function leads to resistance to hyper-algesia and allodynia following nerve injury Therapeutic target for pain associated with cancer,AIDS,and neuropathies;channel blockers are antinociceptive and undergoing clinical evaluationCav3.2-3.1Low-threshold,voltage-gated calcium channels Small and medium DRG neurons,spinal cord,thalamus;increased current density observed in models of neuropathyKnockdown of Cav3.2 leads to antinociceptive effects;knockout reduces pain responses and attenuates thermal hyperalgesia;channel blockers attenuate hyperalgesia(mibefradil)and mechanical allodynia(ethosuximide)Possible involvement in migraine pain and in analgesic effects of N2O and neuroactive steroids Cav21Calcium channel auxil-iary subunitDRG neurons,dorsal horn of spinal cord,brainstem,thalamus;increased expression in DRGs and spinal cord in neuropathic pain models,nerve injury,and tissue inflammation Knockdown reduces pain-related behaviors;R217A 21 knockin mice are unresponsive to the inhibitors gabapentin and pregabalin(used to treat pain)Linked to fibromyalgia pain,posther-petic neuralgia,and neuropathic pain associated with cancer,diabetes,and HIV KCNQ6 TM voltage-gated K+channels of the Kv7 familyKv7.2,Kv7.3,and Kv7.5 are expressed in DRG neurons and at synapses of the pain transmission pathwayRetigabine reduces pain hyper sensitivity,muscoskeletal pain,and behavioral hyper-sensitivity to mechanical and cold stimulation Channel openers and second generation ligands are being developed for the treatment of migraine,muscle pain,and pain associated with osteoporosis,cancer,and neuropathyKv1Kv46 TM voltage-gated,shaker-related K+channelsKv3.4 and Kv1.4 predominate in nociceptive DRG neurons;Kv1.1 and Kv1.2 predominate in large DRG neurons;Kv4.2 is expressed in dorsal horn neurons;expression of Kv3.4 and Kv4.3 in DRG is reduced after injury and Kv1.1-1.4 are reduced after axotomyDownregulation of Kv3.4 causes mechanical hypersensitivity;downregulation of Kv1.1 antagonizes antinociceptionPossible role(Kv1.1)in antinociception induced by TCAs and H1-antihistamines;Kv4.2 may contribute to visceral pain states and to ERK-dependent forms of pain hypersensitivitySK1SK36 TM,small conduc-tance Ca2+-activated K+channelsSK1 and SK2 are expressed in putative nociceptors;SK2 localizes in the superficial laminae of the dorsal horn;SK3 is expressed in DRG neuronsThe SK channel blocker apamin reduces the antinociceptive effects of cannabinoids May moderate afferent input and pain signals;possible roles in antinociception induced by TCAs,H1-antihistamines,and antiepileptic drugsTREK14 TM K+channel Highly expressed in small and medium DRG neuronsMice lacking TREK1 display enhanced sensitivity to painful heat and increased thermal and mechanical hyperalgesia Possible role in polymodal pain perception and anesthetic-mediated antinociceptionKir32 TM family of K+channelsSuperficial layers of dorsal horn;Kir3.1 tyrosine phosphorylation occurs during acute and chronic inflammatory painKir3.1 and Kir3.2 knockout mice display thermal hyperalgesia and reduced sensitivity to morphinePossible mediators of both opioid-and ethanol-induced analgesiaTRPV1ThermoTRP(43C)nonselective cation channelSmall and medium DRG and TG neurons;inflammation sensitizes TRPV1 function and increases expression;upregulated in inflammatory bowel diseaseTRPV1 knockout mice have impaired thermal avoidance and reduced chemical,thermal,and mechanical hyperalgesia;capsaicin alleviates pain after topical application;antagonists alleviate mechanical and thermal hyperalgesiaLinked to gastroesophageal reflux disease,vulvodynia,and osteoarthritis pain;capsaicin transdermal patch is be-ing used for the treatment of neuropathic pain associated with HIV and shinglesTRPV3ThermoTRP(31C 39C)nonselective cation channelSkin,spinal cord,brain,DRG,and TG neuronsLoss of function leads to impaired thermal avoidanceTRPV4ThermoTRP(27C)nonselective cation channelVibrissal Merkel cells,DRG and TG neurons,mechanosensory terminals in the skin;inflammation engages TRPV4 in mechanical hyperalgesiaKnockout mice have impaired osmotic,thermal,and mechanical hyperalgesiaMay be involved in pain in diabetes,alcoholism,aquadynia,and asthmaTRPM8ThermoTRP(22C 26C)nonselective cation channelSubset of small DRG neurons;upregulated expression in DRGs and spinal cord in nerve injury modelsKnockout mice have reduced avoidance of cold temperature and insensitivity to the channel activator icilin;icilin elicits analgesia in multiple models of painLinked to painful bladder syndrome and idiopathic detrusor overactivity;possible role in innocuous and noxious cold transductionTRPA1ThermoTRP(17C)nonselective cation channelSmall peptidergic DRG neurons;activity increased by bradykinin and inflammatory mediatorsKnockout mice have impaired responses to irritants and bradykinin and reduced cold hyperalgesia Possible role in the transduction of noxious cold and mechanical stimuli and in nociceptive responses to irritantsASICAcid-sensing Na+channels,subgroup of the degenerin familyASIC1a,ASIC1b,ASIC2b,and ASIC3 expressed in small DRG neurons;ASIC1a,ASIC2a,ASIC2b,and ASIC3 are abundant in spinal cord;ASIC2 and ASIC3 are present in Meissners corpuscles,palisades of lanceolate fibers,Pilo-Ruffini nerve endings,and Merkel cells;spinal nerve injury induces differential regulation of ASIC subunit expressionKnockdown of ASIC1a attenuates thermal and mechanical hypersensitivity;ASIC3 knockout mice have reduced visceral mechanosensitivity and no gastric acid hyper-responsiveness;channel-block-ing compounds psamotoxin(ASIC1a),amiloride,and A317567(ASIC1-3)have analgesic effectsPossible role in acid-induced nociception,visceral discomfort,and chronic inflammatory arthritis HCNHyperpolarization-activated,cyclic nucleotide-gated channelsDRG neurons,Meissners corpuscules,and Merkel cells;HCN channels accumulate at injury sites ZD7288 reverses tactile allodynia induced by spinal nerve ligation and mild thermal injuryPossible role in mechanical allodynia and ectopic discharges in neuropathic painSnapShot:Ion Channels and PainPatrick DelmasUniversit de la Mditerrane,CNRS,Marseille,France366.e1 Cell 134,July 25,2008 2008 Elsevier Inc.DOI 10.1016/j.cell.2008.07.006GlossaryAIDS:acquired immunodeficiency syndromeAllodynia:a sensation of pain to a stimulus that is not normally painfulAntinociceptive:reduces sensitivity to a painful stimuliAquadynia:pain induced by contact with waterDetrusor overactivity:involuntary contractions of the detrusor muscle of the urinary system during filling of the bladderDRG:dorsal root ganglionERK:extracellular signal-regulated kinaseErythromelalgia:a disorder marked by paroxysmal,bilateral vasodilatation,with burning pain,and increased skin temperatureFibromyalgia:a disorder characterized by chronic widespread pain;patients display enhanced sensitivity to multiple stimuliHIV:human immunodeficiency virusHyperalgesia:an increased sensitivity to painMeissners corpuscles:a nerve ending in the skin that mediates sensation of light touchMerkel cells:sensory cells found in the epidermis and associated with sense of touchPalisades of lanceolate fibers:specialized nerve endings in the skin that surround hair shaftsPilo-Ruffini nerve endings:terminals of slowly adapting mechanoreceptorsPostherpetic neuralgia:a painful complication of shinglesTCA:tricyclic antidepressantTG:trigeminal ganglionTM:transmembraneTRP:transient receptor potentialTTX:tetrodotoxin Vulvodynia:a disorder characterized by chronic pain of the vulvaACKNowlEdGMENTSSupported by the CNRS,ACI,ANR-05-Neur.,ANR-05-PCOD,Arc-InCa,UPSA,and Equipe FRM 2007.REfERENCESAlloui,A.,Zimmermann,K.,Mamet,J.,Duprat,F.,Nol,J.,Chemin,J.,Guy,N.,Blondeau,N.,Voilley,N.,Rubat-Coudert,C.,et al.(2006).TREK-1,a K+channel involved in polymodal pain perception.EMBO 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