Acid-sensing ion channel 3 mediates pain hypersensitivity associated with high-fat diet consumption in mice.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
21 Sep 2023
21 Sep 2023
Historique:
received:
19
09
2022
accepted:
07
07
2023
medline:
21
9
2023
pubmed:
21
9
2023
entrez:
21
9
2023
Statut:
aheadofprint
Résumé
Lipid-rich diet is the major cause of obesity, affecting 13% of the worldwide adult population. Obesity is a major risk factor for metabolic syndrome that includes hyperlipidemia and diabetes mellitus. The early phases of metabolic syndrome are often associated with hyperexcitability of peripheral small diameter sensory fibers and painful diabetic neuropathy. Here, we investigated the effect of high-fat diet-induced obesity on the activity of dorsal root ganglion (DRG) sensory neurons and pain perception. We deciphered the underlying cellular mechanisms involving the acid-sensing ion channel 3 (ASIC3). We show that mice made obese through consuming high-fat diet developed the metabolic syndrome and prediabetes that was associated with heat pain hypersensitivity, whereas mechanical sensitivity was not affected. Concurrently, the slow conducting C fibers in the skin of obese mice showed increased activity on heating, whereas their mechanosensitivity was not altered. Although ASIC3 knockout mice fed with high-fat diet became obese, and showed signs of metabolic syndrome and prediabetes, genetic deletion, and in vivo pharmacological inhibition of ASIC3, protected mice from obesity-induced thermal hypersensitivity. We then deciphered the mechanisms involved in the heat hypersensitivity of mice and found that serum from high-fat diet-fed mice was enriched in lysophosphatidylcholine (LPC16:0, LPC18:0, and LPC18:1). These enriched lipid species directly increased the activity of DRG neurons through activating the lipid sensitive ASIC3 channel. Our results identify ASIC3 channel in DRG neurons and circulating lipid species as a mechanism contributing to the hyperexcitability of nociceptive neurons that can cause pain associated with lipid-rich diet consumption and obesity.
Identifiants
pubmed: 37733484
doi: 10.1097/j.pain.0000000000003030
pii: 00006396-990000000-00408
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-11-LABX-0015-01
Organisme : Agence Nationale de la Recherche
ID : ANR-17-CE16-001
Organisme : Agence Nationale de la Recherche
ID : ANR-20-CE14-0001 RANTES
Informations de copyright
Copyright © 2023 International Association for the Study of Pain.
Références
Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Ärnlöv J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Fürst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang Y-H, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin M-J, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13–27.
Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP; NIH Mouse Metabolic Phenotyping Center Consortium. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 2010;3:525–34.
Banik RK, Brennan TJ. Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. PAIN 2009;141:41–51.
Barber MN, Risis S, Yang C, Meikle PJ, Staples M, Febbraio MA, Bruce CR. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS One 2012;7:e41456.
Bardoni R, Tawfik VL, Wang D, François A, Solorzano C, Shuster SA, Choudhury P, Betelli C, Cassidy C, Smith K, de Nooij JC, Mennicken F, O'Donnell D, Kieffer BL, Woodbury CJ, Basbaum AI, MacDermott AB, Scherrer G. Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 2014;81:1312–27.
Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka F, Lasischka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, Haberkorn U, Brownlee M, Reeh PW, Nawroth PP. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012;18:926–33.
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959;37:911–17.
Boyd JT, LoCoco PM, Furr AR, Bendele MR, Tram M, Li Q, Chang F-M, Colley ME, Samenuk GM, Arris DA, Locke EE, Bach SBH, Tobon A, Ruparel SB, Hargreaves KM. Elevated dietary ω-6 polyunsaturated fatty acids induce reversible peripheral nerve dysfunction that exacerbates comorbid pain conditions. Nat Metab 2021;3:762–73.
Callaghan BC, Feldman EL. Painful diabetic neuropathy: many similarly effective therapies with widely dissimilar costs. Ann Intern Med 2014;161:674–5.
Churyukanov M, Plaghki L, Legrain V, Mouraux A. Thermal detection thresholds of Aδ- and C-fibre afferents activated by brief CO2 laser pulses applied onto the human hairy skin. PLoS One 2012;7:e35817.
Ciardo MG, Ferrer-Montiel A. Lipids as central modulators of sensory TRP channels. Biochim Biophys Acta Biomembr 2017;1859:1615–28.
Deuis JR, Dvorakova LS, Vetter I. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 2017;10:284.
Deval E, Lingueglia E. Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems. Neuropharmacology 2015;94:49–57.
Deval E, Noël J, Gasull X, Delaunay A, Alloui A, Friend V, Eschalier A, Lazdunski M, Lingueglia E. Acid-sensing ion channels in postoperative pain. J Neurosci 2011;31:6059–66.
Deval E, Noël J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J 2008;27:3047–55.
Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J 2004;23:1516–25.
Divisova S, Vlckova E, Hnojcikova M, Skorna M, Nemec M, Dubovy P, Dusek L, Jarkovsky J, Belobradkova J, Bednarik J. Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres. J Peripher Nerv Syst 2012;17:341–50.
Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest 2010;120:3760–72.
Emery EC, Ernfors P. Dorsal root ganglion neuron types and their functional specialization. Oxf Handb Neurobiol Pain 2018;1:128–55.
Fekete K, Györei E, Lohner S, Verduci E, Agostoni C, Decsi T. Long-chain polyunsaturated fatty acid status in obesity: a systematic review and meta-analysis. Obes Rev 2015;16:488–97.
Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primer 2019;5:1–18.
Feldman EL, Nave K-A, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron 2017;93:1296–313.
Gould TD, Dao DT, Kovacsics CE. The open field test. Mood and anxiety related phenotypes in mice: characterization using behavioral tests. Neuromethods. Totowa, NJ: Humana Press, 2009. p. 1–20.
Graessler J, Schwudke D, Schwarz PEH, Herzog R, Shevchenko A, Bornstein SR. Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients. PLoS One 2009;4:e6261.
Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011;29:415–45.
Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004;89:2595–600.
Hitt HC, McMillen RC, Thornton-Neaves T, Koch K, Cosby AG. Comorbidity of obesity and pain in a general population: results from the Southern Pain Prevalence Study. J Pain 2007;8:430–6.
Hong J, Stubbins RE, Smith RR, Harvey AE, Núñez NP. Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J 2009;8:11.
Hsu W-H, Lee C-H, Chao Y-M, Kuo C-H, Ku W-C, Chen C-C, Lin Y-L. ASIC3-dependent metabolomics profiling of serum and urine in a mouse model of fibromyalgia. Sci Rep 2019;9:12123.
Huang S-J, Yang W-S, Lin Y-W, Wang H-C, Chen C-C. Increase of insulin sensitivity and reversal of age-dependent glucose intolerance with inhibition of ASIC3. Biochem Biophys Res Commun 2008;371:729–34.
Hung C-H, Lee C-H, Tsai M-H, Chen C-H, Lin H-F, Hsu C-Y, Lai C-L, Chen C-C. Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain. Ann Rheum Dis 2020;79:1644–56.
Jacquot F, Khoury S, Labrum B, Delanoe K, Pidoux L, Barbier J, Delay L, Bayle A, Aissouni Y, Barriere DA, Kultima K, Freyhult E, Hugo A, Kosek E, Ahmed AS, Jurczak A, Lingueglia E, Svensson CI, Breuil V, Ferreira T, Marchand F, Deval E. Lysophosphatidylcholine 16: 0 mediates chronic joint pain associated to rheumatic diseases through acid-sensing ion channel 3. PAIN 2022;163:1999–2013.
Karczewski J, Spencer RH, Garsky VM, Liang A, Leitl MD, Cato MJ, Cook SP, Kane S, Urban MO. Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2. Br J Pharmacol 2010;161:950–60.
Keijer J, Li M, Speakman JR. What is the best housing temperature to translate mouse experiments to humans? Mol Metab 2019;25:168–76.
King AJ. The use of animal models in diabetes research. Br J Pharmacol 2012;166:877–94.
Kirthi V, Perumbalath A, Brown E, Nevitt S, Petropoulos IN, Burgess J, Roylance R, Cuthbertson DJ, Jackson TL, Malik RA, Alam U. Prevalence of peripheral neuropathy in pre-diabetes: a systematic review. BMJ Open Diabetes Res Care 2021;9:e002040.
Le Thuc O, Stobbe K, Cansell C, Nahon J-L, Blondeau N, Rovère C. Hypothalamic inflammation and energy balance disruptions: spotlight on chemokines. Front Endocrinol 2017;8:197.
Lee CC, Perkins BA, Kayaniyil S, Harris SB, Retnakaran R, Gerstein HC, Zinman B, Hanley AJ. Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: the PROMISE cohort. Diabetes Care 2015;38:793–800.
Lin S-H, Cheng Y-R, Banks RW, Min M-Y, Bewick GS, Chen C-C. Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors. Nat Commun 2016;7:11460.
Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, Gierthmühlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihöfner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Üçeyler N, Valet M, Wasner G, Treede D-R. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. PAIN 2010;150:439–50.
Marcus DA. Obesity and the impact of chronic pain. Clin J Pain 2004;20:186–91.
Marra S, Ferru-Clément R, Breuil V, Delaunay A, Christin M, Friend V, Sebille S, Cognard C, Ferreira T, Roux C, Euller-Ziegler L, Noel J, Lingueglia E, Deval E. Non-acidic activation of pain-related acid-sensing Ion Channel 3 by lipids. EMBO J 2016;35:414–28.
Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth 2019;123:e273–83.
Morselli E, Criollo A, Rodriguez-Navas C, Clegg DJ. Chronic high fat diet consumption impairs metabolic health of male mice. Inflamm Cell Signal 2014;1:e561.
Noël J, Zimmermann K, Busserolles J, Deval E, Alloui A, Diochot S, Guy N, Borsotto M, Reeh P, Eschalier A, Lazdunski M. The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. EMBO J 2009;28:1308–18.
Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001;24:1229–31.
O'Brien PD, Sakowski SA, Feldman EL. Mouse models of diabetic neuropathy. ILAR J 2014;54:259–72.
Obrosova IG, Ilnytska O, Lyzogubov VV, Pavlov IA, Mashtalir N, Nadler JL, Drel VR. High-fat diet–induced neuropathy of pre-diabetes and obesity: effects of “healthy” diet and aldose reductase inhibition. Diabetes 2007;56:2598–608.
Okifuji A, Hare BD. The association between chronic pain and obesity. J Pain Res 2015;8:399–408.
Papalampropoulou-Tsiridou M, Labrecque S, Godin AG, De Koninck Y, Wang F. Differential expression of acid - sensing ion channels in mouse primary afferents in naïve and injured conditions. Front Cell Neurosci 2020;14:103.
Peigneur S, Béress L, Möller C, Marí F, Forssmann W-G, Tytgat J. A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J 2012;26:5141–51.
Pettersson US, Waldén TB, Carlsson P-O, Jansson L, Phillipson M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 2012;7:e46057.
Pickens CA, Vazquez AI, Jones AD, Fenton JI. Obesity, adipokines, and C-peptide are associated with distinct plasma phospholipid profiles in adult males, an untargeted lipidomic approach. Sci Rep 2017;7:6335.
Pidoux L, Delanoe K, Barbier J, Marchand F, Lingueglia E, Deval E. Single subcutaneous injection of lysophosphatidyl-choline evokes ASIC3-dependent increases of spinal dorsal horn neuron activity. Front Mol Neurosci 2022;15:880651.
Pietiläinen KH, Sysi-Aho M, Rissanen A, Seppänen-Laakso T, Yki-Järvinen H, Kaprio J, Orešič M. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects—a monozygotic twin study. PLoS One 2007;2:e218.
Poirot O, Berta T, Decosterd I, Kellenberger S. Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury: ASIC function in rat sensory neurones. J Physiol 2006;576:215–34.
Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 2001;32:1071–83.
Ray L, Lipton RB, Zimmerman ME, Katz MJ, Derby CA. Mechanisms of association between obesity and chronic pain in the elderly. PAIN 2011;152:53–9.
Renaud JF, Scanu AM, Kazazoglou T, Lombet A, Romey G, Lazdunski M. Normal serum and lipoprotein-deficient serum give different expressions of excitability, corresponding to different stages of differentiation, in chicken cardiac cells in culture. Proc Natl Acad Sci 1982;79:7768–72.
Sadler KE, Moehring F, Shiers SI, Laskowski LJ, Mikesell AR, Plautz ZR, Brezinski AN, Mecca CM, Dussor G, Price TJ, McCorvy JD, Stucky CL. Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice. Sci Transl Med 2021;13:eabd7702.
Scholz J, Rathmell JP, David WS, Chad DA, Broderick AC, Perros SG, Shin NS, Wells JL, Davis JB, DiMaggio CJ, Wang S, Tate SN. A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy. PAIN 2016;157:2297.
Song Z, Xie W, Chen S, Strong JA, Print MS, Wang JI, Shareef AF, Ulrich-Lai YM, Zhang J-M. High-fat diet increases pain behaviors in rats with or without obesity. Sci Rep 2017;7:10350.
Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 2006;29:883–7.
Stino AM, Smith AG. Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig 2017;8:646–55.
Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah D, Orengo C, Tesfaye S, Rice ASC, Bennett DLH. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. PAIN 2016;157:1132–45.
Tramunt B, Smati S, Grandgeorge N, Lenfant F, Arnal J-F, Montagner A, Gourdy P. Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 2020;63:453–61.
Tsantoulas C, Laínez S, Wong S, Mehta I, Vilar B, McNaughton PA. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci Transl Med 2017;9:eaam6072.
Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, Hjerling-Leffler J, Haeggström J, Kharchenko O, Kharchenko PV, Linnarsson S, Ernfors P. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci 2015;18:145–53.
Van Belle TL, Taylor P, von Herrath MG. Mouse models for type 1 diabetes. Drug Discov Today Dis Models 2009;6:41–5.
Vistisen D, Witte DR, Brunner EJ, Kivimäki M, Tabák A, Jørgensen ME, Færch K. Risk of cardiovascular disease and death in individuals with prediabetes defined by different criteria: the whitehall II study. Diabetes Care 2018;41:899–906.
von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 2012;73:638–52.
Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, Abdulkader RS, Abdulle AM, Abebo TA, Abera SF, Aboyans V, Abu-Raddad LJ, Ackerman IN, Adamu AA, Adetokunboh O, Afarideh M, Afshin A, Agarwal SK, Aggarwal R, Agrawal A, Agrawal S, Ahmadieh H, Ahmed MB, Aichour MTE, Aichour AN, Aichour I, Aiyar S, Akinyemi RO, Akseer N, Lami FHA, Alahdab F, Al-Aly Z, Alam K, Alam N, Alam T, Alasfoor D, Alene KA, Ali R, Alizadeh-Navaei R, Alkerwi A, Alla F, Allebeck P, Allen C, Al-Maskari F, Al-Raddadi R, Alsharif U, Alsowaidi S, Altirkawi KA, Amare AT, Amini E, Ammar W, Amoako YA, Andersen HH, Antonio CAT, Anwari P, Ärnlöv J, Artaman A, Aryal KK, Asayesh H, Asgedom SW, Assadi R, Atey TM, Atnafu NT, Atre SR, Avila-Burgos L, Avokphako EFGA, Awasthi A, Bacha U, Badawi A, Balakrishnan K, Banerjee A, Bannick MS, Barac A, Barber RM, Barker-Collo SL, Bärnighausen T, Barquera S, Barregard L, Barrero LH, Basu S, Battista B, Battle KE, Baune BT, Bazargan-Hejazi S, Beardsley J, Bedi N, Beghi E, Béjot Y, Bekele BB, Bell ML, Bennett DA, Bensenor IM, Benson J, Berhane A, Berhe DF, Bernabé E, Betsu BD, Beuran M, Beyene AS, Bhala N, Bhansali A, Bhatt S, Bhutta ZA, Biadgilign S, Bicer BK, Bienhoff K, Bikbov B, Birungi C, Biryukov S, Bisanzio D, Bizuayehu HM, Boneya DJ, Boufous S, Bourne RRA, Brazinova A, Brugha TS, Buchbinder R, Bulto LNB, Bumgarner BR, Butt ZA, Cahuana-Hurtado L, Cameron E, Car M, Carabin H, Carapetis JR, Cárdenas R, Carpenter DO, Carrero JJ, Carter A, Carvalho F, Casey DC, Caso V, Castañeda-Orjuela CA, Castle CD, Catalá-López F, Chang H-Y, Chang J-C, Charlson FJ, Chen H, Chibalabala M, Chibueze CE, Chisumpa VH, Chitheer AA, Christopher DJ, Ciobanu LG, Cirillo M, Colombara D, Cooper C, Cortesi PA, Criqui MH, Crump JA, Dadi AF, Dalal K, Dandona L, Dandona R, das NevesJ, Davitoiu DV, de Courten B, Leo DDD, Defo BK, Degenhardt L, Deiparine S, Dellavalle RP, Deribe K, Jarlais DCD, Dey S, Dharmaratne SD, Dhillon PK, Dicker D, Ding EL, Djalalinia S, Do HP, Dorsey ER, dos Santos KPB, Douwes-Schultz D, Doyle KE, Driscoll TR, Dubey M, Duncan BB, El-Khatib ZZ, Ellerstrand J, Enayati A, Endries AY, Ermakov SP, Erskine HE, Eshrati B, Eskandarieh S, Esteghamati A, Estep K, Fanuel FBB, Farinha CSES, Faro A, Farzadfar F, Fazeli MS, Feigin VL, Fereshtehnejad S-M, Fernandes JC, Ferrari AJ, Feyissa TR, Filip I, Fischer F, Fitzmaurice C, Flaxman AD, Flor LS, Foigt N, Foreman KJ, Franklin RC, Fullman N, Fürst T, Furtado JM, Futran ND, Gakidou E, Ganji M, Garcia-Basteiro AL, Gebre T, Gebrehiwot TT, Geleto A, Gemechu BL, Gesesew HA, Gething PW, Ghajar A, Gibney KB, Gill PS, Gillum RF, Ginawi IAM, Giref AZ, Gishu MD, Giussani G, Godwin WW, Gold AL, Goldberg EM, Gona PN, Goodridge A, Gopalani SV, Goto A, Goulart AC, Griswold M, Gugnani HC, Gupta R, Gupta R, Gupta T, Gupta V, Hafezi-Nejad N, Hailu GB, Hailu AD, Hamadeh RR, Hamidi S, Handal AJ, Hankey GJ, Hanson SW, Hao Y, Harb HL, Hareri HA, Haro JM, Harvey J, Hassanvand MS, Havmoeller R, Hawley C, Hay SI, Hay RJ, Henry NJ, Heredia-Pi IB, Hernandez JM, Heydarpour P, Hoek HW, Hoffman HJ, Horita N, Hosgood HD, Hostiuc S, Hotez PJ, Hoy DG, Htet AS, Hu G, Huang H, Huynh C, Iburg KM, Igumbor EU, Ikeda C, Irvine CMS, Jacobsen KH, Jahanmehr N, Jakovljevic MB, Jassal SK, Javanbakht M, Jayaraman SP, Jeemon P, Jensen PN, Jha V, Jiang G, John D, Johnson SC, Johnson CO, Jonas JB, Jürisson M, Kabir Z, Kadel R, Kahsay A, Kamal R, Kan H, Karam NE, Karch A, Karema CK, Kasaeian A, Kassa GM, Kassaw NA, Kassebaum NJ, Kastor A, Katikireddi SV, Kaul A, Kawakami N, Keiyoro PN, Kengne AP, Keren A, Khader YS, Khalil IA, Khan EA, Khang Y-H, Khosravi A, Khubchandani J, Kiadaliri AA, Kieling C, Kim YJ, Kim D, Kim P, Kimokoti RW, Kinfu Y, Kisa A, Kissimova-Skarbek KA, Kivimaki M, Knudsen AK, Kokubo Y, Kolte D, Kopec JA, Kosen S, Koul PA, Koyanagi A, Kravchenko M, Krishnaswami S, Krohn KJ, Kumar GA, Kumar P, Kumar S, Kyu HH, Lal DK, Lalloo R, Lambert N, Lan Q, Larsson A, Lavados PM, Leasher JL, Lee PH, Lee J-T, Leigh J, Leshargie CT, Leung J, Leung R, Levi M, Li Y, Li Y, Kappe DL, Liang X, Liben ML, Lim SS, Linn S, Liu PY, Liu A, Liu S, Liu Y, Lodha R, Logroscino G, London SJ, Looker KJ, Lopez AD, Lorkowski S, Lotufo PA, Low N, Lozano R, Lucas TCD, Macarayan ERK, Razek HMAE, Razek MMAE, Mahdavi M, Majdan M, Majdzadeh R, Majeed A, Malekzadeh R, Malhotra R, Malta DC, Mamun AA, Manguerra H, Manhertz T, Mantilla A, Mantovani LG, Mapoma CC, Marczak LB, Martinez-Raga J, Martins-Melo FR, Martopullo I, März W, Mathur MR, Mazidi M, McAlinden C, McGaughey M, McGrath JJ, McKee M, McNellan C, Mehata S, Mehndiratta MM, Mekonnen TC, Memiah P, Memish ZA, Mendoza W, Mengistie MA, Mengistu DT, Mensah GA, Meretoja TJ, Meretoja A, Mezgebe HB, Micha R, Millear A, Miller TR, Mills EJ, Mirarefin M, Mirrakhimov EM, Misganaw A, Mishra SR, Mitchell PB, Mohammad KA, Mohammadi A, Mohammed KE, Mohammed S, Mohanty SK, Mokdad AH, Mollenkopf SK, Monasta L, Montico M, Moradi-Lakeh M, Moraga P, Mori R, Morozoff C, Morrison SD, Moses M, Mountjoy-Venning C, Mruts KB, Mueller UO, Muller K, Murdoch ME, Murthy GVS, Musa KI, Nachega JB, Nagel G, Naghavi M, Naheed A, Naidoo KS, Naldi L, Nangia V, Natarajan G, Negasa DE, Negoi RI, Negoi I, Newton CR, Ngunjiri JW, Nguyen TH, Nguyen QL, Nguyen CT, Nguyen G, Nguyen M, Nichols E, Ningrum DNA, Nolte S, Nong VM, Norrving B, Noubiap JJN, O'Donnell MJ, Ogbo FA, Oh I-H, Okoro A, Oladimeji O, Olagunju TO, Olagunju AT, Olsen HE, Olusanya BO, Olusanya JO, Ong K, Opio JN, Oren E, Ortiz A, Osgood-Zimmerman A, Osman M, Owolabi MO, Pa M, Pacella RE, Pana A, Panda BK, Papachristou C, Park E-K, Parry CD, Parsaeian M, Patten SB, Patton GC, Paulson K, Pearce N, Pereira DM, Perico N, Pesudovs K, Peterson CB, Petzold M, Phillips MR, Pigott DM, Pillay JD, Pinho C, Plass D, Pletcher MA, Popova S, Poulton RG, Pourmalek F, Prabhakaran D, Prasad NM, Prasad N, Purcell C, Qorbani M, Quansah R, Quintanilla BPA, Rabiee RHS, Radfar A, Rafay A, Rahimi K, Rahimi-Movaghar A, Rahimi-Movaghar V, Rahman MHU, Rahman M, Rai RK, Rajsic S, Ram U, Ranabhat CL, Rankin Z, Rao PC, Rao PV, Rawaf S, Ray SE, Reiner RC, Reinig N, Reitsma MB, Remuzzi G, Renzaho AMN, Resnikoff S, Rezaei S, Ribeiro AL, Ronfani L, Roshandel G, Roth GA, Roy A, Rubagotti E, Ruhago GM, Saadat S, Sadat N, Safdarian M, Safi S, Safiri S, Sagar R, Sahathevan R, Salama J, Saleem HOB, Salomon JA, Salvi SS, Samy AM, Sanabria JR, Santomauro D, Santos IS, Santos JV, Milicevic MMS, Sartorius B, Satpathy M, Sawhney M, Saxena S, Schmidt MI, Schneider IJC, Schöttker B, Schwebel DC, Schwendicke F, Seedat S, Sepanlou SG, Servan-Mori EE, Setegn T, Shackelford KA, Shaheen A, Shaikh MA, Shamsipour M, Islam SMS, Sharma J, Sharma R, She J, Shi P, Shields C, Shifa GT, Shigematsu M, Shinohara Y, Shiri R, Shirkoohi R, Shirude S, Shishani K, Shrime MG, Sibai AM, Sigfusdottir ID, Silva DAS, Silva JP, Silveira DGA, Singh JA, Singh NP, Sinha DN, Skiadaresi E, Skirbekk V, Slepak EL, Sligar A, Smith DL, Smith M, Sobaih BHA, Sobngwi E, Sorensen RJD, Sousa TCM, Sposato LA, Sreeramareddy CT, Srinivasan V, Stanaway JD, Stathopoulou V, Steel N, Stein MB, Stein DJ, Steiner TJ, Steiner C, Steinke S, Stokes MA, Stovner LJ, Strub B, Subart M, Sufiyan MB, Sunguya BF, Sur PJ, Swaminathan S, Sykes BL, Sylte DO, Tabarés-Seisdedos R, Taffere GR, Takala JS, Tandon N, Tavakkoli M, Taveira N, Taylor HR, Tehrani-Banihashemi A, Tekelab T, Terkawi AS, Tesfaye DJ, Tesssema B, Thamsuwan O, Thomas KE, Thrift AG, Tiruye TY, Tobe-Gai R, Tollanes MC, Tonelli M, Topor-Madry R, Tortajada M, Touvier M, Tran BX, Tripathi S, Troeger C, Truelsen T, Tsoi D, Tuem KB, Tuzcu EM, Tyrovolas S, Ukwaja KN, Undurraga EA, Uneke CJ, Updike R, Uthman OA, Uzochukwu BSC, van Boven JFM, Varughese S, Vasankari T, Venkatesh S, Venketasubramanian N, Vidavalur R, Violante FS, Vladimirov SK, Vlassov VV, Vollset SE, Wadilo F, Wakayo T, Wang Y-P, Weaver M, Weichenthal S, Weiderpass E, Weintraub RG, Werdecker A, Westerman R, Whiteford HA, Wijeratne T, Wiysonge CS, Wolfe CDA, Woodbrook R, Woolf AD, Workicho A, Xavier D, Xu G, Yadgir S, Yaghoubi M, Yakob B, Yan LL, Yano Y, Ye P, Yimam HH, Yip P, Yonemoto N, Yoon S-J, Yotebieng M, Younis MZ, Zaidi Z, Zaki MES, Zegeye EA, Zenebe ZM, Zhang X, Zhou M, Zipkin B, Zodpey S, Zuhlke LJ, Murray CJL. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1211–59.
Walder RY, Rasmussen LA, Rainier JD, Light AR, Wemmie JA, Sluka KA. ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J Pain 2010;11:210–8.
Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M. Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem 1997;272:20975–8.
Wang F, Bélanger E, Côté SL, Desrosiers P, Prescott SA, Côté DC, De Koninck Y. Sensory afferents use different coding strategies for heat and cold. Cell Rep 2018;23:2001–13.
Wu W-L, Cheng C-F, Sun W-H, Wong C-W, Chen C-C. Targeting ASIC3 for pain, anxiety, and insulin resistance. Pharmacol Ther 2012;134:127–38.
Wultsch T, Painsipp E, Shahbazian A, Mitrovic M, Edelsbrunner M, Waldmann R, Lazdunski M, Holzer P. Deletion of the acid-sensing ion channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach – brainstem axis. PAIN 2008;134:245–53.
Xu S, Xue Y. Pediatric obesity: causes, symptoms, prevention and treatment. Exp Ther Med 2016;11:15–20.
Yan J, Wei X, Bischoff C, Edelmayer RM, Dussor G. pH-evoked dural afferent signaling is mediated by ASIC3 and is sensitized by mast cell mediators. Headache 2013;53:1250–61.
Yen Y-T, Tu P-H, Chen C-J, Lin Y-W, Hsieh S-T, Chen C-C. Role of acid-sensing ion channel 3 in sub-acute-phase inflammation. Mol Pain 2009;5:1.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. PAIN 1983;16:109.
Zimmermann K, Hein A, Hager U, Kaczmarek JS, Turnquist BP, Clapham DE, Reeh PW. Phenotyping sensory nerve endings in vitro in the mouse. Nat Protoc 2009;4:174–196.