Research progress on the molecular regulatory mechanism of acid-sensing ion channel 3 in craniofacial pain

doi:10.3877/cma.j.issn.1674-1366.2025.03.002

Abstract

Abstract:

Oral and maxillofacial pain，defined as the pain originating from the head and neck，oral and facial regions or various oral tissues，is a common oral condition.Acid-sensing ion channel 3（ASIC3），mainly distributed in peripheral sensory neurons，participates in nociception，mechanosensation and chemosensation，and is a molecular determinant of tissue acidosis-related pain. Studying the role of ASIC3 in oral and maxillofacial pain is of great significance for understanding the mechanism of pain.This article reviews the research progress on the role of ASIC3 in oral and maxillofacial pain and its analgesic effect in recent years.

Key words: Acid sensing ion channels, Facial pain, Tooth movement, Trigeminal ganglion

Hong Yang, Jiayu Lin, Yaomu Xiao, Jingtao Dai, Chufeng Liu. Research progress on the molecular regulatory mechanism of acid-sensing ion channel 3 in craniofacial pain[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2025, 19(03): 153-159.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhkqyxyjzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-1366.2025.03.002

https://zhkqyxyjzz.cma-cmc.com.cn/EN/Y2025/V19/I03/153

Figures/Tables 1

References 66

［1］	Treede RD，Rief W，Barke A，et al. A classification of chronic pain for ICD-11［J］. Pain，2015，156（6）：1003-1007. DOI：10.1097/j.pain.0000000000000160.
［2］	Okeson JP. The classification of orofacial pains ［J］. Oral Maxillofac Surg Clin North Am，2008，20（2）：133-144，v. DOI：10.1016/j.coms.2007.12.009.
［3］	Cohen SP，Vase L，Hooten WM. Chronic pain：An update on burden，best practices，and new advances［J］. Lancet，2021，397（10289）：2082-2097.DOI：10.1016/S0140-6736（21）00393-7.
［4］	Nazeri M，Chamani G，Abareghi F，et al. Sensory and affective dimensions of pain and anxiety like behaviors are altered in an animal model of pain empathy［J］. Iran J Psychiatry，2019，14（3）：221-226.DOI：10.18502/ijps.v14i3.1329.
［5］	Liin SI. ASIC3，a proton-gated ion channel with preference for polyunsaturated lipids with specific headgroup and tail properties［J］. J Gen Physiol，2022，154（7）：e202213171. DOI：10.1085/jgp.202213171.
［6］	Yao L，Sadeghirad B，Li M，et al. Management of chronic pain secondary to temporomandibular disorders：A systematic review and network Meta-analysis of randomised trials［J］. BMJ，2023，383：e076226.DOI：10.1136/bmj-2023-076226.
［7］	Phuong TNT，Jamg SH，Rijal S，et al. GABA- and glycinemimetic responses of linalool on the substantia gelatinosa of the trigeminal subnucleus caudalis in juvenile mice：Pain management through linalool-mediated inhibitory neurotransmission［J］.Am J Chin Med，2021，49（6）：1437-1448. DOI：10.1142/S0192415X21500671.
［8］	Inauen DS，Papadopoulou AK，Eliades T，et al. Pain profile during orthodontic levelling and alignment with fixed appliances reported in randomized trials：A systematic review with Metaanalyses［J］.Clin Oral Investig，2023，27（5）：1851-1868.DOI：10.1007/s00784-023-04931-5.
［9］	Guo R，Zhou Y，Long H，et al. Transient receptor potential Vanilloid 1-based gene therapy alleviates orthodontic pain in rats［J］.Int J Oral Sci，2019，11（1）：11.DOI：10.1038/s41368-019-0044-3.
［10］	Zhou Y，Long H，Ye N，et al. The effect of capsaicin on expression patterns of CGRP in trigeminal ganglion and trigeminal nucleus caudalis following experimental tooth movement in rats［J］. J Appl Oral Sci，2016，24（6）：597-606.DOI：10.1590/1678-775720160150.
［11］	Bai Q，Liu S，Shu H，et al. TNFα in the trigeminal nociceptive system is critical for temporomandibular joint pain［J］. Mol Neurobiol，2019，56（1）：278-291. DOI：10.1007/s12035-018-1076-y.
［12］	Liu S，Tang Y，Shu H，et al. Dopamine receptor D2，but not D1，mediates descending dopaminergic pathway - produced analgesic effect in a trigeminal neuropathic pain mouse model［J］. Pain，2019，160（2）：334-344. DOI：10.1097/j.pain.0000 000000001414.
［13］	Wang Y，Fu X，Huang L，et al. Increased asics expression via the camkii-CREB pathway in a novel mouse model of trigeminal pain［J］. Cell Physiol Biochem，2018，46（2）：568-578. DOI：10.1159/000488624.
［14］	Tao T，Liu Y，Zhang J，et al. NGF-iNDUCED uPRegulation of CGRP in orofacial pain induced by tooth movement is dependent on Atp6v0a1 and vesicle release［J］. Int J Mol Sci，2022，23（19）：11440.DOI：10.3390/ijms231911440.
［15］	Deval E，Lingueglia E. Acid - sensing ion channels and nociception in the peripheral and central nervous systems［J］.Neuropharmacology，2015，94：49-57.DOI：10.1016/j.neuropharm.2015.02.009.
［16］	Huang C，Sun PY，Jiang Y，et al. Sensory ASIC3 channel exacerbates psoriatic inflammation via a neurogenic pathway in female mice［J］. Nat Commun，2024，15（1）：5288. DOI：10.1038/s41467-024-49577-3.
［17］	Zuo Z，Smith RN，Chen Z，et al.Identification of a unique Ca²⁺-binding site in rat acid-sensing ion channel 3［J］. Nat Commun，2018，9（1）：2082.DOI：10.1038/s41467-018-04424-0.
［18］	Yang H，Shan D，Jin Y，et al. The role of acid-sensing ion channel 3 in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement［J］.Neuroscience，2020，442：274-285.DOI：10.1016/j.neuroscience.2020.06.023.
［19］	Wu JJ，Sun ZL，Liu SY，et al. The ASIC3 - M - CSF - M2 macrophage - positive feedback loop modulates fibroblast - to -myofibroblast differentiation in skin fibrosis pathogenesis［J］.Cell Death Dis，2022，13（6）：527. DOI：10.1038/s41419-022-04981-9.
［20］	Wan X，Li F，Li Z，et al. ASIC3-activated key enzymes of de novo lipid synthesis supports lactate - driven EMT and the metastasis of colorectal cancer cells［J］. Cell Commun Signal，2024，22（1）：388.DOI：10.1186/s12964-024-01762-z.
［21］	Han DS，Lee CH，Shieh YD，et al. Involvement of ASIC3 and substance P in therapeutic ultrasound - mediated analgesia in mouse models of fibromyalgia［J］. J Pain，2023，24（8）：1493-1505.DOI：10.1016/j.jpain.2023.04.003.
［22］	Khataei T，Benson CJ. ASIC3 plays a protective role in delayedonset muscle soreness（DOMS）through muscle acid sensation during exercise［J］. Front Pain Res（Lausanne），2023，4：1215197.DOI：10.3389/fpain.2023.1215197.
［23］	Marra S，Ferru-Clément R，Breuil V，et al. Non-acidic activation of pain-related acid-sensing ion channel 3 by lipids［J］. EMBO J，2016，35（4）：414-428.DOI：10.15252/embj.201592335.
［24］	Long H，Wang Y，Jian F，et al. Current advances in orthodontic pain［J］. Int J Oral Sci，2016，8（2）：67-75. DOI：10.1038/ijos.2016.24.
［25］	Gao M，Long H，Ma W，et al. The role of periodontal ASIC3 in orofacial pain induced by experimental tooth movement in rats［J］. Eur J Orthod，2016，38（6）：577-583. DOI：10.1093/ejo/cjv082.
［26］	Callejo G，Castellanos A，Castany M，et al. Acid-sensing ion channels detect moderate acidifications to induce ocular pain［J］. Pain，2015，156（3）：483-495. DOI：10.1097/01.j.pain.0000460335.49525.17.
［27］	Qin L，Li Q，Li J. ASIC3 knockout alters expression and activity of P2X3 in muscle afferent nerves of rat model of peripheral artery disease［J］. FASEB Bioadv，2022，4（5）：329-341. DOI：10.1096/fba.2021-00156.
［28］	Gao M，Yan X，Lu Y，et al. Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3［J］.Int J Oral Sci，2021，13（1）：18. DOI：10.1038/s41368-021-00124-6.
［29］	Lim J， Huang SS， Nikkhoo M， et al. ASIC3 roles in mechanosensitive elongation of nucleus pulposus cells［J］. J Biomech，2024，163：111938. DOI：10.1016/j.jbiomech.2024.111938.
［30］	Jimenez-Torres J，Alcala-Diaz JF，Torres-Pena JD，et al.Mediterranean diet reduces atherosclerosis progression in coronary heart disease：An analysis of the cordioprev randomized controlled trial［J］. Stroke，2021，52（11）：3440-3449. DOI：10.1161/STROKEAHA.120.033214.
［31］	Paez O，Segura-Chama P，Almanza A，et al. Properties and differential expression of H⁺ receptors in dorsal root ganglia：Is a labeled-line coding for acid nociception possible？［J］. Front Physiol，2021，12：733267.DOI：10.3389/fphys.2021.733267.
［32］	Zhu Y，Hu X，Wang L，et al. Recent advances in acid-sensitive ion channels in central nervous system diseases［J］. Curr Pharm Des，2022，28（17）：1406-1411. DOI：10.2174/1381612828666 220422084159.
［33］	Rahman F，Harada F，Saito I，et al. Detection of acid-sensing ion channel 3（ASIC3）in periodontal Ruffini endings of mouse incisors［J］. Neurosci Lett，2011，488（2）：173-177. DOI：10.1016/j.neulet.2010.11.023.
［34］	Cheng YR，Jiang BY，Chen CC. Acid-sensing ion channels：Dual function proteins for chemo-sensing and mechano-sensing［J］. J Biomed Sci，2018，25（1）：46. DOI：10.1186/s12929-018-0448-y.
［35］	Verkest C，Diochot S，Lingueglia E，et al. C-jun N-terminal kinase post-translational regulation of pain-related acid-sensing ion channels 1b and 3［J］. J Neurosci，2021，41（42）：8673-8685.DOI：10.1523/JNEUROSCI.0570-21.2021.
［36］	Hung CH，Chin Y，Fong YO，et al.Acidosis-related pain and its receptors as targets for chronic pain［J］. Pharmacol Ther，2023，247：108444.DOI：10.1016/j.pharmthera.2023.108444.
［37］	Osmakov DI，Tarasova NV，Nedorubov AA，et al. Nocistatin and products of its proteolysis are dual modulators of type 3 acidsensing ion channels （ASIC3） with algesic and analgesic properties［J］.Biochemistry（Mosc），2023，88（12）：2137-2145.DOI：10.1134/S0006297923120155.
［38］	Mao XL，Chen YX，Yu H，et al. Inhibition of acid sensing ion channels by eugenol in rat trigeminal ganglion neurons［J］.Neurosci Lett，2023，803：137192. DOI：10.1016/j.neulet.2023.137192.
［39］	Hildebrand MS，de Silva MG，Klockars T，et al. Characterisation of DRASIC in the mouse inner ear［J］. Hear Res，2004，190（1-2）：149-160.DOI：10.1016/S0378-5955（04）00015-2.
［40］	Wang S，Wu BX，Liu CY，et al. Expression of ASIC3 in the trigeminal nucleus caudalis plays a role in a rat model of recurrent migraine［J］. J Mol Neurosci，2018，66（1）：44-52.DOI：10.1007/s12031-018-1113-3.
［41］	Ambalavanar R，Dessem D. Emerging peripheral receptor targets for deep-tissue craniofacial pain therapies［J］.J Dent Res，2009，88（3）：201-211.DOI：10.1177/0022034508330176.
［42］	Wu WL，Lin YW，Min MY，et al. Mice lacking Asic3 show reduced anxiety-like behavior on the elevated plus maze and reduced aggression［J］. Genes Brain Behav，2010，9（6）：603-614.DOI：10.1111/j.1601-183X.2010.00591.x.
［43］	Messina DN，Peralta ED，Acosta CG. Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats：Involvement of ASIC3 and Nav1.8 in primary sensory neurons［J］.Inflamm Res，2024，73（4）：669-691.DOI：10.1007/s00011-024-01862-z.
［44］	Jurczak A，Delay L，Barbier J，et al.Antibody-induced pain-like behavior and bone erosion：Links to subclinical inflammation，osteoclast activity，and acid-sensing ion channel 3-dependent sensitization［J］.Pain，2022，163（8）：1542-1559.DOI：10.1097/j.pain.0000000000002543.
［45］	Aksoy F，Ege B. Efficacy of submucosal tramadol and lidocaine on success rate of inferior alveolar nerve block in mandibular molars with symptomatic irreversible pulpitis［J］. Odontology，2020.DOI：10.1007/s10266-020-00485-0.
［46］	Hermanstyne TO，Markowitz K，Fan L，et al. Mechanotransducers in rat pulpal afferents［J］. J Dent Res，2008，87（9）：834-838.DOI：10.1177/154405910808700910.
［47］	Xie L，Ma Y，Sun X，et al. The effect of orthodontic pain on dental anxiety：A review［J］.J Clin Pediatr Dent，2023，47（5）：32-36.DOI：10.22514/jocpd.2023.051.
［48］	Osada A，Hitomi S，Nakajima A，et al. Periodontal acidification contributes to tooth pain hypersensitivity during orthodontic tooth movement［J］.Neurosci Res，2022，177：103-110.DOI：10.1016/j.neures.2021.11.007.
［49］	Ruby HA，Sayed RH，Khattab MA，et al. Fenofibrate ameliorates nitroglycerin-induced migraine in rats：Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways ［J］. Eur J Pharmacol，2024，976：176667. DOI：10.1016/j.ejphar.2024.176667.
［50］	Zilliox LA. Neuropathic pain［J］. Continuum（Minneap Minn），2017，23（2）：512-532.DOI：10.1212/CON.0000000000000462.
［51］	Munro G，Christensen JK，Erichsen HK，et al. NS383 selectively inhibits acid-sensing ion channels containing 1a and 3 subunits to reverse inflammatory and neuropathic hyperalgesia in rats［J］.CNS Neurosci Ther，2016，22（2）：135-145. DOI：10.1111/cns.12487.
［52］	Holton CM，Strother LC，Dripps I，et al. Acid-sensing ion channel 3 blockade inhibits durovascular and nitric oxide -mediated trigeminal pain［J］. Br J Pharmacol，2020，177（11）：2478-2486.DOI：10.1111/bph.14990.
［53］	Lin JH，Chiang YH，Chen CC. Research strategies for pain in lumbar radiculopathy focusing on acid-sensing ion channels and their toxins［J］. Curr Top Med Chem，2015，15（7）：617-630.DOI：10.2174/1568026615666150217112652.
［54］	Nasu T，Hori A，Hotta N，et al. Vacuolar-ATPase-mediated muscle acidification caused muscular mechanical nociceptive hypersensitivity after chronic stress in rats，which involved extracellular matrix proteoglycan and ASIC3［J］.Sci Rep，2023，13（1）：13585.DOI：10.1038/s41598-023-39633-1.
［55］	Xu XX，Cao Y，Ding TT，et al.Role of TRPV1 and ASIC3 channels in experimental occlusal interference-induced hyperalgesia in rat masseter muscle［J］. Eur J Pain，2016，20（4）：552-563.DOI：10.1002/ejp.758.
［56］	Sun WH，Chen CC. Roles of proton-sensing receptors in the transition from acute to chronic pain［J］. J Dent Res，2016，95（2）：135-142.DOI：10.1177/0022034515618382.
［57］	Zheng XQ，Wu YH，Huang JF，et al. Neurophysiological mechanisms of cancer-induced bone pain［J］. J Adv Res，2022，35：117-127.DOI：10.1016/j.jare.2021.06.006.
［58］	Qian HY，Zhou F，Wu R，et al. Metformin attenuates bone cancer pain by reducing TRPV1 and ASIC3 expression［J］.Front Pharmacol，2021，12：713944.DOI：10.3389/fphar.2021.713944.
［59］	Nagae M，Hiraga T，Yoneda T.Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization［J］. J Bone Miner Metab，2007，25（2）：99-104.DOI：10.1007/s00774-006-0734-8.
［60］	Hiasa M，Okui T，Allette YM，et al. Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3［J］. Cancer Res，2017，77（6）：1283-1295. DOI：10.1158/0008-5472.CAN-15-3545.
［61］	Deval E，Gasull X，Noel J，et al. Acid-sensing ion channels（ASICs）：Pharmacology and implication in pain［J］. Pharmacol Ther，2010，128（3）：549-558. DOI：10.1016/j.pharmthera.2010.08.006.
［62］	Yuan L，Xiao H，Li H，et al. APETx2 regulates intestinal motility and visceral sensitivity in post-infectious irritable bowel syndrome mice through 5-HT signalling pathway［J］. J Pharm Pharmacol，2023，75（5）：712-717.DOI：10.1093/jpp/rgad017.
［63］	Taguchi T，Katanosaka K，Yasui M，et al. Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model［J］. Pain，2015，156（3）：415-427. DOI：10.1097/01.j.pain.0000460334.49525.5e.
［64］	Gregory NS，Brito RG，Fusaro M，et al. ASIC3 is required for development of fatigue-induced hyperalgesia［J］.Mol Neurobiol，2016，53（2）：1020-1030.DOI：10.1007/s12035-014-9055-4.
［65］	Li X，Le Y，Zhang Z，et al.Viral vector-based gene therapy［J］.Int J Mol Sci，2023，24（9）：7736.DOI：10.3390/ijms24097736.
［66］	Deval E，Noel J，Lay N，et al. ASIC3，a sensor of acidic and primary inflammatory pain［J］. EMBO J，2008，27（22）：3047-3055.DOI：10.1038/emboj.2008.213.

[1]	Yingyu Yi, Yaqin Zhu. Advance in orofacial pain research [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2024, 18(05): 300-306.
[2]	Wenlu Song, Jing Li, Guoying Li, Yanfang Duan, Xinsheng Di, Xin Xu. Clinical effect of piezocision on accelerating tooth movement in orthodontics: A Meta-analysis [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2022, 16(01): 41-48.
[3]	Xushun He, Shijing Chen, Fang Huang. Distalization of inferior molar for space management of the prematural lost primary molars by removable appliance [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2021, 15(06): 360-367.
[4]	Yangyang She, Yaping Ge, Xuehong Xian, Zhiyong Liu, Jieyu Chen, Silian Fang. The clinical effect and risk of minimally invasive corticotomy in the acceleration of tooth movement: a Meta-analysis [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2019, 13(06): 360-367.
[5]	Peina Huang, Bowen Meng, Yangfan Cheng, Chufeng Liu, Dongle Wu, Yang Cao. The role and mechanism of calcineurin injecting into anterior cingulate cortex in alleviating pain in rats following experimental tooth movement [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2018, 12(02): 110-117.
[6]	Zhuannong Zhao, Chufeng Liu, Xiaowei Sun, Lingchao Zhang, Yang Cao. Proteomic analysis related with pain of tooth movement in the anterior cingulate cortex [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2016, 10(02): 112-119.
[7]	Feiyu Wang, Junjie Xue, Jing Wang, Yuanzhi Xu, Linjing Shu, Renhuan Huang. Three-dimensional finite element analysis of rapid canine movement through reducing resistance on parodontium [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2014, 8(03): 186-190.
[8]	Jun ZHENG, Chun-mei WANG. The associations between psychological factors， clinical subgroup of orofacial pain and oral health-related quality of life [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2010, 4(05): 487-493.
[9]	Ya-jing QIAN, Liang-jun ZHONG, Cong-bo MI, Xiao-bing LI, Jing NIE, Xu PAN. The effect of orthodontic force on the inflammatory periodontal tissue remodeling and the expression of IL-6 in rats [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2010, 4(05): 447-455.
[10]	Jun ZHENG, Wong MCM. The association between orofacial pain and abnormal illness behavior in the community in Hong Kong [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2010, 4(03): 288-294.

Please choose a citation manager

Content to export