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Volume 23, Issue 2
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

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2024-05-29
2024-12-26

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References

  1. RajaS.N. CarrD.B. CohenM. FinnerupN.B. FlorH. GibsonS. KeefeF.J. MogilJ.S. RingkampM. SlukaK.A. SongX.J. StevensB. SullivanM.D. TutelmanP.R. UshidaT. VaderK. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises.Pain202016191976198210.1097/j.pain.0000000000001939 32694387
     [Google Scholar]
  2. TreedeR.D. RiefW. BarkeA. AzizQ. BennettM.I. BenolielR. CohenM. EversS. FinnerupN.B. FirstM.B. GiamberardinoM.A. KaasaS. KorwisiB. KosekE. Lavand’hommeP. NicholasM. PerrotS. ScholzJ. SchugS. SmithB.H. SvenssonP. VlaeyenJ.W.S. WangS.J. Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the International Classification of Diseases (ICD-11).Pain20191601192710.1097/j.pain.0000000000001384 30586067
     [Google Scholar]
  3. CaiH. AoZ. TianC. WuZ. KaurichC. ChenZ. GuM. HohmannA.G. MackieK. GuoF. Engineering human spinal microphysiological systems to model opioid-induced tolerance.Bioact. Mater.20232248249010.1016/j.bioactmat.2022.10.007 36330161
     [Google Scholar]
  4. MattaJ.A. GuS. DaviniW.B. BredtD.S. Nicotinic acetylcholine receptor redux: Discovery of accessories opens therapeutic vistas.Science20213736556eabg653910.1126/science.abg6539 34385370
     [Google Scholar]
  5. van KoppenC.J. KaiserB. Regulation of muscarinic acetylcholine receptor signaling.Pharmacol. Ther.200398219722010.1016/S0163‑7258(03)00032‑9 12725869
     [Google Scholar]
  6. DineleyK.T. PandyaA.A. YakelJ.L. Nicotinic ACh receptors as therapeutic targets in CNS disorders.Trends Pharmacol. Sci.20153629610810.1016/j.tips.2014.12.002 25639674
     [Google Scholar]
  7. ElgoyhenA.B. The α9α10 acetylcholine receptor: A non-neuronal nicotinic receptor.Pharmacol. Res.202319010673510.1016/j.phrs.2023.106735 36931539
     [Google Scholar]
  8. AlbuquerqueE.X. PereiraE.F.R. AlkondonM. RogersS.W. Mammalian nicotinic acetylcholine receptors: From structure to function.Physiol. Rev.20098917312010.1152/physrev.00015.2008 19126755
     [Google Scholar]
  9. MarksM. J. Genetic matters: Thirty years of progress using mouse models in nicotinic research.Biochem. Pharmacol.20138681105111310.1016/j.bcp.2013.05.021 23747348
     [Google Scholar]
  10. WillsL. AblesJ.L. BraunscheidelK.M. CaligiuriS.P.B. ElayoubyK.S. FillingerC. IshikawaM. MoenJ.K. KennyP.J. Neurobiological mechanisms of nicotine reward and aversion.Pharmacol. Rev.202274127131010.1124/pharmrev.121.000299 35017179
     [Google Scholar]
  11. BouzatC. LasalaM. NielsenB.E. CorradiJ. EsandiM.C. Molecular function of α7 nicotinic receptors as drug targets.J. Physiol.2018596101847186110.1113/JP275101 29131336
     [Google Scholar]
  12. ZoliM. PucciS. VilellaA. GottiC. Neuronal and extraneuronal nicotinic acetylcholine receptors.Curr. Neuropharmacol.201816433834910.2174/1570159X15666170912110450 28901280
     [Google Scholar]
  13. BuissonB. BertrandD. Nicotine addiction: The possible role of functional upregulation.Trends Pharmacol. Sci.200223313013610.1016/S0165‑6147(00)01979‑9 11879680
     [Google Scholar]
  14. AnderssonU. TraceyK.J. Reflex principles of immunological homeostasis.Annu. Rev. Immunol.201230131333510.1146/annurev‑immunol‑020711‑075015 22224768
     [Google Scholar]
  15. LetsingerA.C. GuZ. YakelJ.L. α7 nicotinic acetylcholine receptors in the hippocampal circuit: Taming complexity.Trends Neurosci.202245214515710.1016/j.tins.2021.11.006 34916082
     [Google Scholar]
  16. BagdasD. GurunM.S. FloodP. PapkeR.L. DamajM.I. New insights on neuronal nicotinic acetylcholine receptors as targets for pain and inflammation: A focus on α7 nAChRs.Curr. Neuropharmacol.201816441542510.2174/1570159X15666170818102108 28820052
     [Google Scholar]
  17. StokesC. TreininM. PapkeR.L. Looking below the surface of nicotinic acetylcholine receptors.Trends Pharmacol. Sci.201536851452310.1016/j.tips.2015.05.002 26067101
     [Google Scholar]
  18. AndersenN. CorradiJ. SineS.M. BouzatC. Stoichiometry for activation of neuronal α7 nicotinic receptors.Proc. Natl. Acad. Sci. USA201311051208192082410.1073/pnas.1315775110 24297903
     [Google Scholar]
  19. CastroN.G. AlbuquerqueE.X. Brief-lifetime, fast-inactivating ion channels account for the α-bungarotoxin-sensitive nicotinic response in hippocampal neurons.Neurosci. Lett.19931641-213714010.1016/0304‑3940(93)90876‑M 7512242
     [Google Scholar]
  20. PapkeR.L. PorterP.J.K. Comparative pharmacology of rat and human α7 nAChR conducted with net charge analysis.Br. J. Pharmacol.20021371496110.1038/sj.bjp.0704833 12183330
     [Google Scholar]
  21. PapkeR.L. Merging old and new perspectives on nicotinic acetylcholine receptors.Biochem. Pharmacol.201489111110.1016/j.bcp.2014.01.029 24486571
     [Google Scholar]
  22. PapkeR.L. WeckerL. StitzelJ.A. Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.J. Pharmacol. Exp. Ther.2010333250151810.1124/jpet.109.164566 20100906
     [Google Scholar]
  23. McCormackT.J. MelisC. ColónJ. GayE.A. MikeA. KarolyR. LambP.W. MolteniC. YakelJ.L. Rapid desensitization of the rat α7 nAChR is facilitated by the presence of a proline residue in the outer β‐sheet.J. Physiol.2010588224415442910.1113/jphysiol.2010.195495 20837638
     [Google Scholar]
  24. MantheyA.A. Kinetic evidence that desensitized nAChR may promote transitions of active nAChR to desensitized states during sustained exposure to agonists in skeletal muscle.Pflugers Arch.2006452334936210.1007/s00424‑006‑0043‑z 16555103
     [Google Scholar]
  25. YangH. SunQ. LiangY. JiangY. LiR. YeJ. Antinociception of the spirocyclopiperazinium salt compound LXM-15 via activating α7 nAChR and M4 mAChR and inhibiting CaMKIIα/] cAMP/CREB/CGRP signalling pathway in mice.Regul. Toxicol. Pharmacol.20189410811410.1016/j.yrtph.2018.01.012 29353067
     [Google Scholar]
  26. MillerD.R. KhoshboueiH. GaraiS. CantwellL.N. StokesC. ThakurG. PapkeR.L. Allosterically potentiated α 7 nicotinic acetylcholine receptors: Reduced calcium permeability and current-independent control of intracellular calcium.Mol. Pharmacol.202098669570910.1124/molpharm.120.000012 33020143
     [Google Scholar]
  27. SaitohD. KawaguchiK. AsanoS. InuiT. MarunakaY. NakahariT. Enhancement of airway ciliary beating mediated via voltage-gated Ca2+ channels/α7-nicotinic receptors in mice.Pflugers Arch.2022474101091110610.1007/s00424‑022‑02724‑5 35819489
     [Google Scholar]
  28. AlkondonM. BragaM.F.M. PereiraE.F.R. MaelickeA. AlbuquerqueE.X. α7 Nicotinic acetylcholine receptors and modulation of gabaergic synaptic transmission in the hippocampus.Eur. J. Pharmacol.20003931-3596710.1016/S0014‑2999(00)00006‑6 10770998
     [Google Scholar]
  29. TakedaD. NakatsukaT. PapkeR. GuJ.G. Modulation of inhibitory synaptic activity by a non-α4β2, non-α7 subtype of nicotinic receptors in the substantia gelatinosa of adult rat spinal cord.Pain20031011132310.1016/S0304‑3959(02)00074‑X 12507696
     [Google Scholar]
  30. YoungT. WittenauerS. ParkerR. VinclerM. Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology.Eur. J. Pharmacol.20085901-316316910.1016/j.ejphar.2008.06.020 18573248
     [Google Scholar]
  31. LykhmusO. GergalovaG. ZouridakisM. TzartosS. KomisarenkoS. SkokM. Inflammation decreases the level of alpha7 nicotinic acetylcholine receptors in the brain mitochondria and makes them more susceptible to apoptosis induction.Int. Immunopharmacol.201529114815110.1016/j.intimp.2015.04.007 25887272
     [Google Scholar]
  32. WangX.L. DengY.X. GaoY.M. DongY.T. WangF. GuanZ.Z. HongW. QiX.L. Activation of α7 nAChR by PNU-282987 improves synaptic and cognitive functions through restoring the expression of synaptic-associated proteins and the CaM-CaMKII-CREB signaling pathway.Aging (Albany NY)202012154357010.18632/aging.102640 31905173
     [Google Scholar]
  33. CriscuoloC. AccorroniA. DomeniciL. OrigliaN. Impaired synaptic plasticity in the visual cortex of mice lacking α7-nicotinic receptor subunit.Neuroscience201529416617110.1016/j.neuroscience.2015.03.022 25797465
     [Google Scholar]
  34. YangY. PaspalasC.D. JinL.E. PicciottoM.R. ArnstenA.F.T. WangM. Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex.Proc. Natl. Acad. Sci. USA201311029120781208310.1073/pnas.1307849110 23818597
     [Google Scholar]
  35. Shorey-KendrickL.E. FordM.M. AllenD.C. KuryatovA. LindstromJ. WilhelmL. GrantK.A. SpindelE.R. Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.Neuropharmacology201596Pt B26327310.1016/j.neuropharm.2015.01.023 25661700
     [Google Scholar]
  36. CourtiesA. OlmerM. MyersK. OrdoukhanianP. HeadS.R. NatarajanP. BerenbaumF. SellamJ. LotzM.K. Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours.Ann. Rheum. Dis.202382571071810.1136/ard‑2022‑223470 36627169
     [Google Scholar]
  37. XiaoH.S. HuangQ.H. ZhangF.X. BaoL. LuY.J. GuoC. YangL. HuangW.J. FuG. XuS.H. ChengX.P. YanQ. ZhuZ.D. ZhangX. ChenZ. HanZ.G. ZhangX. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain.Proc. Natl. Acad. Sci. USA200299128360836510.1073/pnas.122231899 12060780
     [Google Scholar]
  38. YangT. ZhouY. ZhangW. ZhangL. ChenS. ChenC. GaoF. YangH. ManyandeA. WangJ. TianY. TianX. The spinal α7-Nicotinic acetylcholine receptor contributes to the maintenance of cancer-induced bone pain.J. Pain Res.20211444145210.2147/JPR.S286321 33623426
     [Google Scholar]
  39. ElsC. JacksonT.D. HagtvedtR. KunykD. SonnenbergB. LappiV.G. StraubeS. High-dose opioids for chronic non-cancer pain: An overview of Cochrane Reviews.Cochrane Database Syst. Rev.202333CD012299 36961252
     [Google Scholar]
  40. WoolfC.J. A new strategy for the treatment of inflammatory pain. Prevention or elimination of central sensitization.Drugs199447Suppl. 51910.2165/00003495‑199400475‑00003 7525180
     [Google Scholar]
  41. BorovikovaL.V. IvanovaS. ZhangM. YangH. BotchkinaG.I. WatkinsL.R. WangH. AbumradN. EatonJ.W. TraceyK.J. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature2000405678545846210.1038/35013070 10839541
     [Google Scholar]
  42. LiuH. ZhangX. ShiP. YuanJ. JiaQ. PiC. ChenT. XiongL. ChenJ. TangJ. YueR. LiuZ. ShenH. ZuoY. WeiY. ZhaoL. α7 Nicotinic acetylcholine receptor: A key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect.J. Neuroinflammation20232018410.1186/s12974‑023‑02768‑z 36973813
     [Google Scholar]
  43. LinY. WongkrajangK. ShenX. WangP. ZhouZ. ChuprajobT. SornkaewN. YangN. YangL. LuX. ChokchaisiriR. SuksamrarnA. ZhangG. WangF. Discovery of diarylheptanoids that activate α7 nAchR-JAK2-STAT3 signaling in macrophages with anti-inflammatory activity in vitro and in vivo.Bioorg. Med. Chem.20226611681110.1016/j.bmc.2022.116811 35576655
     [Google Scholar]
  44. ZhouY. Leung-PittY. DengH. RenY. YouZ. KemW.R. ShenS. ZhangW. MaoJ. MartynJ.A.J. Nonopioid GTS-21 mitigates burn injury pain in rats by decreasing spinal cord inflammatory responses.Anesth. Analg.2021132124025210.1213/ANE.0000000000005274 33264122
     [Google Scholar]
  45. GaoZ. LiL. HuangY. ZhaoC. XueS. ChenJ. YangZ. XuJ. SuX. Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection.Acta Pharmacol. Sin.202142101642165210.1038/s41401‑020‑00579‑z 33414508
     [Google Scholar]
  46. RowleyT.J. McKinstryA. GreenidgeE. SmithW. FloodP. Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain.Br. J. Anaesth.2010105220120710.1093/bja/aeq113 20511332
     [Google Scholar]
  47. RowleyT.J. PayappillyJ. LuJ. FloodP. The antinociceptive response to nicotinic agonists in a mouse model of postoperative pain.Anesth. Analg.200810731052105710.1213/ane.0b013e318165e0c0 18713928
     [Google Scholar]
  48. ConaghanP.G. CookA.D. HamiltonJ.A. TakP.P. Therapeutic options for targeting inflammatory osteoarthritis pain.Nat. Rev. Rheumatol.201915635536310.1038/s41584‑019‑0221‑y 31068673
     [Google Scholar]
  49. LeeS.E. Choline, an alpha7 nicotinic acetylcholine receptor agonist, alleviates hyperalgesia in a rat osteoarthritis model.Neurosci. Lett.201354829129510.1016/j.neulet.2013.05.073 23769729
     [Google Scholar]
  50. CourtiesA. SellamJ. BerenbaumF. Role of the autonomic nervous system in osteoarthritis.Best Pract. Res. Clin. Rheumatol.201731566167510.1016/j.berh.2018.04.001 30509412
     [Google Scholar]
  51. TengP. LiuY. DaiY. ZhangH. LiuW.T. HuJ. Nicotine attenuates osteoarthritis pain and matrix metalloproteinase-9 expression via the α7 nicotinic acetylcholine receptor.J. Immunol.2019203248549210.4049/jimmunol.1801513 31152077
     [Google Scholar]
  52. KusudaR. CarreiraE.U. UlloaL. CunhaF.Q. KanashiroA. CunhaT.M. Choline attenuates inflammatory hyperalgesia activating nitric oxide/cGMP/ATP-sensitive potassium channels pathway.Brain Res.2020172714656710.1016/j.brainres.2019.146567 31783002
     [Google Scholar]
  53. LiuY. LinH. ZouR. WuJ. HanR. RaymondL.N. ReidP.F. QinZ. Suppression of complete Freund’s adjuvant-induced adjuvant arthritis by cobratoxin.Acta Pharmacol. Sin.200930221922710.1038/aps.2008.20 19169271
     [Google Scholar]
  54. KonstantakakiM. ChangeuxJ.P. TalyA. Docking of α-cobratoxin suggests a basal conformation of the nicotinic receptor.Biochem. Biophys. Res. Commun.2007359341341810.1016/j.bbrc.2007.05.126 17555709
     [Google Scholar]
  55. MordvintsevD.Y. PolyakY.L. RodionovD.I. JakubikJ. DolezalV. KarlssonE. TsetlinV.I. UtkinY.N. Weak toxin WTX from Naja kaouthia cobra venom interacts with both nicotinic and muscarinic acetylcholine receptors.FEBS J.2009276185065507510.1111/j.1742‑4658.2009.07203.x 19682302
     [Google Scholar]
  56. ZhangL. ZhangY. JiangD. ReidP.F. JiangX. QinZ. TaoJ. Alpha-cobratoxin inhibits T-type calcium currents through muscarinic M4 receptor and Go-protein βγ subunits-dependent protein kinase A pathway in dorsal root ganglion neurons.Neuropharmacology20126221062107210.1016/j.neuropharm.2011.10.017 22074645
     [Google Scholar]
  57. ZhangY. ZhangL. WangF. ZhangY. WangJ. QinZ. JiangX. TaoJ. Activation of M3 muscarinic receptors inhibits T-type Ca2+ channel currents via pertussis toxin-sensitive novel protein kinase C pathway in small dorsal root ganglion neurons.Cell. Signal.20112361057106710.1016/j.cellsig.2011.02.001 21329754
     [Google Scholar]
  58. CostaR. MottaE.M. ManjavachiM.N. ColaM. CalixtoJ.B. Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.Neuropharmacology201263579880510.1016/j.neuropharm.2012.06.004 22722030
     [Google Scholar]
  59. AlSharariS.D. BagdasD. AkbaraliH.I. LichtmanP.A. RabornE.S. CabralG.A. CarrollF.I. McGeeE.A. DamajM.I. Sex differences and drug dose influence the role of the α7 nicotinic acetylcholine receptor in the mouse dextran sodium sulfate-induced colitis model.Nicotine Tob. Res.201719446046810.1093/ntr/ntw245 27639096
     [Google Scholar]
  60. AbdrakhmanovaG.R. AlSharariS. KangM. DamajM.I. AkbaraliH.I. α7-nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis.Am. J. Physiol. Gastrointest. Liver Physiol.20102993G761G76810.1152/ajpgi.00175.2010 20595621
     [Google Scholar]
  61. SandersV.R. MillarN.S. Potentiation and allosteric agonist activation of α7 nicotinic acetylcholine receptors: Binding sites and hypotheses.Pharmacol. Res.202319110675910.1016/j.phrs.2023.106759 37023990
     [Google Scholar]
  62. BagdasD. WilkersonJ.L. KulkarniA. TomaW. AlSharariS. GulZ. LichtmanA.H. PapkeR.L. ThakurG.A. DamajM.I. The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain.Br. J. Pharmacol.2016173162506252010.1111/bph.13528 27243753
     [Google Scholar]
  63. BagdasD. MeadeJ.A. AlkhlaifY. MuldoonP.P. CarrollF.I. DamajM.I. Effect of nicotine and alpha‐7 nicotinic modulators on visceral pain‐induced conditioned place aversion in mice.Eur. J. Pain20182281419142710.1002/ejp.1231 29633429
     [Google Scholar]
  64. LopesF. GraepelR. ReyesJ.L. WangA. PetriB. McDougallJ.J. SharkeyK.A. McKayD.M. Involvement of mast cells in α7 nicotinic receptor agonist exacerbation of Freund’s Complete Adjuvant–Induced monoarthritis in mice.Arthritis Rheumatol.201668254255210.1002/art.39411 26314943
     [Google Scholar]
  65. XueR. WanY. SunX. ZhangX. GaoW. WuW. Nicotinic mitigation of neuroinflammation and oxidative stress after chronic sleep deprivation.Front. Immunol.201910254610.3389/fimmu.2019.02546 31736967
     [Google Scholar]
  66. LoramL.C. HarrisonJ.A. ChaoL. TaylorF.R. ReddyA. TravisC.L. GiffardR. Al-AbedY. TraceyK. MaierS.F. WatkinsL.R. Intrathecal injection of an alpha seven nicotinic acetylcholine receptor agonist attenuates gp120-induced mechanical allodynia and spinal pro-inflammatory cytokine profiles in rats.Brain Behav. Immun.201024695996710.1016/j.bbi.2010.03.008 20353818
     [Google Scholar]
  67. AbbasM. AlzareaS. PapkeR.L. RahmanS. The α7 nicotinic acetylcholine receptor positive allosteric modulator attenuates lipopolysaccharide-induced activation of hippocampal IκB and CD11b gene expression in mice.Drug Discov. Ther.201711420621110.5582/ddt.2017.01038 28867753
     [Google Scholar]
  68. AbbasM. AlzareaS. PapkeR.L. RahmanS. The α7 nicotinic acetylcholine receptor positive allosteric modulator prevents lipopolysaccharide-induced allodynia, hyperalgesia and TNF-α in the hippocampus in mice.Pharmacol. Rep.20197161168117610.1016/j.pharep.2019.07.001 31655281
     [Google Scholar]
  69. NamgungU. KimK.J. JoB.G. ParkJ.M. Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats.J. Neuroinflammation20221913310.1186/s12974‑022‑02396‑z 35109857
     [Google Scholar]
  70. SunR. LiuY. HouB. LeiY. BoJ. ZhangW. SunY.E. ZhangY. ZhangZ. LiuZ. HuoW. MaoY. MaZ. GuX. Perioperative activation of spinal α7 nAChR promotes recovery from preoperative stress-induced prolongation of postsurgical pain.Brain Behav. Immun.20197929430810.1016/j.bbi.2019.02.017 30797046
     [Google Scholar]
  71. FontanaI.C. KumarA. NordbergA. The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease.Nat. Rev. Neurol.202319527828810.1038/s41582‑023‑00792‑4 36977843
     [Google Scholar]
  72. PatelH. McIntireJ. RyanS. DunahA. LoringR. Anti-inflammatory effects of astroglial α7 nicotinic acetylcholine receptors are mediated by inhibition of the NF-κB pathway and activation of the Nrf2 pathway.J. Neuroinflammation201714119210.1186/s12974‑017‑0967‑6 28950908
     [Google Scholar]
  73. GodinJ.R. RoyP. QuadriM. BagdasD. TomaW. Narendrula-KothaR. KishtaO.A. DamajM.I. HorensteinN.A. PapkeR.L. SimardA.R. A silent agonist of α7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE.Brain Behav. Immun.20208728630010.1016/j.bbi.2019.12.014 31874200
     [Google Scholar]
  74. ScholzJ. FinnerupN.B. AttalN. AzizQ. BaronR. BennettM.I. BenolielR. CohenM. CruccuG. DavisK.D. EversS. FirstM. GiamberardinoM.A. HanssonP. KaasaS. KorwisiB. KosekE. Lavand’hommeP. NicholasM. NurmikkoT. PerrotS. RajaS.N. RiceA.S.C. RowbothamM.C. SchugS. SimpsonD.M. SmithB.H. SvenssonP. VlaeyenJ.W.S. WangS.J. BarkeA. RiefW. TreedeR.D. The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain.Pain20191601535910.1097/j.pain.0000000000001365 30586071
     [Google Scholar]
  75. CohenS.P. MaoJ. Neuropathic pain: Mechanisms and their clinical implications.BMJ20143486f765610.1136/bmj.f7656 24500412
     [Google Scholar]
  76. AlSharariS.D. FreitasK. DamajM.I. Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: Studies in transgenic mice.Biochem. Pharmacol.20138681201120710.1016/j.bcp.2013.06.018 23811428
     [Google Scholar]
  77. LoramL.C. TaylorF.R. StrandK.A. MaierS.F. SpeakeJ.D. JordanK.G. JamesJ.W. WeneS.P. PritchardR.C. GreenH. Van DykeK. MazarovA. LetchworthS.R. WatkinsL.R. Systemic administration of an alpha-7 nicotinic acetylcholine agonist reverses neuropathic pain in male sprague dawley rats.J. Pain201213121162117110.1016/j.jpain.2012.08.009 23182225
     [Google Scholar]
  78. JacobsonK.A. GiancottiL.A. LauroF. MuftiF. SalveminiD. Treatment of chronic neuropathic pain: Purine receptor modulation.Pain202016171425144110.1097/j.pain.0000000000001857 32187120
     [Google Scholar]
  79. HorváthG. GölöncsérF. CsölleC. KirályK. AndóR.D. BaranyiM. KoványiB. MátéZ. HoffmannK. AlgaierI. BaqiY. MüllerC.E. Von KügelgenI. SperlághB. Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents.Neurobiol. Dis.20147016217810.1016/j.nbd.2014.06.011 24971933
     [Google Scholar]
  80. KhasabovS.G. RognessV.M. BeesonM.B. VulchanovaL. YuanL.L. SimoneD.A. TranP.V. The nAChR Chaperone TMEM35a (NACHO) contributes to the development of hyperalgesia in mice.Neuroscience2021457748710.1016/j.neuroscience.2020.12.027 33422618
     [Google Scholar]
  81. LiuQ. LiuC. JiangL. LiM. LongT. HeW. QinG. ChenL. ZhouJ. α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation.J. Pain Res.2018111129114010.2147/JPR.S159146 29942148
     [Google Scholar]
  82. GonçalvesA.L. Martini FerreiraA. RibeiroR.T. ZukermanE. Cipolla-NetoJ. PeresM.F.P. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention.J. Neurol. Neurosurg. Psychiatry201687101127113210.1136/jnnp‑2016‑313458 27165014
     [Google Scholar]
  83. ZhangY. JiH. WangJ. SunY. QianZ. JiangX. SnutchT.P. SunY. TaoJ. Melatonin‐mediated inhibition of Cav3.2 T‐type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C‐eta isoform.J. Pineal Res.2018644e1247610.1111/jpi.12476 29437250
     [Google Scholar]
  84. NiranjanR. NathC. ShuklaR. Melatonin attenuated mediators of neuroinflammation and alpha-7 nicotinic acetylcholine receptor mRNA expression in lipopolysaccharide (LPS) stimulated rat astrocytoma cells, C6.Free Radic. Res.20124691167117710.3109/10715762.2012.697626 22656125
     [Google Scholar]
  85. AsefyZ. KhusroA. MammadovaS. HoseinnejhadS. EftekhariA. AlghamdiS. DabloolA.S. AlmehmadiM. KazemiE. SahibzadaM.U.K. Melatonin hormone as a therapeutic weapon against neurodegenerative diseases.Cell. Mol. Biol.20216739910610.14715/cmb/2021.67.3.13 34933727
     [Google Scholar]
  86. NakagawaY. ChibaK. Diversity and plasticity of microglial cells in psychiatric and neurological disorders.Pharmacol. Ther.2015154213510.1016/j.pharmthera.2015.06.010 26129625
     [Google Scholar]
  87. LiX. GuoQ. YeZ. WangE. ZouW. SunZ. HeZ. ZhongT. WengY. PanY. PPAR γ prevents neuropathic pain by down-regulating CX3CR1 and attenuating M1 activation of microglia in the spinal cord of rats using a sciatic chronic constriction injury model.Front. Neurosci.20211562052510.3389/fnins.2021.620525 33841075
     [Google Scholar]
  88. JiL. ChenY. WeiH. FengH. ChangR. YuD. WangX. GongX. ZhangM. Activation of alpha7 acetylcholine receptors reduces neuropathic pain by decreasing dynorphin A release from microglia.Brain Res.20191715576510.1016/j.brainres.2019.03.016 30898676
     [Google Scholar]
  89. HanQ.Q. YinM. WangZ.Y. LiuH. AoJ.P. WangY.X. CynandioneA. Cynandione A alleviates neuropathic pain through α7-nAChR-Dependent IL-10/β-Endorphin signaling complexes.Front. Pharmacol.20211161445010.3389/fphar.2020.614450 33584292
     [Google Scholar]
  90. BeloT.C.A. SantosG.X. da SilvaB.E.G. RochaB.L.G. AbdalaD.W. FreireL.A.M. RochaF.S. GaldinoG. IL-10/β-Endorphin-Mediated Neuroimmune Modulation on Microglia during Antinociception.Brain Sci.202313578910.3390/brainsci13050789 37239261
     [Google Scholar]
  91. ShiS. LiangD. BaoM. XieY. XuW. WangL. WangZ. QiaoZ. Gx-50 inhibits neuroinflammation via α7 nAChR activation of the JAK2/STAT3 and PI3K/AKT pathways.J. Alzheimers Dis.201650385987110.3233/JAD‑150963 26836188
     [Google Scholar]
  92. WangZ.Y. HanQ.Q. DengM.Y. ZhaoM.J. ApryaniE. ShoaibR.M. WeiD.Q. WangY.X. Lemairamin, isolated from the Zanthoxylum plants, alleviates pain hypersensitivity via spinal α7 nicotinic acetylcholine receptors.Biochem. Biophys. Res. Commun.202052541087109410.1016/j.bbrc.2020.03.023 32184015
     [Google Scholar]
  93. GrandoS.A. Connections of nicotine to cancer.Nat. Rev. Cancer201414641942910.1038/nrc3725 24827506
     [Google Scholar]
  94. FeiR. ZhangY. WangS. XiangT. ChenW. α7 nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway.Oncol. Rep.20173852619262810.3892/or.2017.5935 28901507
     [Google Scholar]
  95. XiangT. YuF. FeiR. QianJ. ChenW. CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling.Oncol. Rep.2016352999100510.3892/or.2015.4462 26719016
     [Google Scholar]
  96. DaiC.L. ZhangR. AnP. DengY.Q. RahmanK. ZhangH. Cinobufagin: a promising therapeutic agent for cancer.J. Pharm. Pharmacol.20237591141115310.1093/jpp/rgad059 37390473
     [Google Scholar]
  97. ApryaniE. AliU. WangZ.Y. WuH.Y. MaoX.F. AhmadK.A. LiX.Y. WangY.X. The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors.J. Neuroinflammation20201717510.1186/s12974‑019‑1616‑z 32113469
     [Google Scholar]
  98. YangY. ZhaoB. GaoX. SunJ. YeJ. LiJ. CaoP. Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development.J. Exp. Clin. Cancer Res.202140133110.1186/s13046‑021‑02141‑z 34686205
     [Google Scholar]
  99. Di Cesare MannelliL. PaciniA. MateraC. ZanardelliM. MelloT. De AmiciM. DallanoceC. GhelardiniC. Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: Effects of selective activation.Neuropharmacology201479374810.1016/j.neuropharm.2013.10.034 24225197
     [Google Scholar]
  100. BettiM. CatarziD. VaranoF. FalsiniM. VaraniK. VincenziF. PasquiniS. di Cesare MannelliL. GhelardiniC. LucariniE. Dal BenD. SpinaciA. BartolucciG. MenicattiM. ColottaV. Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity.J. Med. Chem.201962156894691210.1021/acs.jmedchem.9b00106 31306001
     [Google Scholar]
  101. Di Cesare MannelliL. TenciB. ZanardelliM. FailliP. GhelardiniC. α 7 nicotinic receptor promotes the neuroprotective functions of astrocytes against oxaliplatin neurotoxicity.Neural Plast.2015201511010.1155/2015/396908 26146570
     [Google Scholar]
  102. HamurtekinE. BagdasD. GurunM.S. Possible involvement of supraspinal opioid and GABA receptors in CDP-choline-induced antinociception in acute pain models in rats.Neurosci. Lett.2007420211612110.1016/j.neulet.2007.04.058 17531379
     [Google Scholar]
  103. KanatO. BagdasD. OzbolukH.Y. GurunM.S. Preclinical evidence for the antihyperalgesic activity of CDP-choline in oxaliplatin-induced neuropathic pain.J. BUON201318410121018 24344031
     [Google Scholar]
  104. BenjaminD. ColombiM. MoroniC. HallM.N. Rapamycin passes the torch: a new generation of mTOR inhibitors.Nat. Rev. Drug Discov.2011101186888010.1038/nrd3531 22037041
     [Google Scholar]
  105. LiS. GuanS. WangY. ChengL. YangQ. TianZ. ZhaoM. WangX. FengB. Nicotine inhibits rapamycin-induced pain through activating mTORC1/S6K/IRS-1-related feedback inhibition loop.Brain Res. Bull.2019149758510.1016/j.brainresbull.2019.04.016 31005665
     [Google Scholar]
  106. KolodnyA. CourtwrightD.T. HwangC.S. KreinerP. EadieJ.L. ClarkT.W. AlexanderG.C. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction.Annu. Rev. Public Health201536155957410.1146/annurev‑publhealth‑031914‑122957 25581144
     [Google Scholar]
  107. ColvinL.A. BullF. HalesT.G. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia.Lancet2019393101801558156810.1016/S0140‑6736(19)30430‑1 30983591
     [Google Scholar]
  108. RenJ. DingX. GreerJ.J. Activating α4β2 nicotinic acetylcholine receptors alleviates fentanyl-induced respiratory depression in rats.Anesthesiology201913061017103110.1097/ALN.0000000000002676 31008764
     [Google Scholar]
  109. ZhangW. LiuY. HouB. GuX. MaZ. Activation of spinal alpha-7 nicotinic acetylcholine receptor attenuates remifentanil-induced postoperative hyperalgesia.Int. J. Clin. Exp. Med.20158218711879 25932115
     [Google Scholar]
  110. GuW. ZhangW. LeiY. CuiY. ChuS. GuX. MaZ. Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats.Mol. Pain20171310.1177/1744806917704769 28425312
     [Google Scholar]
  111. JiaD. LiuG. SunY. HuZ. HuangZ. HuangC. Trifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through α7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats.Biomed. Pharmacother.202315711400110.1016/j.biopha.2022.114001 36375307
     [Google Scholar]
  112. RenY. ZhouY. YouZ. DengH. KemW.R. MaoJ. ZhangW. MartynJ.A.J. The nonopioid cholinergic agonist GTS-21 mitigates morphine-induced aggravation of burn injury pain together with inhibition of spinal microglia activation in young rats.Br. J. Anaesth.2022129695996910.1016/j.bja.2022.07.055 36243579
     [Google Scholar]
  113. PapkeR.L. LindstromJ.M. Nicotinic acetylcholine receptors: Conventional and unconventional ligands and signaling.Neuropharmacology202016810802110.1016/j.neuropharm.2020.108021 32146229
     [Google Scholar]
  114. YangT. XiaoT. SunQ. WangK. The current agonists and positive allosteric modulators of α 7 nAChR for CNS indications in clinical trials.Acta Pharm. Sin. B20177661162210.1016/j.apsb.2017.09.001 29159020
     [Google Scholar]
  115. PandyaA.A. YakelJ.L. Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies.Biochem. Pharmacol.20138681054106210.1016/j.bcp.2013.05.018 23732296
     [Google Scholar]
  116. Camacho-HernandezG.A. StokesC. DugganB.M. KaczanowskaK. Brandao-AraizaS. DoanL. PapkeR.L. TaylorP. Synthesis, pharmacological characterization, and structure-activity relationships of noncanonical selective agonists for α7 nAChRs.J. Med. Chem.20196222103761039010.1021/acs.jmedchem.9b01467 31675224
     [Google Scholar]
  117. FreitasK. GhoshS. Ivy CarrollF. LichtmanA.H. Imad DamajM. Effects of α 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models.Neuropharmacology20136515616410.1016/j.neuropharm.2012.08.022 23079470
     [Google Scholar]
  118. CaillaudM. ThompsonD. TomaW. WhiteA. MannJ. RobertsJ.L. BigbeeJ.W. GewirtzD.A. DamajM.I. Formulated curcumin prevents paclitaxel-induced peripheral neuropathy through reduction in neuroinflammation by modulation of α7 nicotinic acetylcholine receptors.Pharmaceutics2022146129610.3390/pharmaceutics14061296 35745868
     [Google Scholar]
  119. El NebrisiE.G. BagdasD. TomaW. Al SamriH. BrodzikA. AlkhlaifY. YangK.H.S. HowarthF.C. DamajI.M. OzM. Curcumin acts as a positive allosteric modulator of α7-nicotinic acetylcholine receptors and reverses nociception in mouse models of inflammatory pain.J. Pharmacol. Exp. Ther.2018365119020010.1124/jpet.117.245068 29339457
     [Google Scholar]
  120. PapkeR.L. BagdasD. KulkarniA.R. GouldT. AlSharariS.D. ThakurG.A. DamajM.I. The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor.Neuropharmacology201591344210.1016/j.neuropharm.2014.12.002 25497451
     [Google Scholar]
  121. PapkeR.L. QuadriM. GulsevinA. Silent agonists for α7 nicotinic acetylcholine receptors.Pharmacol. Res.202319010673610.1016/j.phrs.2023.106736 36940890
     [Google Scholar]
  122. ChojnackaK. PapkeR.L. HorensteinN.A. Synthesis and evaluation of a conditionally-silent agonist for the α7 nicotinic acetylcholine receptor.Bioorg. Med. Chem. Lett.201323144145414910.1016/j.bmcl.2013.05.039 23746476
     [Google Scholar]
  123. TomaW. KyteS.L. BagdasD. JacksonA. MeadeJ.A. RahmanF. ChenZ.J. Del FabbroE. CantwellL. KulkarniA. ThakurG.A. PapkeR.L. BigbeeJ.W. GewirtzD.A. DamajM.I. The α7 nicotinic receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy in mice without tolerance or altering nicotine reward and withdrawal.Exp. Neurol.201932011301010.1016/j.expneurol.2019.113010 31299179
     [Google Scholar]
  124. ShiY-P. WangJ-D. WangR-H. ZhaoX-D. YuH-T. WangH. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain.Eur. J. Pain201115885886510.1016/j.ejpain.2011.02.001 21388846
     [Google Scholar]
  125. PanZ.Y. WangH. Synergistic interaction between choline and aspirin against acute inflammation induced by carrageenan and lipopolysaccharide.Int. Immunopharmacol.201420122923710.1016/j.intimp.2014.03.004 24656779
     [Google Scholar]
  126. SidhuN. DaviesS. NadarajahA. RiveraJ. WhittingtonR. MercierR.J. ViragL. WangS. FloodP. Oral choline supplementation for postoperative pain.Br. J. Anaesth.2013111224925510.1093/bja/aet031 23568851
     [Google Scholar]
  127. BagdasD. SonatF.A. HamurtekinE. SonalS. GurunM.S. The antihyperalgesic effect of cytidine-5′-diphosphate-choline in neuropathic and inflammatory pain models.Behav. Pharmacol.2011225 and 658959810.1097/FBP.0b013e32834a1efb 21836465
     [Google Scholar]
  128. GurunM.S. ParkerR. EisenachJ.C. VinclerM. The effect of peripherally administered CDP-choline in an acute inflammatory pain model: the role of alpha7 nicotinic acetylcholine receptor.Anesth. Analg.200910851680168710.1213/ane.0b013e31819dcd08 19372354
     [Google Scholar]
  129. IarkovA. MendozaC. EcheverriaV. Cholinergic receptor modulation as a target for preventing dementia in Parkinson’s disease.Front. Neurosci.20211566582010.3389/fnins.2021.665820 34616271
     [Google Scholar]
  130. HoneA.J. McIntoshJ.M. Nicotinic acetylcholine receptors in neuropathic and inflammatory pain.FEBS Lett.201859271045106210.1002/1873‑3468.12884 29030971
     [Google Scholar]
  131. WuJ. LiuQ. TangP. MikkelsenJ.D. ShenJ. WhiteakerP. YakelJ.L. Heteromeric α7β2 nicotinic acetylcholine receptors in the brain.Trends Pharmacol. Sci.201637756257410.1016/j.tips.2016.03.005 27179601
     [Google Scholar]
  132. MowreyD.D. LiuQ. BondarenkoV. ChenQ. SeyoumE. XuY. WuJ. TangP. Insights into distinct modulation of α7 and α7β2 nicotinic acetylcholine receptors by the volatile anesthetic isoflurane.J. Biol. Chem.201328850357933580010.1074/jbc.M113.508333 24194515
     [Google Scholar]
  133. KnowlandD. GuS. EckertW.A.III DaweG.B. MattaJ.A. LimberisJ. WickendenA.D. BhattacharyaA. BredtD.S. Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties.J. Clin. Invest.2020130116158617010.1172/JCI140311 33074244
     [Google Scholar]
  134. RomeroH.K. ChristensenS.B. Di CesareM.L. GajewiakJ. RamachandraR. ElmslieK.S. VetterD.E. GhelardiniC. IadonatoS.P. MercadoJ.L. OliveraB.M. McIntoshJ.M. Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.Proc. Natl. Acad. Sci. USA201711410E1825E183210.1073/pnas.1621433114 28223528
     [Google Scholar]
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The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications
Curr. Neuropharmacol. 23, 129 (2025); https://doi.org/10.2174/1570159X22666240528161117
/content/journals/cn/10.2174/1570159X22666240528161117
/content/journals/cn/10.2174/1570159X22666240528161117
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  • Article Type:     Review Article
Keyword(s): chronic pain; ligand-gated ion channels; peripheral nervous systems; pharmacology; therapeutic approaches; α7 nicotinic acetylcholine receptors

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