Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Neuropharmacology
  4. Volume 23, Issue 3
  5. Article
Volume 23, Issue 3
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Neuropathic pain, a multifaceted and incapacitating disorder, impacts a significant number of individuals globally. Despite thorough investigation, the development of efficacious remedies for neuropathic pain continues to be a formidable task. Recent research has revealed the potential of metabotropic glutamate receptor 5 (mGlu5) as a target for managing neuropathic pain. mGlu5 is a receptor present in the central nervous system that has a vital function in regulating synaptic transmission and the excitability of neurons. This article seeks to investigate the importance of mGlu5 in neuropathic pain pathways, analyze the pharmacological approach of targeting mGlu5 for neuropathic pain treatment, and review the negative allosteric mGlu5 modulators used to target mGlu5. By comprehending the role of mGlu5 in neuropathic pain, we can discover innovative treatment approaches to ease the distress endured by persons afflicted with this incapacitating ailment.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cn/10.2174/1570159X23666241011163035
2024-10-14
2025-03-13

  • From This Site

    /content/journals/cn/10.2174/1570159X23666241011163035
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. BouhassiraD. Neuropathic pain: Definition, assessment and epidemiology.Rev. Neurol.20191751-2162510.1016/j.neurol.2018.09.016 30385075
     [Google Scholar]
  2. CollocaL. LudmanT. BouhassiraD. BaronR. DickensonA.H. YarnitskyD. FreemanR. TruiniA. AttalN. FinnerupN.B. EcclestonC. KalsoE. BennettD.L. DworkinR.H. RajaS.N. Neuropathic pain.Nat. Rev. Dis. Primers2017311700210.1038/nrdp.2017.2 28205574
     [Google Scholar]
  3. DupoironD. BrillS. EeltinkC. BarragánB. BellD. PetersenG. EerdekensM. RyanD. RakušaM. Diagnosis, management and impact on patients’ lives of cancer‐related neuropathic pain (CRNP): A European survey.Eur. J. Cancer Care (Engl.)2022316e1372810.1111/ecc.13728 36222099
     [Google Scholar]
  4. IrvingG.A. Contemporary assessment and management of neuropathic pain.Neurology20056412suppl_3S21S2710.1212/WNL.64.12_suppl_3.S21 15999405
     [Google Scholar]
  5. AleyK.O. ReichlingD.B. LevineJ.D. Vincristine hyperalgesia in the rat: A model of painful vincristine neuropathy in humans.Neuroscience199673125926510.1016/0306‑4522(96)00020‑6 8783247
     [Google Scholar]
  6. FinnerupN.B. KunerR. JensenT.S. Neuropathic pain: From mechanisms to treatment.Physiol. Rev.2021101125930110.1152/physrev.00045.2019 32584191
     [Google Scholar]
  7. HeF. GuX-S. ChuX-L. SongX-Z. LiQ. LiY-R. MingD. Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation.Neural Regen. Res.202217102185219310.4103/1673‑5374.335823 35259827
     [Google Scholar]
  8. BoydA. ByrneS. MiddletonR.J. BanatiR.B. LiuG.J. Control of neuroinflammation through radiation-induced microglial changes.Cells2021109238110.3390/cells10092381 34572030
     [Google Scholar]
  9. InoueK. TsudaM. Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential.Nat. Rev. Neurosci.201819313815210.1038/nrn.2018.2 29416128
     [Google Scholar]
  10. NavarroX. Neural plasticity after nerve injury and regeneration.Int. Rev. Neurobiol.20098748350510.1016/S0074‑7742(09)87027‑X 19682656
     [Google Scholar]
  11. ChabanVV Peripheral sensitization of sensory neurons Ethn Dis2010201S1-36
     [Google Scholar]
  12. MeachamK. ShepherdA. MohapatraD.P. HaroutounianS. Neuropathic pain: Central vs. peripheral mechanisms.Curr. Pain Headache Rep.20172162810.1007/s11916‑017‑0629‑5 28432601
     [Google Scholar]
  13. SharmaA. BehlT. SharmaL. ShahO.P. YadavS. SachdevaM. RashidS. BungauS.G. BusteaC. Exploring the molecular pathways and therapeutic implications of angiogenesis in neuropathic pain.Biomed. Pharmacother.202316211469310.1016/j.biopha.2023.114693 37062217
     [Google Scholar]
  14. NovakovicS.D. TzoumakaE. McGivernJ.G. HaraguchiM. SangameswaranL. GogasK.R. EglenR.M. HunterJ.C. Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions.J. Neurosci.19981862174218710.1523/JNEUROSCI.18‑06‑02174.1998 9482802
     [Google Scholar]
  15. LatremoliereA. WoolfC.J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity.J. Pain200910989592610.1016/j.jpain.2009.06.012 19712899
     [Google Scholar]
  16. NijsJ. Van HoudenhoveB. OostendorpR.A.B. Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice.Man. Ther.201015213514110.1016/j.math.2009.12.001 20036180
     [Google Scholar]
  17. MeeusM. NijsJ. Van de WauwerN. ToebackL. TruijenS. Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: An experimental study.Pain2008139243944810.1016/j.pain.2008.05.018 18617327
     [Google Scholar]
  18. MeeusM. NijsJ. Central sensitization: A biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome.Clin. Rheumatol.200726446547310.1007/s10067‑006‑0433‑9 17115100
     [Google Scholar]
  19. FieldsH.L. RowbothamM. BaronR. Postherpetic neuralgia: Irritable nociceptors and deafferentation.Neurobiol. Dis.19985420922710.1006/nbdi.1998.0204 9848092
     [Google Scholar]
  20. WoolfC.J. ShortlandP. CoggeshallR.E. Peripheral nerve injury triggers central sprouting of myelinated afferents.Nature19923556355757810.1038/355075a0 1370574
     [Google Scholar]
  21. GracelyR.H. LynchS.A. BennettG.J. Painful neuropathy: Altered central processing maintained dynamically by peripheral input.Pain199251217519410.1016/0304‑3959(92)90259‑E 1484715
     [Google Scholar]
  22. OhsawaM. YamamotoS. OnoH. Contribution of the sensitization of supraspinal nociceptive transmission in chronic pain.Yakugaku Zasshi2014134338739510.1248/yakushi.13‑00236‑3 24584020
     [Google Scholar]
  23. WestS.J. BannisterK. DickensonA.H. BennettD.L. Circuitry and plasticity of the dorsal horn – Toward a better understanding of neuropathic pain.Neuroscience201530025427510.1016/j.neuroscience.2015.05.020 25987204
     [Google Scholar]
  24. MillanM.J. Descending control of pain.Prog. Neurobiol.200266635547410.1016/S0301‑0082(02)00009‑6 12034378
     [Google Scholar]
  25. DworkinR.H. O’ConnorA.B. AudetteJ. BaronR. GourlayG.K. HaanpääM.L. KentJ.L. KraneE.J. LeBelA.A. LevyR.M. MackeyS.C. MayerJ. MiaskowskiC. RajaS.N. RiceA.S.C. SchmaderK.E. StaceyB. StanosS. TreedeR.D. TurkD.C. WalcoG.A. WellsC.D. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update.Mayo Clin. Proc.2010853S3S1410.4065/mcp.2009.0649 20194146
     [Google Scholar]
  26. FornasariD. Pharmacotherapy for neuropathic pain: A review.Pain Ther.20176S1253310.1007/s40122‑017‑0091‑4 29178034
     [Google Scholar]
  27. Neuropathic pain in adults: Pharmacological management in nonspecialist settings. NICE, Clinical Guideline.2013Available from: nice.org.uk/guidance/cg173
  28. FinnerupN.B. AttalN. HaroutounianS. McNicolE. BaronR. DworkinR.H. GilronI. HaanpääM. HanssonP. JensenT.S. KamermanP.R. LundK. MooreA. RajaS.N. RiceA.S.C. RowbothamM. SenaE. SiddallP. SmithB.H. WallaceM. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis.Lancet Neurol.201514216217310.1016/S1474‑4422(14)70251‑0 25575710
     [Google Scholar]
  29. SumitaniM. SakaiT. MatsudaY. AbeH. YamaguchiS. HosokawaT. FukuiS. Executive summary of the clinical guidelines of pharmacotherapy for neuropathic pain: Second edition by the Japanese society of pain clinicians.J. Anesth.2018323463478
     [Google Scholar]
  30. MuA. WeinbergE. MoulinD.E. ClarkeH. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement.Can. Fam. Physician20176311844852 29138154
     [Google Scholar]
  31. AttalN. CruccuG. BaronR. HaanpääM. HanssonP. JensenT.S. NurmikkoT. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.Eur. J. Neurol.20101791113e8810.1111/j.1468‑1331.2010.02999.x 20402746
     [Google Scholar]
  32. Guidelines for the pharmacological treatment of neuropathic pain Australian Clinical Practice Guidelines. Available from: https://www.clinicalguidelines. gov.au/portal/2290/guidelines-treatment-neuropathic-pain (Accessed March 22, 2024).
  33. ThouayeM. YalcinI. Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons.Pharmacol. Ther.202325110854610.1016/j.pharmthera.2023.108546 37832728
     [Google Scholar]
  34. HorishitaT. YanagiharaN. UenoS. OkuraD. HorishitaR. MinamiT. OgataY. SudoY. UezonoY. SataT. KawasakiT. Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes.Naunyn Schmiedebergs Arch. Pharmacol.2017390121255127010.1007/s00210‑017‑1424‑x 28905186
     [Google Scholar]
  35. ObataH. Analgesic mechanisms of antidepressants for neuropathic pain.Int. J. Mol. Sci.20171811248310.3390/ijms18112483 29160850
     [Google Scholar]
  36. JensenT.S. MadsenC.S. FinnerupN.B. Pharmacology and treatment of neuropathic pains.Curr. Opin. Neurol.200922546747410.1097/WCO.0b013e3283311e13 19741531
     [Google Scholar]
  37. SmithT. NicholsonR.A. Review of duloxetine in the management of diabetic peripheral neuropathic pain.Vasc. Health Risk Manag.200736833844 18200804
     [Google Scholar]
  38. MoulinD.E. BoulangerA. ClarkA.J. ClarkeH. DaoT. FinleyG.A. FurlanA. GilronI. GordonA. Morley-ForsterP.K. SessleB.J. SquireP. StinsonJ. TaenzerP. VellyA. WareM.A. WeinbergE.L. WilliamsonO.D. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society.Pain Res. Manag.201419632833510.1155/2014/754693 25479151
     [Google Scholar]
  39. LiC.T. WatsonJ.C. Anticonvulsants in the Treatment of Pain.Deer’s Treatment of Pain201914916110.1007/978‑3‑030‑12281‑2_19
     [Google Scholar]
  40. JensenM.P. ChiangY.K. WuJ. Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia.Clin. J. Pain200925428629210.1097/AJP.0b013e318192bf87 19590476
     [Google Scholar]
  41. IrvingG. JensenM. CramerM. WuJ. ChiangY.K. TarkM. WallaceM. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: Results of a double-blind, randomized, placebo-controlled clinical trial.Clin. J. Pain200925318519210.1097/AJP.0b013e3181934276 19333167
     [Google Scholar]
  42. ArezzoJ.C. RosenstockJ. LaMoreauxL. PauerL. Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: A double-blind placebo-controlled trial.BMC Neurol.2008813310.1186/1471‑2377‑8‑33 18796160
     [Google Scholar]
  43. WiffenP.J. DerryS. BellR.F. RiceA.S.C. TölleT.R. PhillipsT. MooreR.A. Gabapentin for chronic neuropathic pain in adults.Cochrane Libr.201720202CD00793810.1002/14651858.CD007938.pub4 28597471
     [Google Scholar]
  44. BirseF. DerryS. MooreR.A. Phenytoin for neuropathic pain and fibromyalgia in adults.Cochrane Libr.201220195CD00948510.1002/14651858.CD009485.pub2 22592741
     [Google Scholar]
  45. WiffenP.J. DerryS. MooreR.A. AldingtonD. ColeP. RiceA.S.C. LunnM.P.T. HamunenK. HaanpaaM. KalsoE.A. Antiepileptic drugs for neuropathic pain and fibromyalgia - An overview of Cochrane reviews.Cochrane Libr.201320195CD01056710.1002/14651858.CD010567.pub2 24217986
     [Google Scholar]
  46. Lankhorst, Michael A Antidepressants and anticonvulsants for neuropathic pain.In: Anesthesiology In-Training Exam Review.ChamSpringer2022
     [Google Scholar]
  47. WiffenP.J. DerryS. MooreR.A. KalsoE.A. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults.Cochrane Libr.201420195CD00545110.1002/14651858.CD005451.pub3 24719027
     [Google Scholar]
  48. BatesD. SchultheisB.C. HanesM.C. JollyS.M. ChakravarthyK.V. DeerT.R. LevyR.M. HunterC.W. A comprehensive algorithm for management of neuropathic pain.Pain Med.201920Suppl. 1S2S1210.1093/pm/pnz075 31152178
     [Google Scholar]
  49. HermannsH. HollmannM.W. StevensM.F. LirkP. BrandenburgerT. PiegelerT. WerdehausenR. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: A narrative review.Br. J. Anaesth.2019123333534910.1016/j.bja.2019.06.014 31303268
     [Google Scholar]
  50. MiclescuA. SchmelzM. GordhT. Differential analgesic effects of subanesthetic concentrations of lidocaine on spontaneous and evoked pain in human painful neuroma: A randomized, double blind study.Scand. J. Pain201581374410.1016/j.sjpain.2015.04.026 29911636
     [Google Scholar]
  51. SommerC. CruccuG. Topical treatment of peripheral neuropathic pain: Applying the evidence.J. Pain Symptom Manage.201753361462910.1016/j.jpainsymman.2016.09.015
     [Google Scholar]
  52. DerryS. WiffenP.J. KalsoE.A. BellR.F. AldingtonD. PhillipsT. GaskellH. MooreR.A. Topical analgesics for acute and chronic pain in adults - An overview of cochrane reviews.Cochrane Libr.201720202CD00860910.1002/14651858.CD008609.pub2 28497473
     [Google Scholar]
  53. AnandP. PriviteraR. DonatienP. FadaviH. TesfayeS. BravisV. MisraV.P. Reversing painful and non-painful diabetic neuropathy with the capsaicin 8% patch: Clinical evidence for pain relief and restoration of function via nerve fiber regeneration.Front. Neurol.20221399890410.3389/fneur.2022.998904 36388188
     [Google Scholar]
  54. DludlaP.V. NkambuleB.B. CirilliI. MarcheggianiF. MabhidaS.E. ZiqubuK. NtamoY. JackB. NyambuyaT.M. HanserS. Mazibuko-MbejeS.E. Capsaicin, its clinical significance in patients with painful diabetic neuropathy.Biomed. Pharmacother.202215311343910.1016/j.biopha.2022.113439 36076554
     [Google Scholar]
  55. CasaleR. SymeonidouZ. BartoloM. Topical treatments for localized neuropathic pain.Curr. Pain Headache Rep.20172131510.1007/s11916‑017‑0615‑y 28271334
     [Google Scholar]
  56. LourencoJ.L. Campelo FeresC. Telles-DiasP.R. Topical preparations for pain relief: Efficacy and patient adherence.J. Pain Res.20104112410.2147/JPR.S9492 21386951
     [Google Scholar]
  57. GilronI. BaileyJ.M. TuD. HoldenR.R. JacksonA.C. HouldenR.L. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial.Lancet200937496971252126110.1016/S0140‑6736(09)61081‑3 19796802
     [Google Scholar]
  58. SiddallP.J. CousinsM.J. OtteA. GriesingT. ChambersR. MurphyT.K. Pregabalin in central neuropathic pain associated with spinal cord injury.Neurology200667101792180010.1212/01.wnl.0000244422.45278.ff 17130411
     [Google Scholar]
  59. SindrupS.H. OttoM. FinnerupN.B. JensenT.S. Antidepressants in the treatment of neuropathic pain.Basic Clin. Pharmacol. Toxicol.200596639940910.1111/j.1742‑7843.2005.pto_96696601.x 15910402
     [Google Scholar]
  60. RowbothamM.C. GoliV. KunzN.R. LeiD. Venlafaxine extended release in the treatment of painful diabetic neuropathy: A double-blind, placebo-controlled study.Pain2004110369770610.1016/j.pain.2004.05.010 15288411
     [Google Scholar]
  61. SindrupS.H. AndersenG. MadsenC. SmithT. BrøsenK. JensenT.S. Tramadol relieves pain and allodynia in polyneuropathy: A randomised, double-blind, controlled trial.Pain1999831859010.1016/S0304‑3959(99)00079‑2 10506675
     [Google Scholar]
  62. BoureauF. LegallicierP. Kabir-AhmadiM. Tramadol in post-herpetic neuralgia: A randomized, double-blind, placebo-controlled trial.Pain2003104132333110.1016/S0304‑3959(03)00020‑4 12855342
     [Google Scholar]
  63. ArbaizaD. VidalO. Tramadol in the treatment of neuropathic cancer pain: A double-blind, placebo-controlled study.Clin. Drug Investig.2007271758310.2165/00044011‑200727010‑00007 17177582
     [Google Scholar]
  64. FreoU. RomualdiP. KressH.G. Tapentadol for neuropathic pain: A review of clinical studies.J. Pain Res.2019121537155110.2147/JPR.S190162 31190965
     [Google Scholar]
  65. SchwartzS. EtropolskiM. ShapiroD.Y. OkamotoA. LangeR. HaeusslerJ. RauschkolbC. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: Results of a randomized-withdrawal, placebo-controlled trial.Curr. Med. Res. Opin.201127115116210.1185/03007995.2010.537589 21162697
     [Google Scholar]
  66. AzamS. JakariaM. KimJ. AhnJ. KimI.S. ChoiD.K. Group I mGluRs in therapy and diagnosis of Parkinson’s disease: Focus on mGluR5 subtype.Biomedicines202210486410.3390/biomedicines10040864 35453614
     [Google Scholar]
  67. CollingridgeG.L. OlsenR.W. PetersJ. SpeddingM. A nomenclature for ligand-gated ion channels.Neuropharmacology20095612510.1016/j.neuropharm.2008.06.063 18655795
     [Google Scholar]
  68. DoréA.S. OkrasaK. PatelJ.C. Serrano-VegaM. BennettK. CookeR.M. ErreyJ.C. JazayeriA. KhanS. TehanB. WeirM. WigginG.R. MarshallF.H. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain.Nature2014511751155756210.1038/nature13396 25042998
     [Google Scholar]
  69. KolberB.J. MontanaM.C. CarrasquilloY. XuJ. HeinemannS.F. MugliaL.J. GereauR.W.IV Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior.J. Neurosci.201030248203821310.1523/JNEUROSCI.1216‑10.2010 20554871
     [Google Scholar]
  70. MazzitelliM. PalazzoE. MaioneS. NeugebauerV. GroupI.I. Group II metabotropic glutamate receptors: Role in pain mechanisms and pain modulation.Front. Mol. Neurosci.20181138310.3389/fnmol.2018.00383 30356691
     [Google Scholar]
  71. HallockR.M. MartyniukC.J. FingerT.E. Group III metabotropic glutamate receptors (mGluRs) modulate transmission of gustatory inputs in the brain stem.J. Neurophysiol.2009102119220210.1152/jn.00135.2009 19369363
     [Google Scholar]
  72. GrueterB.A. WinderD.G. Metabotropic glutamate receptors (mGluRs): Functions.In: Encyclopedia of Neuroscience.Academic press2009795800
     [Google Scholar]
  73. WrightR.A. JohnsonB.G. ZhangC. SalhoffC. KingstonA.E. CalligaroD.O. MonnJ.A. SchoeppD.D. MarekG.J. CNS distribution of metabotropic glutamate 2 and 3 receptors: Transgenic mice and [3H]LY459477 autoradiography.Neuropharmacology201366899810.1016/j.neuropharm.2012.01.019 22313530
     [Google Scholar]
  74. GuG. LorrainD.S. WeiH. ColeR.L. ZhangX. DaggettL.P. SchaffhauserH.J. BristowL.J. LechnerS.M. Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: Implication in emotional responses and central disinhibition.Brain Res.20081197476210.1016/j.brainres.2007.12.057 18242587
     [Google Scholar]
  75. SrivastavaA. DasB. YaoA.Y. YanR. Metabotropic glutamate receptors in Alzheimer’s disease synaptic dysfunction: Therapeutic opportunities and hope for the future.J. Alzheimers Dis.20207841345136110.3233/JAD‑201146 33325389
     [Google Scholar]
  76. MaoL.M. MathurN. MahmoodT. RajanS. ChuX.P. WangJ.Q. Phosphorylation and regulation of group II metabotropic glutamate receptors (mGlu2/3) in neurons.Front. Cell Dev. Biol.202210102254410.3389/fcell.2022.1022544 36407098
     [Google Scholar]
  77. NeugebauerV. Group III metabotropic glutamate receptors (mGlu4, mGlu6, mGlu7, and mGlu8).In: The Glutamate Receptors.New York, NYHumana Press2008489508
     [Google Scholar]
  78. MalherbeP. KewJ.N.C. RichardsJ.G. KnoflachF. KratzeisenC. ZennerM.T. FaullR.L.M. KempJ.A. MutelV. Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum.Brain Res. Mol. Brain Res.20021091-216817810.1016/S0169‑328X(02)00557‑0 12531526
     [Google Scholar]
  79. MinakamiR. IidaK. HirakawaN. SugiyamaH. The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development.J. Neurochem.19956541536154210.1046/j.1471‑4159.1995.65041536.x 7561847
     [Google Scholar]
  80. JolyC. GomezaJ. BrabetI. CurryK. BockaertJ. PinJ.P. Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: Comparison with mGluR1.J. Neurosci.19951553970398110.1523/JNEUROSCI.15‑05‑03970.1995 7751958
     [Google Scholar]
  81. AlvarezF.J. VillalbaR.M. CarrP.A. GrandesP. SomohanoP.M. Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord.J. Comp. Neurol.2000422346448710.1002/1096‑9861(20000703)422:3<464:AID‑CNE11>3.0.CO;2‑# 10861520
     [Google Scholar]
  82. ShigemotoR. NomuraS. OhishiH. SugiharaH. NakanishiS. MizunoN. Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain.Neurosci. Lett.19931631535710.1016/0304‑3940(93)90227‑C 8295733
     [Google Scholar]
  83. RomanoC. SesmaM.A. McDonaldC.T. O’malleyK. van den PolA.N. OlneyJ.W. Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain.J. Comp. Neurol.1995355345546910.1002/cne.903550310 7636025
     [Google Scholar]
  84. HoffpauirB.K. GleasonE.L. Activation of mGluR5 modulates GABA(A) receptor function in retinal amacrine cells.J. Neurophysiol.20028841766177610.1152/jn.2002.88.4.1766 12364505
     [Google Scholar]
  85. SchoeppD.D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system.J. Pharmacol. Exp. Ther.200129911220 11561058
     [Google Scholar]
  86. BudgettR.F. BakkerG. SergeevE. BennettK.A. BradleyS.J. Targeting the type 5 metabotropic glutamate receptor: A potential therapeutic strategy for neurodegenerative diseases?Front. Pharmacol.20221389342210.3389/fphar.2022.893422 35645791
     [Google Scholar]
  87. VincentK. CorneaV.M. JongY.J.I. LaferrièreA. KumarN. MickeviciuteA. FungJ.S.T. BandegiP. Ribeiro-da-SilvaA. O’MalleyK.L. CoderreT.J. Intracellular mGluR5 plays a critical role in neuropathic pain.Nat. Commun.2016711060410.1038/ncomms10604 26837579
     [Google Scholar]
  88. WuH. WangC. GregoryK.J. HanG.W. ChoH.P. XiaY. NiswenderC.M. KatritchV. MeilerJ. CherezovV. ConnP.J. StevensR.C. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.Science20143446179586410.1126/science.1249489 24603153
     [Google Scholar]
  89. OhashiH. MaruyamaT. Higashi-MatsumotoH. NomotoT. TakeuchiY. TakeuchiY. A novel binding assay for metabotropic glutamate receptors using [3H] L-quisqualic acid and recombinant receptors.Z. Naturforsch. C J. Biosci.2002573-434835510.1515/znc‑2002‑3‑425 12064739
     [Google Scholar]
  90. NiswenderC.M. ConnP.J. Metabotropic glutamate receptors: Physiology, pharmacology, and disease.Annu. Rev. Pharmacol. Toxicol.201050129532210.1146/annurev.pharmtox.011008.145533 20055706
     [Google Scholar]
  91. HuangS. CaoJ. JiangM. LabesseG. LiuJ. PinJ.P. RondardP. Interdomain movements in metabotropic glutamate receptor activation.Proc. Natl. Acad. Sci. USA201110837154801548510.1073/pnas.1107775108 21896740
     [Google Scholar]
  92. SevenA.B. Barros-ÁlvarezX. de LapeyrièreM. Papasergi-ScottM.M. RobertsonM.J. ZhangC. NwokonkoR.M. GaoY. MeyerowitzJ.G. RocherJ.P. SchelshornD. KobilkaB.K. MathiesenJ.M. SkiniotisG. G-protein activation by a metabotropic glutamate receptor.Nature2021595786745045410.1038/s41586‑021‑03680‑3 34194039
     [Google Scholar]
  93. NasrallahC. CannoneG. BriotJ. RottierK. BerizziA.E. HuangC.Y. QuastR.B. HohF. BanèresJ.L. MalhaireF. BertoL. DumazerA. Font-InglesJ. Gómez-SantacanaX. CatenaJ. KniazeffJ. GoudetC. LlebariaA. PinJ.P. VinothkumarK.R. LebonG. Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.Cell Rep.202136910964810.1016/j.celrep.2021.109648 34469715
     [Google Scholar]
  94. KoehlA. HuH. FengD. SunB. ZhangY. RobertsonM.J. ChuM. KobilkaT.S. LaeremansT. SteyaertJ. TarraschJ. DuttaS. FonsecaR. WeisW.I. MathiesenJ.M. SkiniotisG. KobilkaB.K. Structural insights into the activation of metabotropic glutamate receptors.Nature20195667742798410.1038/s41586‑019‑0881‑4 30675062
     [Google Scholar]
  95. Van DrieJ.H. TongL. Cryo-EM as a powerful tool for drug discovery.Bioorg. Med. Chem. Lett.2020302212752410.1016/j.bmcl.2020.127524 32890683
     [Google Scholar]
  96. ShenS. ZhaoC. WuC. SunS. LiZ. YanW. ShaoZ. Allosteric modulation of G protein-coupled receptor signaling.Front. Endocrinol.202314113760410.3389/fendo.2023.1137604 36875468
     [Google Scholar]
  97. ChenC.J. JiangC. YuanJ. ChenM. CuylerJ. XieX.Q. FengZ. How do modulators affect the orthosteric and allosteric binding pockets?ACS Chem. Neurosci.202213795997710.1021/acschemneuro.1c00749 35298129
     [Google Scholar]
  98. Jeffrey ConnP. ChristopoulosA. LindsleyC.W. Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders.Nat. Rev. Drug Discov.200981415410.1038/nrd2760 19116626
     [Google Scholar]
  99. ShipeW.D. WolkenbergS.E. WilliamsD.L.Jr LindsleyC.W. Recent advances in positive allosteric modulators of metabotropic glutamate receptors.Curr. Opin. Drug Discov. Devel.200584449457 16022181
     [Google Scholar]
  100. StansleyB.J. ConnP.J. Neuropharmacological insight from allosteric modulation of mglu receptors.Trends Pharmacol. Sci.201940424025210.1016/j.tips.2019.02.006 30824180
     [Google Scholar]
  101. KimS.K. HayashiH. IshikawaT. ShibataK. ShigetomiE. ShinozakiY. InadaH. RohS.E. KimS.J. LeeG. BaeH. MoorhouseA.J. MikoshibaK. FukazawaY. KoizumiS. NabekuraJ. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain.J. Clin. Invest.201612651983199710.1172/JCI82859 27064281
     [Google Scholar]
  102. BushnellM.C. DuncanG.H. HofbauerR.K. HaB. ChenJ.I. CarrierB. Pain perception: Is there a role for primary somatosensory cortex?Proc. Natl. Acad. Sci. USA199996147705770910.1073/pnas.96.14.7705 10393884
     [Google Scholar]
  103. DanjoY. ShigetomiE. HirayamaY.J. KobayashiK. IshikawaT. FukazawaY. ShibataK. TakanashiK. ParajuliB. ShinozakiY. KimS.K. NabekuraJ. KoizumiS. Transient astrocytic mGluR5 expression drives synaptic plasticity and subsequent chronic pain in mice.J. Exp. Med.20222194e2021098910.1084/jem.20210989 35319723
     [Google Scholar]
  104. FellinT. D’AscenzoM. HaydonP.G. Astrocytes control neuronal excitability in the nucleus accumbens.ScientificWorldJournal20077899710.1100/tsw.2007.195 17982581
     [Google Scholar]
  105. MahW. LeeS.M. LeeJ. BaeJ.Y. JuJ.S. LeeC.J. AhnD.K. BaeY.C. A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain.Sci. Rep.2017711362710.1038/s41598‑017‑13561‑3 29051582
     [Google Scholar]
  106. ChenC.C. AkopianA.N. SivilottitL. ColquhounD. BurnstockG. WoodJ.N.A. P2X purinoceptor expressed by a subset of sensory neurons.Nature1995377654842843110.1038/377428a0 7566119
     [Google Scholar]
  107. HeY.Q. LangX.Q. LinL. JiL. YuanX.Y. ChenQ. RanY.M. ChenH.S. LiL. WangJ.M. WangZ.G. GregersenH. ZouD.W. LiangH.P. YangM. P2X3 receptor‐mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD ‐like stress in the dorsal root ganglia of rats.Neurogastroenterol. Motil.2017293e1297610.1111/nmo.12976 27781340
     [Google Scholar]
  108. HuS. SunQ. DuW.J. SongJ. LiX. ZhangP.A. XuJ.T. XuG.Y. Adult stress promotes purinergic signaling to induce visceral pain in rats with neonatal maternal deprivation.Neurosci. Bull.202036111271128010.1007/s12264‑020‑00575‑7 32909219
     [Google Scholar]
  109. PeavyR.D. ChangM.S.S. Sanders-BushE. ConnP.J. Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor.J. Neurosci.200121249619962810.1523/JNEUROSCI.21‑24‑09619.2001 11739572
     [Google Scholar]
  110. PeavyR.D. ConnP.J. Phosphorylation of mitogen-activated protein kinase in cultured rat cortical glia by stimulation of metabotropic glutamate receptors.J. Neurochem.199871260361210.1046/j.1471‑4159.1998.71020603.x 9681450
     [Google Scholar]
  111. YuJ. ZhaoC. LuoX. The effects of electroacupuncture on the extracellular signal-regulated kinase 1/2/P2X3 signal pathway in the spinal cord of rats with chronic constriction injury.Anesth. Analg.2013116123924610.1213/ANE.0b013e31826f0a4a 23223107
     [Google Scholar]
  112. WalkerK. ReeveA. BowesM. WinterJ. WotherspoonG. DavisA. SchmidP. GaspariniF. KuhnR. UrbanL. mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia.Neuropharmacology2001401101910.1016/S0028‑3908(00)00114‑3 11077066
     [Google Scholar]
  113. HamaA. Acute activation of the spinal cord metabotropic glutamate subtype-5 receptor leads to cold hypersensitivity in the rat.Neuropharmacology200344442343010.1016/S0028‑3908(03)00026‑1 12646279
     [Google Scholar]
  114. KarimF. WangC.C. GereauR.W. IV Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice.J. Neurosci.200121113771377910.1523/JNEUROSCI.21‑11‑03771.2001 11356865
     [Google Scholar]
  115. BhaveG. KarimF. CarltonS.M. GereauR.W. IV Peripheral group I metabotropic glutamate receptors modulate nociception in mice.Nat. Neurosci.20014441742310.1038/86075 11276233
     [Google Scholar]
  116. PalazzoE. GenoveseR. MarianiL. SiniscalcoD. MarabeseI. de NovellisV. RossiF. MaioneS. Metabotropic glutamate receptor 5 and dorsal raphe serotonin release in inflammatory pain in rat.Eur. J. Pharmacol.20044922-316917610.1016/j.ejphar.2004.03.063 15178361
     [Google Scholar]
  117. PalazzoE. LuongoL. BelliniG. GuidaF. MarabeseI. BoccellaS. RossiF. MaioneS. de NovellisV. Changes in cannabinoid receptor subtype 1 activity and interaction with metabotropic glutamate subtype 5 receptors in the periaqueductal gray-rostral ventromedial medulla pathway in a rodent neuropathic pain model.CNS Neurol. Disord. Drug Targets201211214816110.2174/187152712800269731 22483283
     [Google Scholar]
  118. Almeida-SantosA.F. MoreiraF.A. GuimaraesF.S. AguiarD.C. 2-Arachidonoylglycerol endocannabinoid signaling coupled to metabotropic glutamate receptor type-5 modulates anxiety-like behavior in the rat ventromedial prefrontal cortex.J. Psychopharmacol.201731674074910.1177/0269881117704986 28440729
     [Google Scholar]
  119. MaioneS. MarabeseI. LeyvaJ. PalazzoE. de NovellisV. RossiF. Characterisation of mGluRs which modulate nociception in the PAG of the mouse.Neuropharmacology199837121475148310.1016/S0028‑3908(98)00126‑9 9886670
     [Google Scholar]
  120. ChungG. ShimH.G. KimC.Y. RyuH.H. JangD.C. KimS.H. LeeJ. KimC.E. KimY.K. LeeY.S. KimJ. KimS.K. WorleyP.F. KimS.J. Persistent activity of metabotropic glutamate receptor 5 in the periaqueductal gray constrains emergence of chronic neuropathic pain.Curr. Biol.2020302346314642.e610.1016/j.cub.2020.09.008 32976802
     [Google Scholar]
  121. SaltT.E. BinnsK.E. Contributions of mGlu1 and mGlu5 receptors to interactions with N-methyl-d-aspartate receptor-mediated responses and nociceptive sensory responses of rat thalamic neurons.Neuroscience2000100237538010.1016/S0306‑4522(00)00265‑7 11008175
     [Google Scholar]
  122. CarrasquilloY. GereauR.W.IV Hemispheric lateralization of a molecular signal for pain modulation in the amygdala.Mol. Pain,200841744-80692410.1186/1744‑8069‑4‑2418573207
     [Google Scholar]
  123. VeinanteP. YalcinI. BarrotM. The amygdala between sensation and affect: A role in pain.J. Mol. Psychiatry201311910.1186/2049‑9256‑1‑9 25408902
     [Google Scholar]
  124. LiW. NeugebauerV. Differential roles of mGluR1 and mGluR5 in brief and prolonged nociceptive processing in central amygdala neurons.J. Neurophysiol.2004911132410.1152/jn.00485.2003 13679408
     [Google Scholar]
  125. CrockL.W. KolberB.J. MorganC.D. SadlerK.E. VogtS.K. BruchasM.R. GereauR.W. IV Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain.J. Neurosci.20123241142171422610.1523/JNEUROSCI.1473‑12.2012 23055491
     [Google Scholar]
  126. JiR.R. Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases.Curr. Drug Targets Inflamm. Allergy20043329930310.2174/1568010043343804 15379598
     [Google Scholar]
  127. MazzitelliM. PrestoP. AntenucciN. MeltanS. NeugebauerV. Recent advances in the modulation of pain by the metabotropic glutamate receptors.Cells20221116260810.3390/cells11162608 36010684
     [Google Scholar]
  128. NicolettiF. BrunoV. NgombaR.T. GradiniR. BattagliaG. Metabotropic glutamate receptors as drug targets: what’s new?Curr. Opin. Pharmacol.201520899410.1016/j.coph.2014.12.002 25506748
     [Google Scholar]
  129. FontJ. López-CanoM. NotartomasoS. ScarselliP. Di PietroP. Bresolí-ObachR. BattagliaG. MalhaireF. RoviraX. CatenaJ. GiraldoJ. PinJ.P. Fernández-DueñasV. GoudetC. NonellS. NicolettiF. LlebariaA. CiruelaF. Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator.eLife20176e2354510.7554/eLife.23545 28395733
     [Google Scholar]
  130. NotartomasoS. AntenucciN. MazzitelliM. RoviraX. BoccellaS. RicciardiF. LiberatoreF. Gomez-SantacanaX. ImbriglioT. CannellaM. ZussyC. LuongoL. MaioneS. GoudetC. BattagliaG. LlebariaA. NicolettiF. NeugebauerV.A. “Double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs.bioRxiv202402.57394510.1101/2024.01.02.573945
     [Google Scholar]
  131. LiJ.Q. ChenS.R. ChenH. CaiY.Q. PanH.L. Regulation of increased glutamatergic input to spinal dorsal horn neurons by mGluR5 in diabetic neuropathic pain.J. Neurochem.2010112116217210.1111/j.1471‑4159.2009.06437.x 19840219
     [Google Scholar]
  132. SotgiuM.L. BellomiP. BiellaG.E.M. The mGluR5 selective antagonist 6-methyl-2-(phenylethynyl)-pyridine reduces the spinal neuron pain-related activity in mononeuropathic rats.Neurosci. Lett.20033421-28088
     [Google Scholar]
  133. KarthaS. GhimireP. WinkelsteinB.A. Inhibiting spinal secretory phospholipase A 2 after painful nerve root injury attenuates established pain and spinal neuronal hyperexcitability by altering spinal glutamatergic signaling.Mol. Pain20211710.1177/17448069211066221 34919471
     [Google Scholar]
  134. HsiehM.C. PengH.Y. HoY.C. LaiC.Y. ChengJ.K. ChenG.D. LinT.B. Transcription repressor Hes1 contributes to neuropathic pain development by modifying CDK9/RNAPII-dependent spinal mGluR5 transcription.Int. J. Mol. Sci.20192017417710.3390/ijms20174177 31454988
     [Google Scholar]
  135. HondaK. ShinodaM. KondoM. ShimizuK. YonemotoH. OtsukiK. AkasakaR. FurukawaA. IwataK. Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity.Pain201715891754176410.1097/j.pain.0000000000000973 28621704
     [Google Scholar]
  136. ZhangW. DrzymalskiD. SunL. XuQ. JiaoC. WangL. XieS. QianX. WuH. XiaoF. FuF. FengY. ChenX. Involvement of mGluR5 and TRPV1 in visceral nociception in a rat model of uterine cervical distension.Mol. Pain20181410.1177/1744806918816850 30444177
     [Google Scholar]
  137. KimY.H. ParkC.K. BackS.K. LeeC.J. HwangS.J. BaeY.C. NaH.S. KimJ.S. JungS.J. OhS.B. Membrane-delimited coupling of TRPV1 and mGluR5 on presynaptic terminals of nociceptive neurons.J. Neurosci.20092932100001000910.1523/JNEUROSCI.5030‑08.2009 19675234
     [Google Scholar]
  138. YuJ. DuJ. FangJ. LiuY. XiangX. LiangY. ShaoX. FangJ. The interaction between P2X3 and TRPV1 in the dorsal root ganglia of adult rats with different pathological pains.Mol. Pain2021171744806921101131510.1177/17448069211011315 33906494
     [Google Scholar]
  139. MontanaM.C. GereauR.W. Metabotropic glutamate receptors as targets for analgesia: Antagonism, activation, and allosteric modulation.Curr. Pharm. Biotechnol.201112101681168810.2174/138920111798357438 21466446
     [Google Scholar]
  140. VarneyM. GereauR.I.V. Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics.Curr. Drug Targets CNS Neurol. Disord.20021328329610.2174/1568007023339300 12769620
     [Google Scholar]
  141. SaabC.Y. WangJ. GuC. GarnerK.N. Al-ChaerE.D. Microglia: A newly discovered role in visceral hypersensitivity?Neuron Glia Biol.20062427127710.1017/S1740925X07000439 18496611
     [Google Scholar]
  142. D’AntoniS. BerrettaA. BonaccorsoC.M. BrunoV. AronicaE. NicolettiF. CataniaM.V. Metabotropic glutamate receptors in glial cells.Neurochem. Res.200833122436244310.1007/s11064‑008‑9694‑9 18438710
     [Google Scholar]
  143. Dogrul, Ahmet Peripheral and spinal antihyperalgesic activity of SIB-1757, a metabotropic glutamate receptor (mGLUR5) antagonist, in experimental neuropathic pain in rats.Neurosci. Lett.20002922110118
     [Google Scholar]
  144. LindströmE. BrusbergM. HughesP.A. MartinC.M. BrierleyS.M. PhillisB.D. MartinssonR. AbrahamssonC. LarssonH. MartinezV. BlackshawA.L. Involvement of metabotropic glutamate 5 receptor in visceral pain.Pain2008137229530510.1016/j.pain.2007.09.008 17937975
     [Google Scholar]
  145. HudsonL.J. BevanS. McNairK. GentryC. FoxA. KuhnR. WinterJ. Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia.J. Neurosci.20022272660266810.1523/JNEUROSCI.22‑07‑02660.2002 11923431
     [Google Scholar]
  146. UrbanM.O. HamaA.T. BradburyM. AndersonJ. VarneyM.A. BristowL. Role of metabotropic glutamate receptor subtype 5 (mGluR5) in the maintenance of cold hypersensitivity following a peripheral mononeuropathy in the rat.Neuropharmacology200344898399310.1016/S0028‑3908(03)00118‑7 12763091
     [Google Scholar]
  147. ZhuC.Z. WilsonS.G. MikusaJ.P. WismerC.T. GauvinD.M. LynchJ.J.III WadeC.L. DeckerM.W. HonoreP. Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities.Eur. J. Pharmacol.2004506210711810.1016/j.ejphar.2004.11.005 15588730
     [Google Scholar]
  148. ChungG. KimC.Y. YunY.C. YoonS.H. KimM.H. KimY.K. KimS.J. Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats.Sci. Rep.201771974310.1038/s41598‑017‑09991‑8 28851991
     [Google Scholar]
  149. HuangL. XiaoW. WangY. LiJ. GongJ. TuE. LongL. XiaoB. YanX. WanL. Metabotropic glutamate receptors (mGluRs) in epileptogenesis: An update on abnormal mGluRs signaling and its therapeutic implications.Neural Regen. Res.202419236036810.4103/1673‑5374.379018 37488891
     [Google Scholar]
  150. NiuY. ZengX. ZhaoL. ZhouY. QinG. ZhangD. FuQ. ZhouJ. ChenL. Metabotropic glutamate receptor 5 regulates synaptic plasticity in a chronic migraine rat model through the PKC/NR2B signal.J. Headache Pain202021113910.1186/s10194‑020‑01206‑2 33276724
     [Google Scholar]
  151. ConnP.J. PinJ.P. Pharmacology and functions of metabotropic glutamate receptors.Annu. Rev. Pharmacol. Toxicol.199737120523710.1146/annurev.pharmtox.37.1.205 9131252
     [Google Scholar]
  152. XieJ.D. ChenS.R. PanH.L. Presynaptic mGluR5 receptor controls glutamatergic input through protein kinase C–NMDA receptors in paclitaxel-induced neuropathic pain.J. Biol. Chem.201729250206442065410.1074/jbc.M117.818476 29074619
     [Google Scholar]
  153. YamakitaS. HoriiY. TakemuraH. MatsuokaY. YamashitaA. YamaguchiY. MatsudaM. SawaT. AmayaF. Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury.Mol. Pain201814174480691876750810.1177/1744806918767508 29592783
     [Google Scholar]
  154. CruzC. CruzF. The ERK 1 and 2 pathway in the nervous system: from basic aspects to possible clinical applications in pain and visceral dysfunction.Curr. Neuropharmacol.20075424425210.2174/157015907782793630 19305741
     [Google Scholar]
  155. CavalloD. LanducciE. GeraceE. LanaD. UgoliniF. HenleyJ.M. GiovanniniM.G. Pellegrini-GiampietroD.E. Neuroprotective effects of mGluR5 activation through the PI3K/Akt pathway and the molecular switch of AMPA receptors.Neuropharmacology202016210781010.1016/j.neuropharm.2019.107810 31600563
     [Google Scholar]
  156. HeX. LiY. DengB. LinA. ZhangG. MaM. WangY. YangY. KangX. The PI3K/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: Mechanisms and therapeutic opportunities.Cell Prolif.2022559e1327510.1111/cpr.13275 35754255
     [Google Scholar]
  157. DolanS. NolanA.M. Blockade of metabotropic glutamate receptor 5 activation inhibits mechanical hypersensitivity following abdominal surgery.Eur. J. Pain200711664465110.1016/j.ejpain.2006.10.002 17113328
     [Google Scholar]
  158. BoccellaS. MarabeseI. IannottaM. BelardoC. NeugebauerV. MazzitelliM. PierettiG. MaioneS. PalazzoE. Metabotropic glutamate receptor 5 and 8 modulate the ameliorative effect of ultramicronized palmitoylethanolamide on cognitive decline associated with neuropathic pain.Int. J. Mol. Sci.2019207175710.3390/ijms20071757 30970677
     [Google Scholar]
  159. ShefflerD.J. GregoryK.J. RookJ.M. ConnP.J. Allosteric modulation of metabotropic glutamate receptors.Adv. Pharmacol.201162377710.1016/B978‑0‑12‑385952‑5.00010‑5 21907906
     [Google Scholar]
  160. Gómez-SantacanaX. PittoloS. RoviraX. LopezM. ZussyC. DaltonJ.A.R. FaucherreA. JoplingC. PinJ.P. CiruelaF. GoudetC. GiraldoJ. GorostizaP. LlebariaA. Illuminating phenylazopyridines to photoswitch metabotropic glutamate receptors: from the flask to the animals.ACS Cent. Sci.201731819110.1021/acscentsci.6b00353 28149957
     [Google Scholar]
  161. FisherK. FundytusM.E. CahillC.M. CoderreT.J. Intrathecal administration of the mGluR compound, (S)-4CPG, attenuates hyperalgesia and allodynia associated with sciatic nerve constriction injury in rats.Pain1998771596610.1016/S0304‑3959(98)00082‑7 9755019
     [Google Scholar]
  162. WalkerK. BowesM. PanesarM. DavisA. GentryC. KesinglandA. GaspariniF. SpoorenW. StoehrN. PaganoA. FlorP.J. VranesicI. LingenhoehlK. JohnsonE.C. VarneyM. UrbanL. KuhnR. Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function.Neuropharmacology20014011910.1016/S0028‑3908(00)00113‑1 11077065
     [Google Scholar]
  163. MontanaM.C. CavalloneL.F. StubbertK.K. StefanescuA.D. KharaschE.D. GereauR.W.IV The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.J. Pharmacol. Exp. Ther.2009330383484310.1124/jpet.109.154138 19515968
     [Google Scholar]
  164. ClevaR.M. WattersonL.R. JohnsonM.A. OliveM.F. Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: Implications for effects on drug self-administration.Front. Pharmacol.201229310.3389/fphar.2011.00093 22232603
     [Google Scholar]
  165. BarnesS.A. ShefflerD.J. SemenovaS. CosfordN.D.P. BespalovA. Metabotropic glutamate receptor 5 as a target for the treatment of depression and smoking: Robust preclinical data but inconclusive clinical efficacy.Biol. Psychiatry2018831195596210.1016/j.biopsych.2018.03.001 29628194
     [Google Scholar]
  166. HuY. DongL. SunB. GuillonM.A. BurbachL.R. NunnP.A. LiuX. VilenskiO. FordA.P.D.W. ZhongY. RongW. The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception.Neurosci. Lett.20094501121710.1016/j.neulet.2008.11.026 19027050
     [Google Scholar]
  167. DaltonJ.A.R. PinJ.P. GiraldoJ. Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand.Sci. Rep.201771494410.1038/s41598‑017‑05095‑5 28694498
     [Google Scholar]
  168. PorterR.H.P. JaeschkeG. SpoorenW. BallardT.M. BüttelmannB. KolczewskiS. PetersJ.U. PrinssenE. WichmannJ. VieiraE. MühlemannA. GattiS. MutelV. MalherbeP. Fenobam: A clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.J. Pharmacol. Exp. Ther.2005315271172110.1124/jpet.105.089839 16040814
     [Google Scholar]
  169. EmmitteK.A. mGlu5 negative allosteric modulators: A patent review (2013-2016).Expert Opin. Ther. Pat.201727669170610.1080/13543776.2017.1280466 28067079
     [Google Scholar]
  170. López-CanoM. FontJ. LlebariaA. Fernández-DueñasV. CiruelaF. Optical modulation of metabotropic glutamate receptor type 5 in vivo using a photoactive drug.Methods Mol. Biol.2019194735135910.1007/978‑1‑4939‑9121‑1_20 30969427
     [Google Scholar]
  171. SwedbergM.D.B. RaboissonP. AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects.J. Pharmacol. Exp. Ther.2014350221222210.1124/jpet.114.215137 24876235
     [Google Scholar]
  172. Study to evaluate the analgesic efficacy of 28 days' oral administration of azd2066 compared with placebo in patients with painful diabetic neuropathy.Available from: ClinicalTrials.gov (Accessed March 31, 2024).2014
     [Google Scholar]
  173. AiN. WoodR.D. WelshW.J. Identification of nitazoxanide as a group i metabotropic glutamate receptor negative modulator for the treatment of neuropathic pain: An in silico drug repositioning study.Pharm. Res.20153282798280710.1007/s11095‑015‑1665‑7 25762088
     [Google Scholar]
  174. ShuebS.S. ErbS.J. LunzerM.M. SpeltzR. Harding-RoseC. AkgünE. SimoneD.A. PortogheseP.S. Targeting MOR-mGluR5 heteromers reduces bone cancer pain by activating MOR and inhibiting mGluR5.Neuropharmacology201916010769010.1016/j.neuropharm.2019.107690 31271770
     [Google Scholar]
  175. AokiT. NaritaM. ShibasakiM. SuzukiT. Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine‐induced rewarding effect in mice.Eur. J. Neurosci.20042061633163810.1111/j.1460‑9568.2004.03609.x 15355330
     [Google Scholar]
  176. GabraB.H. SmithF.L. NavarroH.A. CarrollF.I. DeweyW.L. mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo.Brain Res.20081187586610.1016/j.brainres.2007.10.007 18022146
     [Google Scholar]
  177. AkgünE. JavedM.I. LunzerM.M. SmeesterB.A. BeitzA.J. PortogheseP.S. Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception.Proc. Natl. Acad. Sci. USA201311028115951159910.1073/pnas.1305461110 23798416
     [Google Scholar]
/content/journals/cn/10.2174/1570159X23666241011163035
Loading
Metabotropic Glutamate Receptor 5: A Potential Target for Neuropathic Pain Treatment
Curr. Neuropharmacol. 23, 276 (2025); https://doi.org/10.2174/1570159X23666241011163035
/content/journals/cn/10.2174/1570159X23666241011163035
/content/journals/cn/10.2174/1570159X23666241011163035
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): glutamate; GPCRs; ion channel; mGlu5; neuropathic pain; pain treatment

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test