{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T03:03:39Z","timestamp":1783739019343,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Provoked vulvodynia (PV) is the leading cause of vulvar pain and dyspareunia. The etiology of PV is multifactorial and remains poorly understood. PV is associated with a history of repeated vulvar inflammation and is often accompanied by sensory neuromodulation as a result of activation of the metabotropic glutamate receptor 5 (mGluR5) in the sensory nerve terminals. Therefore, this study aims to examine the role of glutamate-mGluR5 signaling during the initial inflammatory phase in chronic vulvar pain development in an animal model of PV.Thermal and mechanical vulvar sensitivity was assessed for three weeks following zymosan vulvar challenges. Anxiety-like behavior and locomotor activity were assessed at the end of the experiment. To investigate the role of glutamate mGluR5, the MTEP (mGluR5 antagonist) was injected into the vulva during vulvar inflammation. On the other hand, glutamate or CHPG (mGluR5 agonist) were injected in order to examine the effects of mGluR5 activation. RT-PCR was performed to assess changes in the transcription of genes related to neuroinflammation, neuromodulation, and neuroplasticity in the spinal cord (L6-S3). Zymosan-induced inflammation resulted in a significant thermal and mechanical vulvar hypersensitivity that persisted for over a month after the zymosan injection. However, local treatment with MTEP enhanced the vulvar mechanical and thermal hypersensitivity. On the other hand, activation of the mGluR5 via injection of glutamate or CHPG into the vulva leads to long-lasting vulvar mechanical and thermal hypersensitivity. The activation of the glutamate pathway was found to be accompanied by an increase in the transcription level of genes related to neuroinflammation and neuroplasticity in the sacral spine region. The present findings indicate that vulvar hypersensitivity is mediated by mGluR5 activation during inflammation. Hence, modulation of the mGluR5 pathway during the critical period of inflammation contributes to preventing chronic vulvar pain development. Conversely, activation of the mGluR5 pathway leads to long-lasting mechanical and thermal hypersensitivity.<\/jats:p>","DOI":"10.3390\/ijms26020523","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T09:54:27Z","timestamp":1736416467000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Involvement of Glutamate-mGluR5 Signaling in the Development of Vulvar Hypersensitivity"],"prefix":"10.3390","volume":"26","author":[{"given":"Yaseen","family":"Awad-Igbaria","sequence":"first","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8225-3586","authenticated-orcid":false,"given":"Saher","family":"Abu-Ata","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Sakas","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarina","family":"Bang","sequence":"additional","affiliation":[{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"},{"name":"Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4794-0832","authenticated-orcid":false,"given":"Tom","family":"Fishboom","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Shamir","sequence":"additional","affiliation":[{"name":"Psychobiology Research Laboratory, Mazor Mental Health Center, Akko 2412001, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion\u2014Israel Institute of Technology, Haifa 3478403, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1932-5270","authenticated-orcid":false,"given":"Jacob","family":"Bornstein","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Lowenstein","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"},{"name":"Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2032-2974","authenticated-orcid":false,"given":"Eilam","family":"Palzur","sequence":"additional","affiliation":[{"name":"Azriele Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Research Institute of Galilee Medical Center, Nahariya 2210001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Paavonen, J., and Eschenbach, D.A. (2021). Localized Provoked Vulvodynia-An Ignored Vulvar Pain Syndrome. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.678961"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.12688\/f1000research.9603.1","article-title":"Recent advances in understanding provoked vestibulodynia","volume":"5","author":"Witkin","year":"2016","journal-title":"F1000Res"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"437","DOI":"10.2147\/IJWH.S37660","article-title":"Etiology, diagnosis, and clinical management of vulvodynia","volume":"6","author":"Sadownik","year":"2014","journal-title":"Int. J. Womens Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.esxm.2020.05.009","article-title":"Exploring Pain-Related Anxiety and Depression in Female Patients With Provoked Vulvodynia With Associated Overactive Pelvic Floor Muscle Dysfunction","volume":"8","author":"Govind","year":"2020","journal-title":"Sex. Med."},{"key":"ref_5","first-page":"457618","article-title":"Pain Symptoms in Fibromyalgia Patients with and without Provoked Vulvodynia","volume":"2014","author":"Ghizzani","year":"2014","journal-title":"Pain. Res. Treat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.esxm.2019.03.002","article-title":"Provoked Vestibulodynia in Women with Pelvic Pain","volume":"7","author":"Bao","year":"2019","journal-title":"Sex. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.jpain.2017.12.264","article-title":"Daily Anxiety and Depressive Symptoms in Couples Coping With Vulvodynia: Associations With Women\u2019s Pain, Women\u2019s Sexual Function, and Both Partners\u2019 Sexual Distress","volume":"19","author":"Rosen","year":"2018","journal-title":"J. Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1159\/000503321","article-title":"Pain, anxiety, depression, and quality of life in patients with vulvodynia","volume":"236","author":"Canal","year":"2020","journal-title":"Dermatology"},{"key":"ref_9","first-page":"315","article-title":"Vulvodynia: A review of pathophysiological factors and treatment options","volume":"28","author":"Pukall","year":"2008","journal-title":"Basic Clin. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41572-020-0164-2","article-title":"Vulvodynia","volume":"6","author":"Bergeron","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1007\/s10096-018-3299-2","article-title":"Abnormal vaginal microbioma is associated with severity of localized provoked vulvodynia. Role of aerobic vaginitis and Candida in the pathogenesis of vulvodynia","volume":"37","author":"Donders","year":"2018","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_12","first-page":"339","article-title":"Changes in the Vaginal Microbiota of Women With Secondary Localized Provoked Vulvodynia","volume":"26","author":"Palzur","year":"2022","journal-title":"J. Low. Genit. Tract. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1097\/LGT.0000000000000780","article-title":"Is Vulvodynia Associated With an Altered Vaginal Microbiota?: A Systematic Review","volume":"28","author":"Sacinti","year":"2023","journal-title":"J. Low. Genit. Tract. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1097\/LGT.0000000000000445","article-title":"Localized Provoked Vulvodynia: Association with Nerve Growth Factor and Transient Receptor Potential Vanilloid Type 1 Genes Polymorphisms","volume":"23","author":"Kalfon","year":"2019","journal-title":"J. Low Genit. Tract. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1016\/j.pain.2014.05.010","article-title":"Vulvodynia: Current state of the biological science","volume":"155","author":"Wesselmann","year":"2014","journal-title":"Pain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1067\/mob.2002.121869","article-title":"Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome","volume":"186","author":"Gerber","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0002-9378(00)70212-2","article-title":"Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis","volume":"182","author":"Jeremias","year":"2000","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0301-2115(02)00276-2","article-title":"Interleukin-1\u03b2 gene polymorphism in women with vulvar vestibulitis syndrome","volume":"107","author":"Gerber","year":"2003","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Aalto, A., Huotari-Orava, R., Luhtala, S., M\u00e4enp\u00e4\u00e4, J., and Staff, S. (2020). Expression of Estrogen-Related Receptors in Localized Provoked Vulvodynia. Biores. Open Access., 9.","DOI":"10.1089\/biores.2019.0049"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1095\/biolreprod.104.030023","article-title":"Estrogen regulates vaginal sensory and autonomic nerve density in the rat","volume":"71","author":"Ting","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_21","first-page":"379","article-title":"Is localized, provoked vulvodynia an inflammatory condition?","volume":"52","author":"Eva","year":"2007","journal-title":"J. Reprod. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/GME.0000000000000985","article-title":"A randomized, multicenter, double-blind study to evaluate the safety and efficacy of estradiol vaginal cream 0.003% in postmenopausal women with dyspareunia as the most bothersome symptom","volume":"25","author":"Kroll","year":"2018","journal-title":"Menopause"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.jogc.2016.10.011","article-title":"Treatment of Secondary Vestibulodynia with Conjugated Estrogen Cream: A Pilot, Double-Blind, Randomized Placebo-Controlled Trial","volume":"39","author":"Langlais","year":"2017","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/aje\/kwf037","article-title":"Use of Oral Contraceptive Pills and Vulvar Vestibulitis: A Case-Control Study","volume":"156","author":"Bouchard","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1055\/s-0035-1554919","article-title":"Vulvodynia: The Role of Inflammation in the Etiology of Localized Provoked Pain of the Vulvar Vestibule (Vestibulodynia)","volume":"33","author":"Akopians","year":"2015","journal-title":"Semin. Reprod. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.2147\/JIR.S367193","article-title":"Characterization of Early Inflammatory Events Leading to Provoked Vulvodynia Development in Rats","volume":"15","author":"Dadon","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nakhleh-Francis, Y., Awad-Igbaria, Y., Sakas, R., Bang, S., Abu-Ata, S., Palzur, E., Lowenstein, L., and Bornstein, J. (2024). Exploring Localized Provoked Vulvodynia: Insights from Animal Model Research. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084261"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101ra91","DOI":"10.1126\/scitranslmed.3002613","article-title":"Repeated Vulvovaginal Fungal Infections Cause Persistent Pain in a Mouse Model of Vulvodynia","volume":"3","author":"Farmer","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108467","DOI":"10.1016\/j.pharmthera.2023.108467","article-title":"Inflammation, lipids, and pain in vulvar disease","volume":"248","author":"Falsetta","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.jpain.2021.03.144","article-title":"Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia","volume":"22","author":"Falsetta","year":"2021","journal-title":"J. Pain"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Falsetta, M.L. (2023). Editorial: Vulvodynia and beyond: Innate immune sensing, microbes, inflammation, and chronic pain. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1338659"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Martinov, T., Glenn-Finer, R., Burley, S., Tonc, E., Balsells, E., Ashbaugh, A., Swanson, L., Daughters, R.S., and Chatterjea, D. (2013). Contact Hypersensitivity to Oxazolone Provokes Vulvar Mechanical Hyperalgesia in Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078673"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1097\/j.pain.0000000000000973","article-title":"Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity","volume":"158","author":"Honda","year":"2017","journal-title":"Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0006-8993(01)03240-1","article-title":"Mechanisms underlying the nociception and paw oedema caused by injection of glutamate into the mouse paw","volume":"924","author":"Beirith","year":"2002","journal-title":"Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1046\/j.0022-3042.2001.00721.x","article-title":"Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: Involvement of peripheral ionotropic glutamate receptors and capsaicin-sensitive sensory afferents","volume":"80","author":"Liu","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.2147\/JPR.S251948","article-title":"Electroacupuncture regulates pain transition by inhibiting the mglur5-pkc\u03b5 signaling pathway in the dorsal root ganglia","volume":"13","author":"Wang","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1523\/JNEUROSCI.21-11-03771.2001","article-title":"Metabotropic Glutamate Receptor Subtypes 1 and 5 Are Activators of Extracellular Signal-Regulated Kinase Signaling Required for Inflammatory Pain in Mice","volume":"21","author":"Karim","year":"2001","journal-title":"J. Neuroscience."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gujar, V., Pande, R.D., and Das, S. (2024). Nerve Growth Factor Shows Biphasic Expression during Adjuvant-Induced Neurogenic Inflammation. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202403.0036.v1"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/1742-2094-9-258","article-title":"Metabotropic glutamate receptor 5 contributes to inflammatory tongue pain via extracellular signal-regulated kinase signaling in the trigeminal spinal subnucleus caudalis and upper cervical spinal cord","volume":"9","author":"Liu","year":"2012","journal-title":"J. Neuroinflammation."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lin, Y.R., Chen, H.H., Lin, Y.C., Ko, C.H., and Chan, M.H. (2009). Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain. J. Biomed. Sci., 16.","DOI":"10.1186\/1423-0127-16-94"},{"key":"ref_41","first-page":"6","article-title":"Inflammation-induced mast cell-derived nerve growth factor: A key player in chronic vulvar pain?","volume":"5","author":"Edelman","year":"2024","journal-title":"Brain"},{"key":"ref_42","first-page":"820","article-title":"Inflammation, lipid dysregulation, and transient receptor potential cation channel subfamily V member 4 signaling perpetuate chronic vulvar pain","volume":"165","author":"Bekauri","year":"2024","journal-title":"Pain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.bbi.2022.08.010","article-title":"Differential roles of NMDAR subunits 2A and 2B in mediating peripheral and central sensitization contributing to orofacial neuropathic pain","volume":"106","author":"Zhang","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jpain.2009.06.012","article-title":"Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity","volume":"10","author":"Latremoliere","year":"2009","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Castro, J., Harrington, A.M., Chegini, F., Matusica, D., Spencer, N.J., Brierley, S.M., Haberberger, R.V., and Barry, C.M. (2022). Clodronate Treatment Prevents Vaginal Hypersensitivity in a Mouse Model of Vestibulodynia. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.784972"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.expneurol.2008.10.018","article-title":"Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain","volume":"215","author":"Qu","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/s41467-022-28429-y","article-title":"Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain","volume":"13","author":"Xie","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.sjpain.2017.08.014","article-title":"Hyperbaric oxygenation alleviates chronic constriction injury (CCI)-induced neuropathic pain and inhibits GABAergic neuron apoptosis in the spinal cord","volume":"17","author":"Fu","year":"2017","journal-title":"Scand. J. Pain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","article-title":"Cellular and Molecular Mechanisms of Pain","volume":"139","author":"Basbaum","year":"2009","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/ALN.0000000000002130","article-title":"Neuroinflammation and central sensitization in chronic and widespread pain","volume":"129","author":"Ji","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.bbi.2022.10.013","article-title":"Spinal GABAergic disinhibition allows microglial activation mediating the development of nociplastic pain in male mice","volume":"107","author":"McDonough","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1876386301609010001","article-title":"Changes in Spinal Cord Following Inflammatory and Neuropathic Pain and the Effectiveness of Resiniferatoxin","volume":"9","author":"Abooj","year":"2016","journal-title":"Open Pain J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1186\/s12967-023-04414-x","article-title":"HBO treatment enhances motor function and modulates pain development after sciatic nerve injury via protection the mitochondrial function","volume":"21","author":"Ferreira","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1124\/jpet.109.154138","article-title":"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","volume":"330","author":"Montana","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10000","DOI":"10.1523\/JNEUROSCI.5030-08.2009","article-title":"Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons","volume":"29","author":"Kim","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Brackley, A.D., Gomez, R., Guerrero, K.A., Akopian, A.N., Glucksman, M.J., Du, J., Carlton, S.M., and Jeske, N.A. (2017). A-Kinase Anchoring Protein 79\/150 Scaffolds Transient Receptor Potential A 1 Phosphorylation and Sensitization by Metabotropic Glutamate Receptor Activation. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-01999-4"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Roughan, W.H., Campos, A.I., Garc\u00eda-Mar\u00edn, L.M., Cu\u00e9llar-Partida, G., Lupton, M.K., Hickie, I.B., Medland, S.E., Wray, N.R., Byrne, E.M., and Ngo, T.T. (2021). Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.643609"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6340","DOI":"10.1523\/JNEUROSCI.2780-17.2018","article-title":"Brain Circuits Mediating Opposing Effects on Emotion and Pain","volume":"38","author":"Cai","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Yessick, L.R., Pukall, C.F., Ioachim, G., Chamberlain, S.M., and Stroman, P.W. (2021). An Investigation of Descending Pain Modulation in Women with Provoked Vestibulodynia: Alterations of Brain Connectivity. Front. Pain Res., 2.","DOI":"10.3389\/fpain.2021.682484"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.jpain.2013.01.767","article-title":"Augmented central pain processing in vulvodynia","volume":"14","author":"Hampson","year":"2013","journal-title":"J. Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.nicl.2017.07.017","article-title":"Brain responses to vestibular pain and its anticipation in women with Genito-Pelvic Pain\/Penetration Disorder","volume":"16","author":"Pazmany","year":"2017","journal-title":"Neuroimage Clin."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"109788","DOI":"10.1016\/j.neuropharm.2023.109788","article-title":"Exploring venlafaxine effects on chronic vulvar pain: Changes in mood and pain regulation networks","volume":"243","author":"Lowenstein","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1089\/jwh.2014.5001","article-title":"Depression and Posttraumatic Stress Disorder among Women with Vulvodynia: Evidence from the Population-Based Woman to Woman Health Study","volume":"24","author":"Harlow","year":"2015","journal-title":"J. Womens Health"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1097\/j.pain.0000000000000767","article-title":"Long-lasting antinociceptive effects of green light in acute and chronic pain in rats","volume":"158","author":"Ibrahim","year":"2017","journal-title":"Pain"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Abu-Ata, S., Shukha, O.N., Awad-Igbaria, Y., Ginat, K., Palzur, E., Golani, I., and Shamir, A. (2023). Blocking the ErbB pathway during adolescence affects the induction of anxiety-like behavior in young adult maternal immune activation offspring. Pharmacol. Biochem. Behav., 222.","DOI":"10.1016\/j.pbb.2022.173497"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12967-023-03916-y","article-title":"Predisposition to cortical neurodegenerative changes in brains of hypertension prone rats","volume":"21","author":"Sela","year":"2023","journal-title":"J. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/2\/523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:25:56Z","timestamp":1759919156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/2\/523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":66,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26020523"],"URL":"https:\/\/doi.org\/10.3390\/ijms26020523","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]}}}