Allosteric modulation of glutamate transporter GLT-1 provides antinociception in a neuropathic pain model

Allosteric modulation of glutamate transporter GLT-1 provides antinociception in a neuropathic pain model | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 29 December 2025 V1 Latest version Share on Allosteric modulation of glutamate transporter GLT-1 provides antinociception in a neuropathic pain model Authors : Rhea Temmermand , Simran K. Gill , Arthur K. Burns , Jagger Godarzi , Anna Frasier , Yuzhen Tian , Danielle R. Stern , Xiangdang Shi , Ellen Unterwald , Ole V. Mortensen , Joseph M. Salvino 0000-0002-2184-5980 , and Andreia C. K. Fontana 0000-0002-4791-8746 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176701345.52797415/v1 229 views 75 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background and Purpose: Neuropathic pain is a complex somatosensory disorder, which is challenging to treat due to limited efficacy and side effects of current therapies. A promising target for pain modulation is astrocytic glutamate transporter GLT-1 (EAAT2), which plays a key role in maintaining extracellular glutamate homeostasis. GLT-1 expression enhancers reduce nociception in neuropathic pain models, but clinical development of selective enhancers remains challenging. This study investigates the antinociceptive efficacy and mechanism of a novel positive allosteric modulator (PAM) of GLT-1, NA-014, in a mouse neuropathic pain model. Experimental Approach: A spared nerve injury model of neuropathic pain was used in adult male and female C57BL/6J mice. Evoked and spontaneous pain were assessed using behavioral assays, including von Frey, acetone evaporation, conditioned place preference, and mechanical conflict avoidance. Key results: NA-014 reduced mechanical allodynia and cold hypersensitivity in both sexes, achieving efficacy comparable to gabapentin, without causing locomotor, anxiety-like behavior, or cognitive impairment (evaluated through open field, Y-maze, and elevated plus maze tests) at effective doses. Systemic and intrathecal delivery produced robust antinociception, whereas anterior cingulate cortex (ACC) administration was ineffective. siRNA knockdown of GLT-1 in the spinal cord (but not in the ACC) abolished the antinociceptive effect of NA-014, indicating a spinal mechanism. Conclusions and Implications: These findings demonstrate that NA-014 enhances the activity of spinal GLT-1 to produce effective, non-sedating anti-nociception in neuropathic models. This highlights GLT-1 as a key target and supports the development of GLT-1 PAMs as promising novel non-opioid therapies for treatment of neuropathic pain. Supplementary Material File (table 1.docx) Download 18.45 KB File (temmermand et al pain_manuscript december 28 2025.docx) Download 20.87 MB Information & Authors Information Version history V1 Version 1 29 December 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Rhea Temmermand Drexel University View all articles by this author Simran K. Gill Drexel University View all articles by this author Arthur K. Burns Drexel University View all articles by this author Jagger Godarzi Drexel University View all articles by this author Anna Frasier Drexel University View all articles by this author Yuzhen Tian Drexel University View all articles by this author Danielle R. Stern Temple University View all articles by this author Xiangdang Shi Temple University View all articles by this author Ellen Unterwald Temple University View all articles by this author Ole V. Mortensen Drexel University View all articles by this author Joseph M. Salvino 0000-0002-2184-5980 Wistar Institute View all articles by this author Andreia C. K. Fontana 0000-0002-4791-8746 [email protected] Drexel University View all articles by this author Metrics & Citations Metrics Article Usage 229 views 75 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Rhea Temmermand, Simran K. Gill, Arthur K. Burns, et al. Allosteric modulation of glutamate transporter GLT-1 provides antinociception in a neuropathic pain model. Authorea . 29 December 2025. DOI: https://doi.org/10.22541/au.176701345.52797415/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.176701345.52797415/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00c7c74881341e2',t:'MTc3OTYyNzY1Ng=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();