{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:48:05Z","timestamp":1784630885480,"version":"3.55.0"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis (<jats:bold>OA<\/jats:bold>) is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of quality-adjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector (<jats:bold>rdHSV<\/jats:bold>) incorporating a modified carbonic anhydrase-8 transgene (<jats:bold>CA8*<\/jats:bold>) produces analgesia and treats monoiodoacetate-induced (<jats:bold>MIA<\/jats:bold>) chronic knee pain due to OA. We observed transduction of lumbar DRG sensory neurons with these viral constructs (vHCA8*) (~40% of advillin-positive cells and\u2009~\u200950% of TrkA-positive cells colocalized with V5-positive cells) using the intra-articular (<jats:bold>IA<\/jats:bold>) knee joint (<jats:bold>KJ<\/jats:bold>) route of administration. vHCA8* inhibited chronic mechanical OA knee pain induced by MIA was dose- and time-dependent. Mechanical thresholds returned to Baseline by D17 after IA KJ vHCA8* treatment, and exceeded Baseline (analgesia) through D65, whereas negative controls failed to reach Baseline responses. Weight-bearing and automated voluntary wheel running were improved by vHCA8*, but not negative controls. Kv7 voltage-gated potassium channel-specific inhibitor XE-991 reversed vHCA8*-induced analgesia. Using IHC, IA KJ of vHCA8* activated DRG Kv7 channels via dephosphorylation, but negative controls failed to impact Kv7 channels. XE-991 stimulated Kv7.2\u20137.5 and Kv7.3 phosphorylation using western blotting of differentiated SH-SY5Y cells, which was inhibited by vHCA8* but not by negative controls. The observed prolonged dose-dependent therapeutic effects of IA KJ administration of vHCA8* on MIA-induced chronic KJ pain due to OA is consistent with the specific activation of Kv7 channels in small DRG sensory neurons. Together, these data demonstrate for the first-time local IA KJ administration of vHCA8* produces opioid-independent analgesia in this MIA-induced OA chronic pain model, supporting further therapeutic development.<\/jats:p>","DOI":"10.3389\/fnmol.2024.1416148","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T12:52:55Z","timestamp":1721220775000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Disease-modifying rdHSV-CA8* non-opioid analgesic gene therapy treats chronic osteoarthritis pain by activating Kv7 voltage-gated potassium channels"],"prefix":"10.3389","volume":"17","author":[{"given":"Gerald Z.","family":"Zhuang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William F.","family":"Goins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munal B.","family":"Kandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marzulli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingdi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Glorioso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Levitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos D.","family":"Sarantopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy C.","family":"Levitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/361315a0","article-title":"Inositol trisphosphate and calcium signalling","volume":"361","author":"Berridge","year":"1993","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1111\/j.1526-4637.2011.01075.x","article-title":"Societal costs of prescription opioid abuse, dependence, and misuse in the United States","volume":"12","author":"Birnbaum","year":"2011","journal-title":"Pain Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/s0014-2999(02)02924-2","article-title":"The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain","volume":"460","author":"Blackburn-Munro","year":"2003","journal-title":"Eur. 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