{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:04:36Z","timestamp":1784873076852,"version":"3.55.0"},"reference-count":54,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T00:00:00Z","timestamp":1580083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005622","name":"Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Local microvascular dysfunction and consequent tissue ischemia\/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti\u2010allodynic effect of a combination of two NO\u2010modulating drugs: meldonium and N\u2010acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post\u2010ischemic pain (CPIP), a rat model of CRPS, as well as\u00a0chronic constriction injury (CCI) of the sciatic nerve and chemotherapy\u2010induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium\u2010NAC produced significant anti\u2010allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium\u2010NAC produced an increase in the duration of anti\u2010allodynia in the CPIP and CCI rats. While pre\u2010treatment with an NO synthase inhibitor attenuated the anti\u2010allodynic effects of meldonium\u2010NAC, 30\u2010min hyperbaric oxygen treatment combined with a non\u2010effective dose of meldonium\u2010NAC produced significant anti\u2010allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti\u2010allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium\u2010NAC and revealed significantly increased plantar muscle NO levels in drug\u2010treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia\/hypoxia in these conditions, with emphasis on the role of NO.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14943-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14943","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T09:19:27Z","timestamp":1576747167000},"page":"570-584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Topical combination of meldonium and N\u2010acetyl cysteine relieves allodynia in rat models of CRPS\u20101 and peripheral neuropathic pain by enhancing NO\u2010mediated tissue oxygenation"],"prefix":"10.1111","volume":"152","author":[{"given":"Oli A.","family":"Fulas","sequence":"first","affiliation":[{"name":"Department of Anesthesia McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Laferriere","sequence":"additional","affiliation":[{"name":"Department of Anesthesia McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin S.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Scott","family":"Bohle","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6776-5081","authenticated-orcid":false,"given":"Terence J.","family":"Coderre","sequence":"additional","affiliation":[{"name":"Department of Anesthesia McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0b013e31816b2f26"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.208"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90209-6"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2015.11.012"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(00)00286-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2010.06.001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.08.001"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/c1967000583b"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/EJA.0000000000000590"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-7061(03)00863-X"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0b013e318156db3b"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-7-91"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880160405"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1423-0127-21-3"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/147323000403200304"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300019"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(02)00484-0"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12403"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-6576.2009.01937.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000000141"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-812348-5.00008-8"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12990-015-0057-7"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4040-14.2015"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-004-1663-5"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11916-017-0629-5"},{"key":"e_1_2_7_28_1","first-page":"265","article-title":"N\u2010acetylcysteine: Multiple clinical applications","volume":"80","author":"Millea P. J.","year":"2009","journal-title":"American Family Physician"},{"key":"e_1_2_7_29_1","first-page":"11","article-title":"A review on various uses of N\u2010acetyl cysteine","volume":"19","author":"Mokhtari V.","year":"2017","journal-title":"Cell Journal"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(01)00363-3"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2012.10.004"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2014.11.024"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31822a63c9"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1549-8719.2011.00129.x"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ajp.0000169672.49438.67"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000229931.40631.31"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI12188"},{"key":"e_1_2_7_38_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1097\/01.fjc.0000211732.76668.d2","article-title":"Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics","volume":"47","author":"Sesti C.","year":"2006","journal-title":"Journal of Cardiovascular Pharmacology"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2005.tb00267.x"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2004.05.006"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.1719"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1006\/S0014-4886(96)92000-2"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.01.076"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1997.82.1.317"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-016-0460-z"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2011.03.027"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpain.2010.12.003"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1155\/2004\/150503"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2008.02.003"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.47.3.457"},{"key":"e_1_2_7_51_1","volume-title":"Inorganic experiments","author":"Woollins J. D.","year":"2010"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2006.08.044"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/10715760500484336"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.08.016"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-013-0121-x"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.14943","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14943","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.14943","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14943","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T02:44:54Z","timestamp":1694054694000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.14943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,27]]},"references-count":54,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1111\/jnc.14943"],"URL":"https:\/\/doi.org\/10.1111\/jnc.14943","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,27]]},"assertion":[{"value":"2019-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}