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The objective of this study was to determine efficacy and mechanism of CB2 activation on cyclophosphamide (CYP)\u2010induced cystitis in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cystitis was induced by intraperitoneal (IP) injection of CYP in female C57BL\/6J mice. Mice were pretreated with CB2 agonist JWH\u2010133 (1\u2009mg\/kg, intraperitoneally), CB2 antagonist AM\u2010630 (1\u2009mg\/kg, intraperitoneally) or autophagy inhibitor 3\u2010methyladenine (3\u2010MA) (50\u2009mM, intraperitoneally) before IP injection of CYP. Peripheral nociception and spontaneous voiding were investigated in these mice. Bladders were collected, weighed, and processed for real\u2010time polymerase chain reaction, immunoblotting analysis, histological and immunohistochemical analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010four hours after IP injection of CYP, the bladder of CYP\u2010treated mice showed histological evidence of inflammation. The expression of CB2 in bladder was significantly increased in CYP\u2010treated mice. Mechanical sensitivity was significantly increased in CYP\u2010treated mice and CB2 agonist JWH\u2010133 attenuated this effect (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05). The number of urine spots was significantly increased after CYP treatment and it was decreased in JWH\u2010133 treated mice (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05). Activating CB2 with JWH\u2010133 significantly alleviated bladder tissue inflammatory responses and oxidative stress induced by CYP. Activation of CB2 by JWH\u2010133 increased the expression of LC3\u2010II\/LC3\u2010I ratio, and decreased the expression of SQSTM1\/p62 in the bladder of cystitis mice, whereas AM\u2010630 induced inverse effects. Further study indicated that JWH\u2010133 could promote autophagy and blocking autophagy by 3\u2010MA dismissed the effort of CB2 in alleviating bladder tissue inflammatory responses and oxidative stress injury. Furthermore, treatment with 3\u2010MA decreased the expression of p\u2010AMPK and induced the phosphorylation of mTOR in the presence of JWH\u2010133 stimulation in cystitis model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Activation of CB2 decreased severity of CYP\u2010induced cystitis and ameliorated bladder inflammation. CB2 activation is protective in cystitis through the activation of autophagy and AMPK\u2010mTOR pathway may be involved in the initiation of autophagy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/nau.24205","type":"journal-article","created":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T04:37:21Z","timestamp":1573792641000},"page":"158-169","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Cannabinoid receptor 2 activation decreases severity of cyclophosphamide\u2010induced cystitis via regulating autophagy"],"prefix":"10.1002","volume":"39","author":[{"given":"Qinggang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonglong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology Qilu Hospital of Shandong University  Jinan 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