title: Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord.
abstract: Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain. However, its complex cellular and molecular mechanisms in bone cancer pain remain unclear. And less relevant reports concerned its time-dependent effects on the long-lasting modifications of behavior, spinal inflammatory cytokines levels, astrocytes activity induced by bone cancer pain. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells was utilized. Pain behaviors at different time points were assessed by ambulatory pain scores and paw withdrawal mechanical threshold (PWMT). Pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor alpha (TNF-α), were quantitated by Western blots. Glial activity was assessed by immunohistochemistry. Intra-tibia inoculation of Walker 256 mammary gland carcinoma cells induced progressive bone cancer pain; a long-term up-regulation of IL-1β, IL-6, IL-18, and TNF-α; and the activation of glia in spinal cord. Activation of microglia was first evident on day 4 after surgery and reached to a peak on day 7 while activation of astrocytes was on day 10. A single intrathecal injection of JWH-015 attenuated bone cancer induced spontaneous pain and mechanical allodynia, reduced the expression of pro-inflammatory cytokines, and inhibited the activity of astrocytes. All the modifications were transient and peaked at 24 h after JWH-015 administration. Furthermore, the protective effects of JWH-015 were reversed in the presence of CB2-selective antagonist AM630. Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu Province, China, lucuie608@163.com.
authors.forename: Cui'e
authors.initials: C
authors.lastname: Lu
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
authors.forename: Yu'e
authors.initials: Y
authors.lastname: Sun
authors.forename: Bailing
authors.initials: B
authors.lastname: Hou
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D007211:Indoles / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007278:Injections, Spinal; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; C402944:JHW 015