title: Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn.
abstract: BACKGROUND
  We previously reported that immune activation in the spinal dorsal horn contributes to pain induced by chronic pancreatitis (CP). Targeting immune response in the CNS may provide effective treatments for CP-induced pain. Recent findings demonstrate that resolvin D1 (RvD1) can potently dampen inflammatory pain. We hypothesized that intrathecal injection of RvD1 may inhibit pain of CP.
  
  
  METHODS
  Rat CP model was built through intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). All the rats were divided into three groups: TNBS, sham, and naïve controls and were further divided for intrathecal RvD1 administration. Pain behavior of rats was tested with von Frey filaments. Anxiety-like behavior and free locomotor and exploration of rats were evaluated by open field test and elevated plus maze. Pancreatic histology was evaluated with hematoxylin and eosin staining. Phosphorylation of NMDA receptor and expression of inflammatory cytokines were examined with Western blot, real-time RT-PCR and ELISA.
  
  
  RESULTS
  Behavioral study indicated that compared to the vehicle control, RvD1 (100 ng/kg) significantly decreased TNBS-induced mechanical allodynia at 2 h after administration (response frequencies: 49.2 ± 3.7% vs 71.3 ± 6.1%), and this effect was dose-dependent. Neither CP nor RvD1 treatment could affect anxiety-like behavior. CP or RvD1 treatment could not affect free locomotor and exploration of rats. Western blot analysis showed that compared with that of naïve group, phosphorylated NR1 (pNR1) and pNR2B in TNBS rats were significantly increased in the spinal cord (pNR1: 3.87±0.31 folds of naïve control, pNR2B: 4.17 ± 0.24 folds of naïve control). Compared to vehicle control, 10 ng/kg of RvD1 could significantly block expressions of pNR1 (2.21 ± 0.26 folds of naïve) and pNR2B (3.31 ± 0.34 folds of naïve). Real-time RT-PCR and ELISA data showed that RvD1 (10 ng/kg) but not vehicle could significantly block expressions of TNF-alpha, IL-1beta and IL-6. In addition, RvD1 did not influence pain behavior, NMDA receptor phosphorylation or cytokines production in sham-operated rats.
  
  
  CONCLUSIONS
  These data highly suggest that RvD1 could be a novel and effective treatment for CP-induced chronic pain.
authors.affiliation: Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, No, 127 West Changle Road, Xi'an, 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Quan-Xin
authors.forename: Feng
authors.initials: F
authors.lastname: Fan
authors.forename: Feng
authors.initials: F
authors.lastname: Xiang-Ying
authors.forename: Li
authors.initials: L
authors.lastname: Shu-Jun
authors.forename: Wang
authors.initials: W
authors.lastname: Shi-Qi
authors.forename: Liu
authors.initials: L
authors.lastname: Zhao-Xu
authors.forename: Zhang
authors.initials: Z
authors.lastname: Xu-Jie
authors.forename: Zhao
authors.initials: Z
authors.lastname: Qing-Chuan
authors.forename: Wang
authors.initials: W
authors.lastname: Wei
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D014302:Trinitrobenzenesulfonic Acid