title: Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats.
abstract: BACKGROUND
  In the present study we examined the effect of the tumor necrosis factor (TNF)-α antagonist etanercept on the antinociceptive effect of morphine in morphine-tolerant rats.
  
  
  METHODS
  Male Wistar rats were implanted with 2 intrathecal catheters, and 1 was connected to a mini-osmotic pump for either morphine (15 μg/h) or saline (1 μL/h) infusion for 5 days. On day 5, either etanercept (5 μg, 25 μg, and 50 μg/10 μL) or saline (10 μL) was injected via the other catheter after morphine infusion was discontinued. Three hours later, morphine (15 μg/10 μL, intrathecally) was given and tail-flick latency was measured to evaluate the antinociceptive effect of morphine. Rats were then killed and their spinal cords were removed for quantitative real-time polymerase chain reaction and immunohistochemistry to measure proinflammatory cytokines expression.
  
  
  RESULTS
  We found that acute etanercept (50 μg) treatment preserved a significant antinociceptive effect of morphine in morphine-tolerant rats. In addition, the expression of TNFα mRNA was increased by 2.5-fold, interleukin (IL)-1β mRNA increased by 13-fold and IL-6 mRNA by 111-fold in the dorsal spinal cord of morphine-tolerant rats. The increase in TNFα, IL-1β, and IL-6 mRNA expression was blocked by 50 μg etanercept pretreatment. The immunohistochemistry analysis revealed that 50 μg etanercept suppressed proinflammatory cytokines expression and neuroinflammation in the microglia.
  
  
  CONCLUSIONS
  The present study demonstrates that etanercept restores the antinociceptive effect of morphine in morphine-tolerant rats by inhibition of proinflammatory cytokine TNF-α, IL-1β, and IL-6 expression and spinal neuroinflammation. The results suggest that etanercept could also be an adjuvant therapy for morphine tolerance, which extends the effectiveness of opioids in clinical pain management.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Shen
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Meng-Shen
authors.initials: MS
authors.lastname: Shih
authors.forename: Shinn-Long
authors.initials: SL
authors.lastname: Lin
authors.forename: Yueh-Hwa
authors.initials: YH
authors.lastname: Tai
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chien
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001522:Behavior, Animal; D004361:Drug Tolerance; D000068800:Etanercept; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000008:administration & dosage*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007260:Infusion Pumps; D007263:Infusions, Parenteral; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009020:Morphine / Q000008:administration & dosage* / Q000633:toxicity; D017288:Pain Threshold / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000893:Anti-Inflammatory Agents; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009020:Morphine; D000068800:Etanercept