Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats

Anesth Analg. 2011 Feb;112(2):454-9. doi: 10.1213/ANE.0b013e3182025b15. Epub 2010 Nov 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / toxicity
  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Behavior, Animal
  • Drug Tolerance*
  • Etanercept
  • Gene Expression Regulation
  • Immunoglobulin G / administration & dosage*
  • Immunohistochemistry
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Inflammation / prevention & control*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Infusion Pumps
  • Infusions, Parenteral
  • Injections, Spinal
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Male
  • Microglia / drug effects
  • Microglia / immunology
  • Morphine / administration & dosage*
  • Morphine / toxicity
  • Pain Threshold / drug effects*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reaction Time
  • Receptors, Tumor Necrosis Factor / administration & dosage*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / drug effects*
  • Spinal Cord / immunology
  • Time Factors
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Analgesics, Opioid
  • Anti-Inflammatory Agents
  • Immunoglobulin G
  • Inflammation Mediators
  • Interleukin-1beta
  • Interleukin-6
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Morphine
  • Etanercept