Etanercept Restores the Antinociceptive Effect of Morphine and Suppresses Spinal Neuroinflammation in Morphine-Tolerant Rats

Abstract

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. 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. 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. 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.