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.
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: Mark R Hutchinson; Yehuda Shavit; Peter M Grace; Kenner C Rice; Steven F Maier; Linda R Watkins Journal: Pharmacol Rev Date: 2011-07-13 Impact factor: 25.468
Authors: Lori N Eidson; Kiyoshi Inoue; Larry J Young; Malu G Tansey; Anne Z Murphy Journal: Neuropsychopharmacology Date: 2016-07-27 Impact factor: 7.853