Intrathecal Etanercept Partially Restores Morphine's Antinociception in Morphine-Tolerant Rats via Attenuation of the Glutamatergic Transmission

BACKGROUND: Long-term exposure to morphine leads to analgesic tolerance. In addition to an opioid receptor conformational change, enhancing the glutamatergic signal transmission is also involved in morphine tolerance. Tumor necrosis factor-alpha has been demonstrated to correlate with neuronal plasticity via activation of glutamatergic transmission. We examined the effect of etanercept, a tumor necrosis factor-alpha inhibitor on morphine tolerance in rats. METHODS: Male Wistar rats were implanted with 2 intrathecal (IT) catheters, and 1 IT catheter was connected to a mini-osmotic pump, used for either morphine infusion (15 mu g/h) or saline (1 mu L/h) infusion for 5 days. On day 5, either etanercept (50 mu g) or saline (10 mu L) was injected after discontinued morphine infusion. Three hours later, acute morphine (15 mu g/10 mu L, IT) treatment was given and all rats received a nociceptive tail-flick test. RESULTS: The results showed that acute etanercept (50 mu g) treatment caused a significant antinociceptive effect of morphine in morphine-tolerant rats. Western blotting indicated that etanercept attenuated the downregulation of membrane glutamate transporters GLT-1 and GLAST in morphine-tolerant rats. Etanercept also inhibited the upregulation of surface AMPA-receptor and N-methyl-D-aspartate-receptor subunits, including GluR1/GluR2 and NR1/NR2A. CONCLUSIONS: These results demonstrate that etanercept partially restores the antinociceptive effect of morphine in morphine tolerance after a morphine challenge. Etanercept has potential for use in the clinical management of pain, particularly in patients who require long-term opioid treatment, and the effectiveness of which can be hampered by tolerance. (Anesth Analg 2011; 113:184-90)