['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-α has been demonstrated to correlate with neuronal plasticity via activation of glutamatergic transmission. We examined the effect of etanercept, a tumor necrosis factor-α inhibitor on morphine tolerance in rats.', '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 μg/h) or saline (1 μL/h) infusion for 5 days. On day 5, either etanercept (50 μg) or saline (10 μL) was injected after discontinued morphine infusion. Three hours later, acute morphine (15 μg/10 μL, IT) treatment was given and all rats received a nociceptive tail-flick test.', 'The results showed that acute etanercept (50 μg) 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.'] Does intrathecal etanercept partially restore morphine 's antinociception in morphine-tolerant rats via attenuation of the glutamatergic transmission?