title: Intrathecal etanercept partially restores morphine's antinociception in morphine-tolerant rats via attenuation of the glutamatergic transmission.
abstract: 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-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.
  
  
  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 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Shen
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Yueh-Hwa
authors.initials: YH
authors.lastname: Tai
authors.forename: Shinn-Long
authors.initials: SL
authors.lastname: Lin
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chien
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000502:physiology; D000818:Animals; D004357:Drug Synergism; D004361:Drug Tolerance / Q000502:physiology*; D000068800:Etanercept; D018698:Glutamic Acid / Q000378:metabolism*; D007074:Immunoglobulin G / Q000008:administration & dosage*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D027322:Amino Acid Transport System X-AG; D007074:Immunoglobulin G; D017470:Receptors, Glutamate; D018124:Receptors, Tumor Necrosis Factor; D018698:Glutamic Acid; D009020:Morphine; D000068800:Etanercept