title: Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.
abstract: OBJECTIVE
  As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine.
  
  
  METHODS
  Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 μg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 μl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 μl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 μg in 5 μl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective).
  
  
  RESULTS
  Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine.
  
  
  CONCLUSIONS
  This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management.
authors.affiliation: General Education Center, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
authors.forename: Kuang-Yi
authors.initials: KY
authors.lastname: Chou
authors.affiliation: General Education Center, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan; Neuropathic Pain and Translational Medicine Research Laboratory, Cathay General Hospital, Taipei, Taiwan.
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.affiliation: Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan.
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Tsai
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ching-Tang
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chun-Chang
authors.initials: CC
authors.lastname: Yeh
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan. Electronic address: cherng1018@yahoo.com.tw.
authors.forename: Chen-Hwan
authors.initials: CH
authors.lastname: Cherng
authors.affiliation: Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan; Neuropathic Pain and Translational Medicine Research Laboratory, Cathay General Hospital, Taipei, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan. Electronic address: w82556@gmail.com.
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000818:Animals; D004361:Drug Tolerance; D006358:Hot Temperature; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D009294:Narcotics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012684:Sensory Thresholds / Q000187:drug effects*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D009020:Morphine
keywords: antinociception; intrathecal injection; morphine-tolerance; neuropathy