title: Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats.
abstract: The aim of the present study was to examine the effect of ultra-low-dose naloxone on pertussis toxin (PTX)-induced thermal hyperalgesia in rats and its underlying mechanisms. Male Wistar rats, implanted with an intrathecal catheter with or without a microdialysis probe, received a single intrathecal injection of PTX (1 microg in 5 microl saline). Four days after PTX injection, they were randomly given a different dose of naloxone (either 15 microg or 15 ng in 5 microl saline), followed by a morphine injection (10 microg in 5 microl saline) after 30 min. The results found that PTX injection induced thermal hyperalgesia and increasing excitatory amino acid (EAA; L-glutamate and L-aspartate) concentration in the spinal CSF dialysates. Ultra-low-dose naloxone not only preserved the antinociceptive effect of morphine but also suppressed the PTX-evoked EAA release as well. Moreover, ultra-low-dose naloxone plus morphine administration inhibited the downregulation of L-glutamate transporters (GTs) and the L-glutamate-metabolizing enzyme glutamine synthetase (GS), and, moreover, inhibited microglial activation and suppressed cytokine expression in PTX-treated rat spinal cords. These results show that ultra-low-dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The mechanisms include (a) inhibition of pro-inflammatory cytokine expression, (b) attenuation of PTX-evoked EAA release, and (c) reversion of the downregulation of GT expression.
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Fong-Lin
authors.initials: FL
authors.lastname: Jang
authors.forename: Yueh-Hua
authors.initials: YH
authors.lastname: Tai
authors.forename: Shinn-Long
authors.initials: SL
authors.lastname: Lin
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Shen
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use*; D009270:Naloxone / Q000008:administration & dosage* / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D037342:Pertussis Toxin / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009270:Naloxone; D009020:Morphine; D037342:Pertussis Toxin