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Neuropsychopharmacology. 2008 Oct;33(11):2772-82. doi: 10.1038/sj.npp.1301672. Epub 2008 Jan 23.

Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats.

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Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.


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.

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