1. ¹Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
2. ²Department of Psychiatry, Chi-Mei Medical Center, Yong-Kong, Tainan, Taiwan
3. ³Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
4. ⁴Department of Anesthesiology, Taichung Veterans General Hospital, Taipei, Taiwan

Correspondence: Dr Chih-Shung Wong, Department of Anesthesiology, Tri-Service General Hospital, no. 325, Chenggung Road, Section 2, Neihu, Taipei 114, Taiwan. Tel: +886 2 87927007; Fax: +886 2 87927009; E-mail: w82556@ndmctsgh.edu.tw

Received 21 September 2007; Revised 18 December 2007; Accepted 18 December 2007; Published online 23 January 2008.

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 g in 5 l saline). Four days after PTX injection, they were randomly given a different dose of naloxone (either 15 g or 15 ng in 5 l saline), followed by a morphine injection (10 g in 5 l 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.