The present study was undertaken to examine the effect of amitriptyline on the antinociceptive effect of morphine and its underlying mechanisms in regulating glutamate transporters trafficking in morphine-tolerant rats. Long-term morphine infusion induced antinociceptive tolerance and down-regulation of glutamate transporters (GTs), GLAST, GLT-1, and EAAC1, expression in the rat spinal cord dorsal horn. Acute amitriptyline treatment potentiated morphine's antinociceptive effect, with a 5.3-fold leftward shift of morphine's dose-response curve in morphine-tolerant rats, and this was associated with GLAST and GLT-1 trafficking onto the cell surface. Similar to our previous studies, morphine challenge (10 microg/10 microl, i.t.) significant by increased the excitatory amino acids (EAAs) aspartate and glutamate level in the CSF dialysates of morphine-tolerant rats. Acute amitriptyline treatment not only suppressed this morphine-evoked EAA release, but further reduced the EAA concentration than baseline level. Furthermore, long-term morphine infusion up-regulated PKA and PKC protein expression in the spinal cord dorsal horn, while amitriptyline inhibited the increase in expression of phospho-PKA, PKCalpha, PKCbetaII, and PKCgamma. In morphine-tolerant rats, acute treatment with PKA inhibitor H89 and PKC inhibitor Gö6805 attenuated morphine tolerance and the morphine-induced CSF glutamate and aspartate elevation, and induced trafficking of GLAST and GLT-1 from cytosol onto the cell surface. These results show that acute amitriptyline treatment preserved morphine's antinociceptive effect in morphine-tolerant rats; the mechanisms may be involved in inhibition of phospho-PKA and PKC expression, and thus inducing the GLAST and GLT-1 trafficking onto glial cell surface which enhances the EAA uptake from the synaptic cleft and reduces EAA concentration in the spinal CSF.

The present study demonstrates that etanercept restores the antinociceptive effect of morphine in morphine-tolerant rats by inhibition of proinflammatory cytokine TNF-α, IL-1β, and IL-6 expression and spinal neuroinflammation. The results suggest that etanercept could also be an adjuvant therapy for morphine tolerance, which extends the effectiveness of opioids in clinical pain management.

These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.

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Resveratrol attenuates morphine tolerance by inhibiting neuroinflammation and down-regulating NMDAR NR1 and NR2B subunit expression. Resveratrol regulates the NMDAR expression, which might be involved in a loss of scaffolding postsynaptic density-95 protein.

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