Attenuation of morphine tolerance by intrathecal gabapentin is associated with suppression of morphine-evoked excitatory amino acid release in the rat spinal cord

This study was designed to investigate the effect of acute and chronic intrathecal (i.t.) injection of gabapentin (GBP) on the antinociceptive effect of morphine and tolerance development using a tail-flick latency test. Levels of excitatory amino acids (EAA) in i.t. CSF dialysates were also measured by high performance liquid chromatography. Male Wistar rats were implanted with either one or two i.t. catheters for drug injection or pump infusion and with a microdialysis probe for CSF dialysate collection. The effect of acute GBP (10 μg i.t.) injection on the morphine dose response was examined in both naïve rats and rats made tolerant by continuous infusion of morphine (15 μg/h i.t.) for 5 days. At such a low dose (10 μg i.t.), GBP did not enhance morphine's antinociception in naïve rats. In morphine-tolerant rats, however, acute GBP (10 μg i.t.) injection potentiated morphine's antinociception and yielded a 14.6-fold shift in morphine's dose-response curve. When GBP (10 μg/h i.t.) was co-infused with morphine (15 μg/h i.t.) to examine its effect on the development of morphine tolerance, GBP attenuated the development of morphine tolerance. The effect of GBP and morphine on CSF glutamate and aspartate levels was examined in naïve rats, and the effect of morphine challenge on CSF glutamate and aspartate levels was examined in rats previously infused for 5 days with morphine alone or morphine plus GBP. Acute injection of GBP (10 μg i.t.), morphine (50 μg i.t.), or GBP (10 μg i.t.) followed by morphine (50 μg i.t.) 30 min later had no significant effect on CSF EAA concentration in naïve rats; however, in tolerant rats, morphine challenge (50 μg i.t.) increased aspartate and glutamate levels to 221 ± 22% and 296 ± 43%, respectively, of those before morphine challenge, and this phenomenon was inhibited by GBP co-infusion. Our results show that GBP, at a dose without enhanced effect on morphine's antinociception in naïve rats, not only potentiates morphine's antinociceptive effect in morphine-tolerant rats but also attenuates the development of morphine tolerance. The mechanism of the effect of GBP on morphine tolerance might be via suppression of the EAA concentration in spinal CSF dialysate.