This study used
streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed
mechanical hyperalgesia as soon
as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat
mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of
morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the
GABA(B) agonist, (+/-)
baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)
baclofen was necessary to reverse 4 week-diabetic rat
hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-
peptide antagonist for the
substance P, neurokinin, (NK1) receptor,
RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the
mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the
N-methyl-D-aspartate (
NMDA) receptor for
glutamate, (+)
MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced
mechanical hyperalgesia. These data suggest that diabetes-induced
hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of
glutamate and activation of the
NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and
GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing
pain. It is suggested that
NMDA receptor antagonists may constitute an alternative
therapy for diabetic
neuropathic pain.