Diabetic
neuropathic pain remains an unmet clinical problem and is poorly relieved by conventional
analgesics.
N-methyl-D-aspartate (
NMDA) receptors play an important role in central sensitization in
neuropathic pain. Although
NMDA antagonists are highly effective in reducing
neuropathic pain, these agents cause severe side effects at therapeutic doses, which limit their clinical uses.
Neramexane and
memantine are uncompetitive
NMDA antagonists with minimal side effects at therapeutic doses. Here we determined the antinociceptive effect of chronic administration of
neramexane and compared its effect with that of
memantine and
gabapentin in a rat model of diabetic
neuropathic pain.
Mechanical hyperalgesia was measured with a noxious pressure stimulus, and
tactile allodynia was assessed with von Frey filaments in diabetic rats induced by
streptozotocin. Compared with vehicle-treated rats, treatment with
neramexane (12.3, 24.6, and 49.2 mg/kg/day) for 2 weeks via an osmotic minipump produced dose-dependent and sustained effects on
mechanical hyperalgesia and
allodynia. Administration of
memantine (20 mg/kg/day) or
gabapentin (50 mg/kg/day) for 2 weeks also produced significant and persistent antinociceptive effects on
mechanical hyperalgesia and
allodynia. The magnitude of the antinociceptive effect produced by the intermediate and high doses of
neramexane was comparable to that of
gabapentin and
memantine. The plasma level achieved by
neramexane at 12.3, 24.6, and 49.2 mg/kg/day was 0.26 +/- 0.04, 0.50 +/- 0.05, and 1.21 +/- 0.16 microM, respectively. These data suggest that
neramexane at therapeutically relevant doses attenuates diabetic
neuropathic pain. Our study provides valuable information about the therapeutic potential of chronic administration of
neramexane and
memantine for
painful diabetic neuropathy.