Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain.
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.
Department of Anesthesiology and Perioperative Medicine (SRC, HLP), The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
Shao-Rui
SR
Chen
Gary
G
Samoriski
Hui-Lin
HL
Pan
D000588:Amines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003517:Cyclopentanes / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000077206:Gabapentin; D008297:Male; D008559:Memantine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013311:Streptozocin; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D013311:Streptozocin; D000077206:Gabapentin; C114144:neramexane; D008559:Memantine