Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain.
N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.
Research and Development Department, Chiesi Farmaceutici SpA, Parma, Italy. g.villetti@chiesigroup.com
Gino
G
Villetti
Marco
M
Bergamaschi
Franco
F
Bassani
Pier Tonino
PT
Bolzoni
Marisa
M
Maiorino
Claudio
C
Pietra
Ivano
I
Rondelli
Philippe
P
Chamiot-Clerc
Michele
M
Simonato
Mario
M
Barbieri
D000818:Animals; D002351:Carrageenan; D003080:Cold Temperature; D003920:Diabetes Mellitus / Q000097:blood / Q000139:chemically induced; D004195:Disease Models, Animal; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007189:Indans / Q000097:blood / Q000627:therapeutic use*; D007249:Inflammation; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013311:Streptozocin
D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D016194:Receptors, N-Methyl-D-Aspartate; D013311:Streptozocin; D002351:Carrageenan; D005998:Glycine; C431890:indantadol