Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Abstract

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 ϭ 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED ϭ 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 ϭ 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED ϭ 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 ϭ 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED ϭ 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED ϭ 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.

Effects of the NMDA receptor antagonist memantine on the expression and development of acute opiate dependence as assessed by withdrawal-potentiated startle and hyperalgesia

“…Significantly different from the SAL-SAL-SAL group (*p<0.05, **p<0.01) before withdrawal is precipitated (Blokhina et al 2000;Kawasaki et al 2005;Jin et al 2006). The ability of memantine to block the expression of withdrawal-induced hyperalgesia is also consistent with its ability to block hyperalgesia induced by neuropathic injury or administration of the inflammatory agent carrageenan (Carlton and Hargett 1995;Eisenberg et al 1995;Villetti et al 2003).…”

Intrathecal herpes simplex virus type 1 amplicon vector-mediated human proenkephalin reduces chronic constriction injury-induced neuropathic pain in rats

“…Pain threshold testing was performed by investigators blinded to the drugs being administered. The PWMT was determined using an automated testing device (electronic von Frey anesthesiometer; 2390 series, iiTc life Science, uSa) as described previously (24,25). a steel rod (diameter, 0.5 mm) was pushed against the ventral surface of the hindpaw with ascending force.…”

Preclinical efficacy of a gastro-sparing novel thiazolidin-4-one in alleviating secondary lesions of polyarthritis: A multi-parametric approach

“…Mechanical allodynia in both hind paws of AIA rats was measured using dynamic plantar aesthesiometer (UGO Basile, Srl, Comerio, VA, Italy) as described previously (Villetti et al, 2003). In brief, animals were placed on a metal mesh table and allowed to acclimatize for 15 min.…”