Antinociceptive effect in mice of intraperitoneal N‐methyl‐d‐aspartate receptor antagonists in the formalin test

Abstract

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and 80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.

Tyrosine Phosphorylation of Kir3.1 in Spinal Cord Is Induced by Acute Inflammation, Chronic Neuropathic Pain, and Behavioral Stress

“…pY12-K ir 3.1 in Formalin-induced Inflammation-As a chronic pain stimulus, sciatic nerve ligation produces neurochemical changes distinct from those observed during acute inflammatory pain (11). To investigate whether acute inflammatory pain also elevated pY12-K ir 3.1-IR, we injected the left hindpaw of mice with saline or 4% formalin (27). In accordance with previously published literature (28 -29), effectiveness of formalin treatment was confirmed by observing more paw flinches and licks in the 40-min interval post-injection (120 Ϯ 22, n ϭ 5) compared with saline-injected controls (0.67 Ϯ 0.54, n ϭ 6).…”

Nitric Oxide Synthase Modulates the Antihyperalgesic Effect of the NMDA Receptor Antagonist MK-801 on Carrageenan-Induced Inflammatory Pain in Rats

“…Similar analgesic effects of MK-801 have been reported in the other models of inflammatory pain. Systemic administration of MK-801 has been reported to suppress formalin-induced tonic pain (Yamamoto and Yaksh 1992;Vaccarino et al 1993;Berrino et al 2003;Gong et al 2011). MK-801 prevented the late phase of formalin pain, but was not effective in reversing of the established pain state (Yamamoto and Yaksh 1992;Vaccarino et al 1993).…”

“…Also, injection of rats with (+)-MK-801 has been successfully employed in experimental models of both the positive and negative symptoms of schizophrenia (Rung et al 2005). Its analgesic effect is recognized in neuropathic (Begon et al 2000) and inflammatory pain (Hama et al 2003;Andreasen et al 2013), after systemic (Ren et al 1992a, b;Berrino et al 2003;Chen et al 2010) or local applications (Jackson et al 1995;Davidson et al 1997;Du et al 2003). However, the mechanism of MK-801 action in inflammatory pain remains to be elucidated.…”

Common animal models for spasticity and pain

“…The intensities of these nociceptive behaviors are dependent on the concentration of formalin used, and the second phase involves a period of sensitization during which inflammatory phenomena occur. These inflammatory phenomena are possibly a result of central processes triggered by the neuronal activation during the first phase, since glutamate NMDA receptor antagonists significantly and dose-dependently reduce nociceptive activity during the second phase of the formalin test when they are given before the formalin [84].…”