Decreased pain response in mice following cortex-specific knockout of the N-methyl-D-aspartate NR1 subunit

Abstract

Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. In this study, we used cortex-specific NR1 knockout mice (C57BL/6 strain) to elucidate the role of cortical NMDA receptors in pain processes. On post-natal day 20, paw withdrawal latency (PWL) to a noxious thermal stimulus was measured in male and female knockout (KO), control (Ctrl), and C57BL/6 (C57) mice. Twenty-four hours later, the same mice were tested in the formalin-pain assay (20 microl of 5% formalin injected into one hind-paw). The results show that KO mice (both male and female) have significantly reduced pain responses during both early and late phases of formalin test, as compared with Ctrl and C57 mice (p<0.01). By contrast, no differences among groups were found in PWL to a noxious thermal stimulus. Taken together, these results demonstrate dissociation in the role of cortical NMDA receptors in mediating different types of pain.

Fig. 1

Paw withdrawal latency (PWL) to thermal stimuli in cortex-specific NR1 knockout (KO), genetic control (Ctrl), and C57BL/6 (C57) mice. Data are expressed as mean time (sec ± S.E.M.) of PWL after application of a heat stimulus to the hind-paw. No significant differences were found between KO, Ctrl and C57 groups (male F(2, 39)= 2.003, p = 0.149, n.s.; female F(2, 31) = 3.519, p = 0.042, n.s.

Fig. 2

Pain responses in KO, Ctrl, and C57 mice (abbreviations as above) during the early (0–5 min) and late (10–60 min) phases of the formalin test. Data are expressed as mean time (sec ± S.E.M.) spent licking/biting the hind-paw after injection of 20 μl of 5% formalin. Significant differences were found between KO and Ctrl or C57 mice in both early (0–5 min) and late (10–60 min) phases. Ctrl and C57 mice did not differ from each other. *Male: early phase F(2, 38) = 15.220, p<0.001; late phase F(2, 38) = 14.013, p<0.001. Female: early phase F(2, 29) = 9.215, p<0.001; late phase: F(2, 29) = 9.678, p<0.001.