Qualitative review on N-methyl-D-aspartate receptor expression in rat spinal cord during the postnatal development: Implications for central sensitization and pain

Abstract

The N-methyl-D-aspartate receptor (NMDAR) is an important mediator of central sensitization and nociception in the rat spinal dorsal horn. The NMDAR subunits and splice variants determine the properties of the receptor. Understanding the expression of NMDAR subunits in spinal cord during the neonatal development is important as it may have consequences for the process of central sensitization and nociception in later life. In this review, a systematic literature search was conducted using three databases: Medline, Embase, and PubMed. A quality assessment was performed on predetermined entities of bias. Thirteen articles were identified to be relevant. The results show that NMDAR subunits and splice variants are dynamically expressed during postnatal development in the spinal dorsal horn. During the first 2 weeks, the expression of less excitable GluN2A subunit and more sensitive GluN2B subunit increases while the expression of high excitable GluN2C subunit decreases. During the 2nd week of postnatal development GluN1 subunits with exon 21 spliced in but exon 22 spliced out are predominantly expressed, increasing phosphorylation, and transport to the membrane. The data suggest that in rats, the nociceptive system is most susceptible to central sensitization processes during the first two postnatal weeks. This may have important consequences for nociception and pain responses in later life. From this, we conclude that targeted therapy directed toward specific NMDAR subunits is a promising candidate for mechanism-based treatment of pain in neonates.

Keywords: NMDA-receptor; central sensitization; dorsal horn; expression; neurodevelopment; pain.

FIGURE 1

Flowchart of the study selection [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Picture and legend adapted and compressed from Kalb et al. (1992) with permission: Binding patterns of L‐[3H]glutamate for all glutamate receptors (a, c, e, and g) and NMDAR antagonist [3H]MK‐801 for binding patterns of the NMDAR‐specific (b, d, f, and h). Spinal cords from animals of various postnatal ages were labeled (P7: a,b; P14: c,d; P21:E,F; adult: g,h). P7 shows high binding of all glutamate receptors and NMDAR‐specific (a,b), including dorsal and ventral horn. At P14 the signal of both all glutamate receptor binding and NMDAR‐specific is slightly diminished throughout the spinal cord with exception of the substantia gelatinosa (Rexed lamina II) (c,d). By P21 a further decrease in both binding patterns was seen (ef). Finally, in adult rats high binding of all glutamate receptors as well as NMDAR‐specific binding was found only in the substantia gelatinosa and low levels were seen in the ventral horn. (Bar = 50 µm)