The role of N-methyl-D-aspartate (NMDA) receptors in pain and morphine tolerance.

To determine the importance of the N-methyl-D-aspartate (NMDA) receptor in pain hypersensitivity following injury, the NMDAR1 subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adeno-associated virus expressing the Cre recombinase into floxed NR1 mice. This procedure resulted in more than an 80% reduction in the expression of both NR1 mRNA and protein and a corresponding loss of NMDA, but not AMPA currents, in the lamina II neurons in the injected area. This spatially and temporally restricted knockout dramatically reduced the response to pain hypersensitivity resulting from the intraplantar injection of formalin but did not alter heat or cold paw withdrawal latencies, mechanical threshold, or motor function. Thus, the NMDA receptor in the spinal cord dorsal horn is essential for central sensitization, the central facilitation of pain transmission produced by peripheral injury. Agents that act on these spinal receptors may provide a therapeutic approach to ameliorate injury-induced pain.