Transgenic mice over-expressing substance P exhibit allodynia and hyperalgesia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists

A transgenic mouse has been developed which, during development, over-expre sses nerve growth factor under the control of a myelin basic protein promot er. These animals display an ectopic network of substance P-containing sens ory fibers in the white matter of the spinal cord. To study the functional significance of this model to nociception, these mice were studied in a tes t measuring the latency to tail withdrawal from a noxious radiant heat stim ulus. Baseline reaction times were significantly less in transgenic mice, s uggesting thermal allodynia. A mechanical stimulus was then applied to the tip of the tail at either 450 g or 1400 g for 2 s and tail withdrawal readi ngs were taken for another 10 min. In control mice, the 450 g stimulus was without effect, suggesting that it is normally innocuous. In transgenic mic e, this stimulus induced a transient decrease in withdrawal latency at 1 mi n. Thus, transgenic mice exhibited mechanical allodynia. The 1400 g stimulu s decreased withdrawal latency in both transgenic and control mice. However , the response was greater in transgenic mice, indicating that they exhibit ed mechanical hyperalgesia. The neurokinin-l receptor antagonist CP-96,345, but not the inactive stereoisomer CP-96,344, administered subcutaneously 3 0 min before the 450g stimulus, blocked the stimulation-induced allodynia i n transgenic mice, and revealed a transient antinociception in transgenic a nd control mice. Ketamine, an N-methyl-D-aspartate receptor antagonist, giv en intraperitonally 10 min before 450 g stimulation, blocked the allodynia in transgenic mice. These results indicate that these transgenic mice display hyperalgesia and allodynia, and that these nociceptive responses are reversed by substance P and N-methyl-D-aspartate receptor antagonists. (C) 1999 IBRO. Published by Elsevier Science Ltd.