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-expresses nerve growth factor under the control of a myelin basic protein promoter. These animals display an ectopic network of substance P-containing sensory 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 test measuring the latency to tail withdrawal from a noxious radiant heat stimulus. Baseline reaction times were significantly less in transgenic mice, suggesting 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 readings were taken for another 10 min. In control mice, the 450 g stimulus was without effect, suggesting that it is normally innocuous. In transgenic mice, this stimulus induced a transient decrease in withdrawal latency at 1 min. Thus, transgenic mice exhibited mechanical allodynia. The 1400 g stimulus decreased withdrawal latency in both transgenic and control mice. However, the response was greater in transgenic mice, indicating that they exhibited mechanical hyperalgesia. The neurokinin-1 receptor antagonist CP-96,345, but not the inactive stereoisomer CP-96,344, administered subcutaneously 30 min before the 450 g stimulus, blocked the stimulation-induced allodynia in transgenic mice, and revealed a transient antinociception in transgenic and control mice. Ketamine, an N-methyl-D-aspartate receptor antagonist, given intraperitoneally 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.
McLeod
A L
AL
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
Ritchie
J
J
Cuello
A C
AC
Julien
J P
JP
Ribeiro-Da-Silva
A
A
Henry
J L
JL
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics; D064729:Neurokinin-1 Receptor Antagonists; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D011401:Promoter Regions, Genetic; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D013314:Stress, Mechanical; D013373:Substance P / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000700:Analgesics; D001713:Biphenyl Compounds; D018691:Excitatory Amino Acid Antagonists; D004676:Myelin Basic Protein; D064729:Neurokinin-1 Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D013373:Substance P; D007649:Ketamine; C066892:CP 96345