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Altered nociception, analgesia and aggression in mice lacking the receptor for substance P

Naturevolume 392, pages394–397 (1998)Cite this article

Abstract

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system1,2,3,4. Substance P is synthesized by small-diameter sensory ‘pain’ fibres5, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation6 promotes central hyperexcitability and increased sensitivity to pain7,8,9,10. However, despite the availability of specific NK-1 antagonists4, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification (‘wind up’) and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.

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Figure 1: NK-1 receptor gene disruption by homologous recombination.
Figure 2: Nociceptive withdrawal reflex response following mechanical and electrical stimulation of the hind paw.
Figure 3: Acute nociceptive responses and sensitivity to morphine.
Figure 4: Adjuvant-induced inflammation and swim-stress-induced analgesia.
Figure 5: Anxiety and aggression.

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References

  1. Maeono, H., Kiyama, H. & Tohyama, M. Distribution of the substance P receptor (NK-1 receptor) in the central nervous system.Mol. Brain Res.18, 43–58 (1993).

    Article  Google Scholar 

  2. Nakaya, Y.et al. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat.J. Comp. Neurol.347, 249–274 (1994).

    Article ADS CAS  Google Scholar 

  3. Yokota, Y.et al. Molecular characterization of a functional cDNA for rat substance P receptor.J. Biol. Chem.264, 17649–17652 (1989).

    CAS PubMed  Google Scholar 

  4. Maggi, C. A., Patacchini, R., Rovero, P. & Giachetti, A. Tachykinin receptors and tachykinin receptor antagonists.J. Auton. Pharmacol.13, 23–93 (1993).

    Article CAS  Google Scholar 

  5. McCarthy, P. W. & Lawson, S. N. Cell type and conduction velocity of rat primary sensory neurons with substance P-like immunoreactivity.Neuroscience28, 745–753 (1989).

    Article CAS  Google Scholar 

  6. Duggan, A. W., Hendry, I. A., Morton, C. R., Hutchison, W. D. & Zhao, Z. Q. Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat.Brain Res.451, 261–273 (1988).

    Article CAS  Google Scholar 

  7. Laird, J. M. A., Hargreaves, R. J. & Hill, R. G. Effect of RP 67580, a non-peptide neurokinin-1 receptor antagonist, on facilitation of a nociceptive spinal flexion reflex in the rat.Br. J. Pharmacol.109, 713–718 (1993).

    Article CAS  Google Scholar 

  8. Ma, Q-P. & Woolf, C. J. Involvement of neurokinin receptors in the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones.J. Physiol. (Lond.)486, 769–777 (1995).

    Article CAS  Google Scholar 

  9. Xu, X-J., Dalsgaard, C.-J. & Wiesenfeld-Hallin, Z. Intrathecal CP-96,345 blocks reflex facilitation induced in rats by substance P and C-fiber-condtioning stimulation.Eur. J. Pharmacol.216, 337–344 (1992).

    Article CAS  Google Scholar 

  10. Neumann, S., Doubell, T. P., Leslie, T. & Woolf, C. J. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons.Nature384, 360–364 (1996).

    Article ADS CAS  Google Scholar 

  11. Nehls, M.et al. Two genetically separable steps in the differentiation of thymic epithelium.Science272, 886–889 (1996).

    Article ADS CAS  Google Scholar 

  12. Mantyh, P. W., Gates, T., Mantyh, C. R. & Maggio, J. E. Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues.J. Neurosci.9, 258–279 (1989).

    Article CAS  Google Scholar 

  13. De Felipe, C., Pinnock, R. D. & Hunt, S. P. Modulation of chemotropism in the developing spinal cord by substance P.Science267, 899–902 (1995).

    Article ADS CAS  Google Scholar 

  14. Herrero, J. F. & Headley, P. M. Functional evidence for multiple receptor activation by κ-ligands in the inhibition of spinal nociceptive reflexes in the rat.Br. J. Pharmacol.110, 303–309 (1993).

    Article CAS  Google Scholar 

  15. Cervero, F. & Plenderleith, M. B. C-fibre excitation and tonic descending inhibition of dorsal horn neurones in adult rats treated at birth with capsaicin.J. Physiol. (Lond.)365, 223–237 (1985).

    Article CAS  Google Scholar 

  16. Woolf, C. J. & Thompson, S. W. N. The induction and maintenance of central sensitization is dependent onN-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.Pain44, 293–299 (1991).

    Article CAS  Google Scholar 

  17. König, M.et al. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin.Nature383, 535–538 (1996).

    Article ADS  Google Scholar 

  18. Yaksh, T. L. & Malmbery, A. B. inThe Textbook of Pain(eds Wall, P. D. & Melzack, R.) 165–200 (Churchill-Livingstone, London, (1994)).

    Google Scholar 

  19. Bozic, C. R., Lu, B., Höpken, U. E., Gerard, C. & Gerard, N. P. Neurogenic amplification of immune complex inflammation.Science273, 1722–1725 (1996).

    Article ADS CAS  Google Scholar 

  20. Noguchi, K. & Ruda, M. A. Gene regulation in an ascending nociceptive pathway: inflammation-induced increase in preprotachykinin mRNA in rat lamina I spinal projection neurons.J. Neurosci.12, 2563–2572 (1992).

    Article CAS  Google Scholar 

  21. Abbadie, C., Taylor, B. K., Peterson, M. A. & Basbaum, A. I. Differential contribution of the two phases of the formalin test to the pattern of c-fos expression in the rat spinal cord: studies with remifentanil and lodocaine.Pain69, 101–110 (1997).

    Article CAS  Google Scholar 

  22. Rupniak, N. M. J., Carlson, E., Boyce, S., Webb, J. K. & Hill, R. G. Enantioselective inhibition of the formalin paw late phase by the NK1receptor antagonist L-733,060 in gerbils.Pain67, 189–195 (1996).

    Article CAS  Google Scholar 

  23. Hunt, S. P., Pini, A. & Evan, G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation.Nature328, 632–634 (1987).

    Article ADS CAS  Google Scholar 

  24. Chapman, V., Buritova, J., Honoré, P. & Besson, J.-M. Physiological contributions of neurokinin 1 receptor activation, and interactions with NMDA receptors, to inflammatory-evoked spinal c-Fos expression.J. Neurophysiol.76, 1817–1827 (1996).

    Article CAS  Google Scholar 

  25. Rubinstein, M.et al. Absence of opioid stress-induced analgesia in mice lacking β-endorphin by site-directed mutagenesis.Proc. Natl Acad. Sci. USA93, 3995–4000 (1996).

    Article ADS CAS  Google Scholar 

  26. Marek, P., Mogil, J. S., Sternberg, W. F., Panocka, I. & Liebeskind, J. C.N-Methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. II. Comparison across three swim-stress paradigms in selectively bred mice.Brain Res.578, 197–202 (1992).

    Article CAS  Google Scholar 

  27. Vanderah, T. W.et al. Mediation of swim-stress antinociception by the opioiddelta2 receptor in the mouse.J. Pharmacol. Exp. Therapeut.262, 190–197 (1992).

    CAS  Google Scholar 

  28. Jessell, T. M. & Iversen, L. L. Opiate analgesics inhibit substance P release from rat trigeminal nucleus.Nature268, 549–551 (1977).

    Article ADS CAS  Google Scholar 

  29. Siegel, A., Schubert, K. & Shaiku, M. B. Neurochemical mechanisms underlying amygdaloid modulation of aggressive behaviour in the cat.Aggr. Behav.21, 49–62 (1995).

    Article CAS  Google Scholar 

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Acknowledgements

We thank N. Unwin, W. Wisden, R. Munglani and R. Twyman for reading the manuscript; S. Nakanishi for the NK1 receptor cDNA; J. Ure, A. Jones, C. Roza and L. Singh for technical advice or assistance; S. Ingham for photographic assistance; P. Mantyh for suggestions and discussion. This work was supported by grants from MRC-ROPA, BBSRC, EC and DGICYT.

Author information

Authors and Affiliations

  1. Instituto de Neurociencias, Universidad Miguel Hernandez, Ap. correos 374, Alicante, 03080, Spain

    Carmen De Felipe & Carlos Belmonte

  2. Departamento de Fisiologia, Universidad de Alcala, Facultad de Medicina, Campus Universitario, Alcal de Henares, Madrid, 28871, Spain

    Juan F. Herrero, Jennifer M. A. Laird & Fernando Cervero

  3. Neurobiology Division, MRC Laboratory of Molecular Biology, Hills Road, CB2 2QH, Cambridge, UK

    John A. O'Brien, James A. Palmer, Christopher A. Doyle & Stephen P. Hunt

  4. Centre for Genome Research, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JQ, UK

    Andrew J. H. Smith

Authors
  1. Carmen De Felipe
  2. Juan F. Herrero
  3. John A. O'Brien
  4. James A. Palmer
  5. Christopher A. Doyle
  6. Andrew J. H. Smith
  7. Jennifer M. A. Laird
  8. Carlos Belmonte
  9. Fernando Cervero
  10. Stephen P. Hunt

Corresponding author

Correspondence toStephen P. Hunt.

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Felipe, C., Herrero, J., O'Brien, J.et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.Nature392, 394–397 (1998). https://doi.org/10.1038/32904

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