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

Nature volume 392, pages 394–397 (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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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.

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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

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  1. Carmen De Felipe
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  2. Juan F. Herrero
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  4. James A. Palmer
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  7. Jennifer M. A. Laird
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  8. Carlos Belmonte
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  9. Fernando Cervero
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  10. Stephen P. Hunt
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Correspondence to Stephen 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. Nature 392, 394–397 (1998). https://doi.org/10.1038/32904

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