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


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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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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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).

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