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Primary afferent tachykinins are required to experience moderate to intense pain

Abstract

The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation1. Because blockers of glutamate receptors reliably reduce pain behaviour2,3,4, it is assumed that ‘pain’ messages are mediated by glutamate action on dorsal horn neurons. The contribution of substance P, however, is still unclear. We have now disrupted the mouse preprotachykinin A gene (PPT-A), which encodes substance P and a related tachykinin, neurokinin A (ref. 5). We find that although the behavioural response to mildly painful stimuli is intact in these mice, the response to moderate to intense pain is significantly reduced. Neurogenic inflammation, which results from peripheral release of substance P and neurokinin A (ref. 6), is almost absent in the mutant mice. We conclude that the release of tachykinins from primary afferent pain-sensing receptors (nociceptors) is required to produce moderate to intense pain.

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Figure 1: Generation of SP and NKA-deficient mice.
Figure 2: ‘Pain’ responses to different thermal or mechanical stimulus intensities.
Figure 3: ‘Pain’ responses to noxious chemical stimulation of cutaneous or visceral tissue.
Figure 4: Magnitude of neurogenic and non-neurogenic inflammatory responses in wild-type (white bars), homozygous mutant (black bars) and heterozygous (grey bars) mice.

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Acknowledgements

We thank A. Doupe, D. Julius, J. Levine, S. Lisberger, A. Malmberg and W. Martin for critical comments on the manuscript. R. Montenson for the pNTK vector and S. Vigna for antisera against the NK-1 receptor. This work was supported by the NINDS, NIDR, NIDK of the NIH and an RRP from HHMI.

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Correspondence to Allan I. Basbaum.

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Cao, Y., Mantyh, P., Carlson, E. et al. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392, 390–394 (1998). https://doi.org/10.1038/32897

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