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Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor

Abstract

Neuropeptide Y (NPY) is believed to exert antinociceptive actions by inhibiting the release of substance P and other ‘pain neurotransmitters’ in the spinal cord dorsal horn1,2,3. However, the physiological significance and potential therapeutic value of NPY remain obscure4. It is also unclear which receptor subtype(s) are involved. To identify a possible physiological role for the NPY Y1 receptor in pain transmission, we generated NPY Y1 receptor null mutant (Y1-/-) mice by homologous recombination techniques. Here we show that Y1-/- mice develop hyperalgesia to acute thermal, cutaneous and visceral chemical pain, and exhibit mechanical hypersensitivity. Neuropathic pain is increased, and the mice show a complete absence of the pharmacological analgesic effects of NPY. In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage. We conclude that the Y1 receptor is required for central physiological and pharmacological NPY-induced analgesia and that its activation is both sufficient and required for the release of substance P and initiation of neurogenic inflammation.

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Figure 1: Targeted mutagenesis of the Y1 receptor and expression analysis of Y1 and SP receptors.
Figure 2: Cutaneous and visceral nociception of wild-type (black bars) and Y1-/- (white bars) mice in the hot-plate, tail-flick, formalin, acetic acid, MgSO4, von Frey hair and neuropathic pain assays, as well as in stress- and NPY-produced analgesia.
Figure 3: Neurogenic and non-neurogenic inflammation in wild-type and Y1-/- mice.
Figure 4: Measurement of SP release by capsaicin administration in the skin by EIA and effects of Y1 agonist and antagonist in inflammation-induced plasma extravasation.

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Acknowledgements

We thank L. Klevenvall-Fridvall for technical assistance and L. Johansson for secretarial assistance. This research was supported by the Swedish Medical Research Council the Biotechnology Program of the European Union and the Swedish Cancer Society.

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Correspondence to Patrik Ernfors.

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Naveilhan, P., Hassani, H., Lucas, G. et al. Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor. Nature 409, 513–517 (2001). https://doi.org/10.1038/35054063

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