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Nocistatin, a peptide that blocks nociceptin action in pain transmission

Abstract

Prolonged tissue damage or injury often leads to chronic pain states such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia)1,2. The neuropeptide nociceptin3,4, also known as orphanin FQ (ref. 5), is an endogenous ligand for the orphan opioid-like receptor6,7,8 which induces both hyperalgesia and allodynia when administered by injection through the theca of the spinal cord into the subarachnoid space (that is, intrathecally)4,9. Here we show that the nociceptin precursor3,10,11,12,13 contains another biologically active peptide which we call nocistatin. Nocistatin blocks nociceptin-induced allodynia and hyperalgesia, and attenuates pain evoked by prostaglandin E2. It is the carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln), which is conserved in bovine, human and murine species, that possesses allodynia-blocking activity. We have also isolated endogenous nocistatin from bovine brain. Furthermore, intrathecal pretreatment with anti-nocistatin antibody decreases the threshold for nociceptin-induced allodynia. Although nocistatin does not bind to the nociceptin receptor, it binds to the membrane of mouse brain and of spinal cord with high affinity. Our results show that nocistatin is a new biologically active peptide produced from the same precursor as nociceptin and indicate that these two peptides may play opposite roles in pain transmission.

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Figure 1: Alignment of deduced amino-acid sequences among bovine, human, mouse and rat prepronociceptins.
Figure 2: Effects of putative peptides deduced from bovine prepronociceptin on allodynia (a, c) and hyperalgesia (b, d).
Figure 3: Existence of PNP-3.
Figure 4: Biological action of PNP-3.

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Acknowledgements

We thank K. Uegaki and N. Yumoto for peptide synthesis; H. Minakata for amino-acid sequence analysis and mass spectrometry; and Y. Masu for discussion and comments. This work was supported by the Ministry of Education, Science, Culture, and Sports of Japan and the Japan Private School Promotion Foundation.

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Correspondence to Seiji Ito.

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Okuda-Ashitaka, E., Minami, T., Tachibana, S. et al. Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature 392, 286–289 (1998). https://doi.org/10.1038/32660

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