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Black mamba venom peptides target acid-sensing ion channels to abolish pain


Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels1,2. In the field of pain, they led to important advances in basic research3,4,5,6 and even to clinical applications7,8. Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway9, including in humans10. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain11. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.

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Figure 1: Mambalgins represent a new class of three-finger toxins targeting ASIC channels.
Figure 2: Intrathecal injections of mambalgin-1 exert potent naloxone-resistant and ASIC1a-dependent analgesia in mice.
Figure 3: The central analgesic effect of mambalgin-1 shows reduced tolerance compared with morphine, no respiratory depression and involves the ASIC2a subunit.
Figure 4: Intraplantar injections of mambalgin-1 evoke peripheral analgesic effects through ASIC1b-containing channels.

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Data deposits

Mambalgin-1 cDNA and mambalgin-1 and -2 protein sequences have been deposited in GenBank and UniProt Knowledgebase under accession numbers JX428743, B3EWQ5 and B3EWQ4, respectively.


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We are grateful to M. P. Price and M. J. Welsh for their gift of the ASIC1a–/– mice, to A. Zimmer for providing the Penk1–/– mice, to H. Schweitz and L. Beress for their gift of pre-purified peptidic fractions of black mamba venom, to J. Noël for cultures of hippocampal neurons and comments, to E. Deval, P. Inquimbert, A. Delaunay and M. Christin for discussions, to C. Heurteaux and N. Blondeau for help with stereotaxic injections, to A. Lazzari for support with plethysmography, to V. Thieffin, N. Leroudier, S. Boulakirba, T. Lemaire, C. Karoutchi and G. Marrane for technical assistance, and to C. Chevance for secretarial assistance. We thank E. Bourinet, F. Rassendren and M. B. Emerit for providing the Cav3.2, P2X2 and 5-HT3A cDNAs, respectively. This work was supported by the Fondation pour la Recherche Medicale, the Association Française contre les Myopathies and the Agence Nationale de la Recherche. Part of this work has been supported by EMMAservice under European Union contract Grant Agreement number 227490 of the EC FP7 Capacities Specific Programme.

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Authors and Affiliations



S.D. and A.B. conducted a large part of the experiments including the screening and high-performance liquid chromatography purification of mambalgins (S.D.) and pain experiments, analysed the data and participated to the preparation of the manuscript. M.S. conducted the cloning of mambalgin cDNA and electrophysiological experiments. D. Douguet realized the three-dimensional modelling. S.S., A.-S.D.-G. and D. Debayle performed the mass spectrometry experiments and the amino-acid sequencing. V.F. performed validation of the siRNAs and provided technical support. A.A. was associated with pain behaviour experiments. M.L. contributed to initial aspects of the work and participated in the final preparation of the manuscript. E.L. supervised the project and participated in data analysis and manuscript preparation.

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Correspondence to Anne Baron or Eric Lingueglia.

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Competing interests

M. Lazdunski is a founder of Theralpha and the president of its scientific advisory board. The company has taken an option on the mambalgin patent. The other authors declare no competing financial interests.

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Diochot, S., Baron, A., Salinas, M. et al. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 490, 552–555 (2012).

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