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TRPA1, substance P, histamine and 5-hydroxytryptamine interact in an interdependent way to induce nociception

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Abstract

Background

Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo.

Methods and results

The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat’s hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT1A or 3 receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT1A or 3 receptors.

Conclusion

Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.

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Acknowledgements

This study was supported by grants from CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nıvel Superior) and CNPq (Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico), Brazil. N.F.S. was recipient of a master fellowship from CAPES–Brazil (Master of Science).

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Authors and Affiliations

  1. Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil

    Luana Fischer, Maria Isabel Lavoranti, Mariana de Oliveira Borges, Alana Farias Miksza, Natalia Fantin Sardi & Bruno Jacson Martynhak

  2. Department Functional and Structural Biology, Institute of Biology, State University of Campinas-UNICAMP, Campinas, São Paulo, Brazil

    Claudia H. Tambeli & Carlos Amílcar Parada

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  1. Luana Fischer
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  2. Maria Isabel Lavoranti
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Correspondence to Luana Fischer.

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Responsible Editor: Jason J. McDougall.

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Fischer, L., Lavoranti, M.I., de Oliveira Borges, M. et al. TRPA1, substance P, histamine and 5-hydroxytryptamine interact in an interdependent way to induce nociception. Inflamm. Res. 66, 311–322 (2017). https://doi.org/10.1007/s00011-016-1015-1

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  • DOI: https://doi.org/10.1007/s00011-016-1015-1

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