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α2-Adrenoceptor agonist induces peripheral antinociception via the endocannabinoid system

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Abstract

Background

Xylazine is an α2 adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine.

Methods

The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E2, was performed.

Results

Xylazine administered via an intraplantar injection (25, 50 and 100 μg) induced a peripheral antinociceptive effect against prostaglandin E2 (2 μg)-induced hyperalgesia. This effect was blocked by treatment with the selective CB1 cannabinoid antagonist AM251 (20, 40 and 80 μg) but not by the selective CB2 cannabinoid antagonist AM630 (100 μg). The anandamide reuptake inhibitor VDM11 (2.5 μg) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 μg), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 μg), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 μg) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE2.

Conclusions

The present results provides evidence that the peripheral antinociceptive effect of the α2 adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB1 cannabinoid receptor activation.

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Acknowledgements

TRLR would like to thank the financial support from Fundação de Amparo a Pesquisa de Minas Gerais—FAPEMIG—PPMFAPEMIG 2015 Process no 00474-15. MGMC would like to thank the financial support from Fundação de Amparo a Pesquisa de Minas Gerais—FAPEMIG—UNIVERSAL Process no 01307-14. TRLR would like to thank the Fellowships by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Biological Sciences, ICB-UFMG, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, CEP 31.270-100, Brazil

    Thiago Roberto Lima Romero, Marina Gomes Miranda e Castor & Igor Dimitri Gama Duarte

  2. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, via Campi Flegrei, 34, Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy

    Cosimo Parrella, Fabiana Piscitelli & Vincenzo Di Marzo

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  1. Thiago Roberto Lima Romero
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Romero, T.R.L., Miranda e Castor, M.G., Parrella, C. et al. α2-Adrenoceptor agonist induces peripheral antinociception via the endocannabinoid system. Pharmacol. Rep 72, 96–103 (2020). https://doi.org/10.1007/s43440-019-00053-6

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