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The role of peripheral adenosine receptors in glutamate-induced pain nociceptive behavior

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Abstract

The role of peripheral adenosine receptors in pain is a controversial issue and seems to be quite different from the roles of spinal and central adenosine receptors. The present study is aimed at clarifying the role of these receptors in peripheral nociception. To clarify this, studies were done on Swiss mice with adenosine receptor agonists and antagonists. Nociceptive behavior was induced by subcutaneous injection of glutamate (10 μmol) into the ventral surface of the hind paw of mice. Statistical analyses were performed by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results showed that intraplantar (i.pl.) administration of N6-cyclohexyl-adenosine (CHA), an adenosine A1 receptor agonist, at 1 or 10 μg/paw significantly reduced glutamate-induced nociception (p<0.01 and p<0.001 vs. vehicle, respectively, n=8−10). In contrast, i.pl. injection of hydrochloride hydrate (CGS21680, an adenosine A2A receptor agonist) (1 μg/paw) induced a significant increase in glutamate-induced nociception compared to the vehicle (p<0.05, n=8), while 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, an adenosine A2A receptor antagonist) (20 μg/paw) caused a significant reduction (p<0.05, n=7−8). There were no significant effects on i.pl. administration of four additional adenosine receptor drugs—8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A1 antagonist, 1–10 μg/paw), N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA, an A2B agonist, 1–100 μg/paw), alloxazine (an A2B antagonist, 0.1–3 μg/paw), and 2-hexyn-1-yl-N(6)-methyladenosine (HEMADO) (an A3 agonist, 1–100 μg/paw) (p>0.05 vs. vehicle for all tests). We also found that prior administration of DPCPX (3 μg/paw) significantly blocked the anti-nociceptive effect of CHA (1 μg/paw) (p<0.05, n=7–9). Similarly, ZM241385 (20 μg/paw) administered prior to CGS21680 (1 μg/paw) significantly blocked CGS21680-induced exacerbation of nociception (p<0.05, n=8). Finally, inosine (10 and 100 μg/paw), a novel endogenous adenosine A1 receptor agonist recently reported by our research group, was also able to reduce glutamate-induced nociception (p<0.001 vs. vehicle, n=7–8). Interestingly, as an A1 adenosine receptor agonist, the inosine effect was significantly blocked by the A1 antagonist DPCPX (3 μg/paw) (p<0.05, n=7−9) but not by the A2A antagonist ZM241385 (10 μg/paw, p>0.05). In summary, these results demonstrate for the first time that i.pl administration of inosine induces an anti-nociceptive effect, similar to that elicited by CHA and possibly mediated by peripheral adenosine A1 receptor activation. Moreover, our results suggest that peripheral adenosine A2A receptor activation presents a pro-nociceptive effect, exacerbating glutamate-induced nociception independent of inosine-induced anti-nociceptive effects.

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Acknowledgments

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNpQ) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support.

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The datasets supporting the conclusions of this article are included within the article and its additional files.

Funding

This study was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil

    S. J. Macedo-Júnior & F. P. Nascimento

  2. Centro de Inovação e Ensaios Pré-clínicos – CIEnP, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil

    S. J. Macedo-Júnior

  3. Programa de Pós-Graduação em Biociências, Instituto Latino-Americano de Ciências da Vida e da Natureza, Universidade Federal da Integração Latino-Americana, Foz do Iguaçu, PR, 85868-020, Brazil

    F. P. Nascimento

  4. Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil

    M. Luiz-Cerutti & A. R. S. Santos

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  1. S. J. Macedo-Júnior
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Correspondence to F. P. Nascimento.

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Macedo-Júnior, S.J., Nascimento, F.P., Luiz-Cerutti, M. et al. The role of peripheral adenosine receptors in glutamate-induced pain nociceptive behavior. Purinergic Signalling 17, 303–312 (2021). https://doi.org/10.1007/s11302-021-09781-y

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