PLoS ONE (Jan 2020)

Restoration of Cyclo-Gly-Pro-induced salivary hyposecretion and submandibular composition by naloxone in mice.

  • Igor Santana Melo,
  • Návylla Candeia-Medeiros,
  • Jamylle Nunes Souza Ferro,
  • Polliane Maria Cavalcante-Araújo,
  • Tales Lyra Oliveira,
  • Cassio Eráclito Alves Santos,
  • Leia Cardoso-Sousa,
  • Emilia Maria Gomes Aguiar,
  • Stephanie Wutke Oliveira,
  • Olagide Wagner Castro,
  • Renata Pereira Alves-Balvedi,
  • Luciano Pereira Rodrigues,
  • Jandir M Hickmann,
  • Douglas Alexsander Alves,
  • Igor Andrade Santos,
  • Ana Carolina Gomes Jardim,
  • Walter Luiz Siqueira,
  • Angelo Ricardo Fávaro Pipi,
  • Luiz Ricardo Goulart,
  • Emiliano de Oliveira Barreto,
  • Robinson Sabino-Silva

DOI
https://doi.org/10.1371/journal.pone.0229761
Journal volume & issue
Vol. 15, no. 3
p. e0229761

Abstract

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Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.