Download PDF
CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2020; 78(01): 21-27
DOI: 10.1590/0004-282X20190137
Article

Spinal protein kinase A and phosphorylated extracellular signal-regulated kinase signaling are involved in the antinociceptive effect of phytohormone abscisic acid in rats

A proteína quinase A da medula espinhal e a sinalização da quinase fosforilada regulada por sinal extracelular estão envolvidas no efeito antinociceptivo do ácido fito-hormônio abscísico em ratos
Mahtab MOLLASHAHI 
1   Shahid Bahonar University of Kerman, Faculty of Sciences, Department of Biology, Kerman, Iran.
,
Mehdi ABBASNEJAD 
1   Shahid Bahonar University of Kerman, Faculty of Sciences, Department of Biology, Kerman, Iran.
2   Kerman University of Medical Sciences, Kerman Neuroscience Research Center (KNRC), Laboratory of Molecular Neuroscience, Kerman, Iran.
,
Saeed ESMAEILI-MAHANI 
1   Shahid Bahonar University of Kerman, Faculty of Sciences, Department of Biology, Kerman, Iran.
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Objective: The phytohormone abscisic acid (ABA) as a signaling molecule exists in various types of organisms from early multicellular to animal cells and tissues. It has been demonstrated that ABA has an antinociceptive effect in rodents. The present study was designed to assess the possible role of PKA and phosphorylated ERK (p-ERK) on the antinociceptive effects of intrathecal (i.t.) ABA in male Wistar rats. Methods: The animals were cannulated intrathecally and divided into different experimental groups (n=6‒7): Control (no surgery), vehicle (received ABA vehicle), ABA-treated groups (received ABA in doses of 10 or 20 µg/rat), ABA plus H.89 (PKA inhibitor)-treated group which received the inhibitor 15 min prior to the ABA injection. Tail-flick and hot-plate tests were used as acute nociceptive stimulators to assess ABA analgesic effects. p-ERK was evaluated in the dorsal portion of the spinal cord using immunoblotting. Results: Data showed that a microinjection of ABA (10 and 20 µg/rat, i.t.) significantly increased the nociceptive threshold in tail flick and hot plate tests. The application of PKA inhibitor (H.89, 100 nM/rat) significantly inhibited ABA-induced analgesic effects. Expression of p-ERK was significantly decreased in ABA-injected animals, which were not observed in the ABA+H.89-treated group. Conclusions: Overall, i.t. administration of ABA (10 µg/rat) induced analgesia and p-ERK down-expression likely by involving the PKA-dependent mechanism.

Resumo

Objetivo: O ácido fito-hormônio abscísico (ABA) existe como molécula sinalizadora em vários tipos de organismos, de multicelulares a células e tecidos animais. Foi demonstrado que o ABA tem efeito antinociceptivo em roedores. O presente estudo foi desenhado para avaliar o possível papel da PKA e da ERK fosforilada (p-ERK) nos efeitos antinociceptivos do ABA intratecal (i.t.) em ratos Wistar machos. Métodos: Os animais foram canulados por via i.t. e divididos em diferentes grupos experimentais (n=6‒7): controle (sem cirurgia), veículo (veículo ABA recebido), grupos tratados com ABA (recebeu ABA em doses de 10 ou 20 µg/rato), grupo tratado com ABA mais H.89 (inibidor de PKA) que recebeu o inibidor 15 minutos antes da injeção de ABA. Os testes de movimento da cauda e placa quente foram utilizados como estimuladores nociceptivos agudos para avaliar os efeitos analgésicos da ABA. A p-ERK foi avaliada na porção dorsal da medula espinhal por imunotransferência. Resultados: A microinjeção de ABA (10 e 20 µg/rato, i.t.) aumentou significativamente o limiar nociceptivo nos testes de movimento da cauda e placa quente. A aplicação de inibidor de PKA (H.89, 100 nM/rato) inibiu significativamente os efeitos analgésicos induzidos por ABA. A expressão de p-ERK diminuiu significativamente em animais injetados com ABA que não foram observados no grupo tratado com ABA+H.89. Conclusões: No geral, a administração i.t. de ABA (10 µg/rato) induziu a analgesia e expressão negativa de p-ERK provavelmente envolvendo mecanismo dependente de PKA.

Keywords:

abscisic acid - anti-nociception - PKA - p-ERK - rats

Palavras-chave:

ácido abscísico - antinocicepção - PKA - p-ERK - ratos

Support:

Support: This study was supported by the Kerman Neuroscience Research Center with grant (#95/26), Kerman University of Medical Sciences.




Publication History

Received: 14 August 2019

Accepted: 05 September 2019

Article published online:
13 June 2023

© 2020. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Xiong L, Zhu JK. Regulation of abscisic acid biosynthesis. Plant Phys. 2003 Sep;133(1):29-36. https://doi.org/10.1104/pp.103.025395
  • 2 Mauch-Mani B, Mauch F. The role of abscisic acid in plant-pathogen interactions. Curr Opin Plant Biol. 2005 Aug;8(4):409-14. https://doi.org/10.1016/j.pbi.2005.05.015
  • 3 Le Page-Degivry M-T, Bidard J, Rouvier E, Bulard C, Lazdunski M. Presence of abscisic acid, a phytohormone, in the mammalian brain. Proc Natl Acad Sci. 1986 Feb;83(4):1155-8. https://doi.org/10.1073/pnas.83.4.1155
  • 4 Li HH, Hao RL, Wu SS, Guo PC, Chen CJ, Pan LP, et al. Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans. Biochem Pharmacol. 1986; 83(4):1155-8. https://doi.org/10.1016/j.bcp.2011.06.042
  • 5 Lievens L, Pollier J, Goossens A, Beyaert R, Staal J. Abscisic acid as pathogen effector and immune regulator. Front Plant Sci. 2017 Apr;8:587. https://doi.org/10.3389/fpls.2017.00587
  • 6 Guri AJ, Hontecillas R, Si H, Liu D, Bassaganya-Riera J. Dietary abscisic acid ameliorates glucose tolerance and obesity-related inflammation in db/db mice fed high-fat diets. Clin Nutr. 2007 Feb;26(1):107-16. https://doi.org/10.1016/j.clnu.2006.07.008.
  • 7 Guri AJ, Misyak SA, Hontecillas R, Hasty A, Liu D, Si H, et al. Abscisic acid ameliorates atherosclerosis by suppressing macrophage and CD4+ T cell recruitment into the aortic wall. J Nutr Biochem. 2010 Dec;21(12):1178-85. https://doi.org/10.1016/j.jnutbio.2009.10.003. PMC2891372
  • 8 Guri AJ, Hontecillas R, Bassaganya-Riera J. Abscisic acid ameliorates experimental IBD by downregulating cellular adhesion molecule expression and suppressing immune cell infiltration. Clin Nutr. 2010 Dec;29(6):824-31. https://doi.org/10.1016/j.clnu.2010.02.009
  • 9 Bassaganya-Riera J, Skoneczka J, Kingston D, Krishnan A, Misyak S, Guri A, et al. Mechanisms of action and medicinal applications of abscisic acid. Curr Med Chem. 2010;17(5):467-78. https://doi.org/10.2174/092986710790226110
  • 10 Bassaganya-Riera J, Guri AJ, Lu P, Climent M, Carbo A, Sobral BW, et al. Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor γ. J Biol Chem. 2011 Jan;286(4):2504-16. https://doi.org/10.1074/jbc.M110.160077
  • 11 Naderi R, Esmaeili-Mahani S, Abbasnejad M. Phosphatidylinositol-3-kinase and protein kinase C are involved in the pro-cognitive and anti-anxiety effects of phytohormone abscisic acid in rats. Biomed Pharmacother. 2017 Dec;96:112-9. https://doi.org/10.1016/j.biopha.2017.09.089
  • 12 Bruzzone S, Bodrato N, Usai C, Guida L, Moreschi I, Nano R, et al. Abscisic acid is an endogenous stimulator of insulin release from human pancreatic islets with cyclic ADP ribose as second messenger. J Biol Chem. 2008 Nov;283(47):32188-97. https://doi.org/10.1074/jbc.M802603200
  • 13 Mollashahi M, Abbasnejad M, Esmaeili-Mahani S. Phytohormone abscisic acid elicits antinociceptive effects in rats through the activation of opioid and peroxisome proliferatoractivated receptors beta/delta. Eur J Pharmacol. 2018 Aug;832:75-80. https://doi.org/10.1016/j.ejphar.2018.05.013
  • 14 Alves JM, Lin K. Neuropathic Pain: A Review of Interneuronal Disinhibition. Arch Neurosci. 2018;5(1):e12290. https://doi.org/10.5812/archneurosci.12290
  • 15 Ji R-R, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999 Dec;2(12):1114-9. https://doi.org/10.1038/16040
  • 16 Galan A, Lopez-Garcia JA, Cervero F, Laird JM. Activation of spinal extracellular signaling-regulated kinase-1 and-2 by intraplantar carrageenan in rodents. Neurosci Lett. 2002 Mar;322(1):37-40. https://doi.org/10.1016/S0304-3940(02)00078-2
  • 17 Yaksh TL, Rudy TA. Chronic catheterization of spinal ubarachnoid space. Physiol Behav. 1976 Dec;17(6):1031-6. https://doi.org/10.1016/0031-9384(76)90029-9
  • 18 Solomon US, Olugbemide A. Antinociceptive effects of methyl jasmonate in experimental animals. J Nat Med. 2011 Jan;65(3-4):466-70. https://doi.org/10.1007/s11418-011-0520-3
  • 19 Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase = (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain. 2002 Sep;99(1-2):175-84. https://doi.org/10.1016/s0304-3959(02)00097-0
  • 20 Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, et al. Diabetes induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol. 2006 Oct;70(4):1246-54. https://doi.org/10.1124/mol.106.025478
  • 21 Jang SP, Park SH, Jung JS, Lee HJ, Hong JW, Lee JY, et al. Characterization of changes of pain behavior and signal transduction system in food-deprived mice. Animal cells and systems. 2018;22(4):227-33. https://doi.org/10.1080/19768354.2018.1490348
  • 22 Park SH, Lee JR, Jang SP, Park SH, Lee HJ, Hong JW, et al. Antinociceptive profiles and mechanisms of centrally administered oxyntomodulin in various mouse pain models Neuropeptides. 2018 Apr;68:7-14. https://doi.org/10.1016/j.npep.2018.01.002
  • 23 Cho IH, Lee MJ, Jang M, Gwak NG, Lee KY, Jung HS. Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation. Mol. Pain. 2012;8(1):13. https://doi.org/10.1186/1744-8069-8-13
  • 24 Cruz CD, Neto FL, Castro-Lopes J, et al. Inhibition of ERK phosphorylation decreases nociceptive behaviour in monoarthritic rats. Pain. 2005 Aug;116(3):411-9. https://doi.org/10.1016/j.pain.2005.05.031
  • 25 Zocchi E, Carpaneto A, Cerrano C, Bavestrello G, Giovine M, Bruzzone S, et al. The temperature-signaling cascade in sponges involves a heat-gated cation channel, abscisic acid, and cyclic ADP-ribose. Proc Natl Acad Sci U S A. 2001 Dec;98(26):14859-64. https://doi.org/10.1073/pnas.261448698
  • 26 Puce S, Basile G, Bavestrello G, Bruzzone S, Cerrano C, Giovine M, et al. Abscisic acid signaling through cyclic ADP-ribose in hydroid regeneration. J Biol Chem. 2004 Sep;279(38):39783-8. https://doi.org/10.1074/jbc.M405348200
  • 27 Hook V, Toneff T, Baylon S, Sei C. Differential activation of enkephalin, galanin, somatostatin, NPY, and VIP neuropeptide production by stimulators of protein kinases A and C in neuroendocrine chromaffin cells. Neuropeptides. 2008 Oct-Dec;42(5-6):503-11. https://doi.org/10.1016/j.npep.2008.05.001
  • 28 Suh HW, Hudson PM, Hong JS. Expression of the proenkephalin A gene and [Met5]- enkephalin secretion induced by arachidonic acid in bovine adrenal medullary chromaffin cells: involvement of second messengers. J Neurochem. 1995 Feb;64(2):608-13. https://doi.org/10.1046/j.1471-4159.1995.64020608.x
  • 29 Jiang YL, He XF, Shen YF, Yin XH, Du JY, Liang YI, et al. Analgesic roles of peripheral intrinsic met-enkephalin and dynorphin A in long-lasting inflammatory pain induced by complete Freund's adjuvant in rats. Exp Ther Med. 2015 Jun;9(6): 2344-8. https://doi.org/10.3892/etm.2015.2407
  • 30 Mudge AW, Leeman SE, Fischbach GD. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc Natl Acad Sci. 1979 Jan;76(1):526-30. https://doi.org/10.1073/pnas.76.1.526
  • 31 Delgado M, Ganea D. Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents. Brain Behav Immun. 2008 Nov;22(8): 1146-51. https://doi.org/10.1016/j.bbi.2008.06.001
  • 32 Song Y, Huang L-YM. Modulation of glycine receptor chloride channels by cAMP dependent protein kinase in spinal trigeminal neurons. Nature. 1990 Nov;348:242-5. https://doi.org/10.1038/348242a0
  • 33 Gu Y, Huang LY. Cross⃞modulation of glycine⃞activated Cl- channels by protein kinase C and cAMP⃞dependent protein kinase in the rat. J Physiol. 1998 Jan 15; 506(Pt 2):331-9. https://doi.org/10.1111/j.1469-7793.1998.331bw.x
  • 34 Pidoplichko VI, Reymann KG. Abscisic acid potentiates NMDA-gated currents in hippocampal neurones. Neuroreport. 1994 Nov;5(1):2311-6. https://doi.org/10.1097/00001756-199411000-00026
  • 35 Kumar S, Ren Q, Beckley JH, O'Buckley TK, Gigante ED, Santerre JL, et al. Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis. Front Neurosci. 2012 Ape;6:44. https://doi.org/10.3389/fnins.2012.00044
  • 36 Chen JT, Guo D, Campanelli D, Frattini F, Mayer F, Zhou L, et al. Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction. Nat Commun. 2014 Oct;5:5331. https://doi.org/10.1038/ncomms6331
  • 37 Soti M, Abbasnejad M, Kooshki R, Esmaeili-Mahani S. Central microinjection of phytohormone abscisic acid changes feeding behavior, decreases body weight, and reduces brain oxidative stress in rats. Nutr Neurosci. 2018 Feb;22(10):679-87. https://doi.org/10.1080/1028415X.2018.1431093
  • 38 Gårdmark M, Höglund AU, Hammarlund⃞Udenaes M. Aspects on Tail⃞Flick, Hot⃞Plate and Electrical Stimulation Tests for Morphine Antinociception. Pharmacol Toxicol. 1998 Dec;83(6):252-8. https://doi.org/10.1111/j.1600-0773.1998.tb01478.x
  • 39 Mulder GB, Pritchett K. Rodent analgesiometry: the hot plate, tail flick and Von Frey hairs. J Am Assoc Lab Anim Sci. 2004 May;43(3):54-5.