Peripheral Rho-associated Protein Kinase Activation Mediates Acupuncture Analgesia

Overview

Journal Integr Med Res

Publisher Elsevier

Specialty Rehabilitation Medicine

Date 2024 Sep 2

PMID 39219984

Authors

Ji-Yeun Park

Jae-Hwan Jang

Yang-Hwa Kang

Songhee Jeon

Seung-Nam Kim

Yeon-Hee Ryu

Hi-Joon Park

Affiliations

Soon will be listed here.

Abstract

Background: Acupuncture has been proven effective for various types of pain, and peripheral molecular signals around acupuncture-treated areas have been suggested to contribute to the analgesic effects of acupuncture. However, the underlying mechanism from these peripheral molecular signals to central ones remains unclear. The purpose of this study was to investigate whether peripheral Rho-associated protein kinase (ROCK) activation induced by acupuncture treatment mediates acupuncture analgesia, and also to investigate the relationship between ROCK activation and extracellular signal-regulated kinase (ERK), which has previously been proven to mediate acupuncture analgesia and other related molecular changes during acupuncture.

Methods: Acupuncture was treated at the bilateral GB34 acupoints of C57BL/6 mice, after which changes in ROCK activation and the location of its expression in the skin were analyzed. To verify the role of ROCK in acupuncture analgesia, we administrated ROCK inhibitor Y-27632 (0.3 μg/ul) into the skin before acupuncture treatment with formalin and complete Freund adjuvant (CFA) induced pain models, then the nociceptive responses were analyzed.

Results: Acupuncture treatment produced ROCK2 activation in the skin after 30 and 60 min, and the histological analyses revealed that ROCK2 was activated in the fibroblast of the dermis. The acupuncture-induced ROCK2 expression was significantly attenuated by the ERK inhibitor, whereas phospho-ERK expression was not inhibited by ROCK inhibitor. In both the formalin- and CFA-induced mouse pain models, acupuncture analgesia was blocked by ROCK inhibitor administration.

Conclusion: Acupuncture treatment-induced ROCK2 expression is a downstream effector of phospho-ERK in the skin and plays a crucial role in acupuncture analgesia.

References

Dai Y, Iwata K, Fukuoka T, Kondo E, Tokunaga A, Yamanaka H . Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci. 2002; 22(17):7737-45. PMC: 6757977. View

Park J, Park J, Jeon S, Doo A, Kim S, Lee H . From peripheral to central: the role of ERK signaling pathway in acupuncture analgesia. J Pain. 2014; 15(5):535-49. PMC: 4196675. DOI: 10.1016/j.jpain.2014.01.498. View

Favata M, Horiuchi K, Manos E, Daulerio A, Stradley D, Feeser W . Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998; 273(29):18623-32. DOI: 10.1074/jbc.273.29.18623. View

Lock F, Hotchin N . Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One. 2009; 4(12):e8190. PMC: 2780731. DOI: 10.1371/journal.pone.0008190. View

Takano T, Chen X, Luo F, Fujita T, Ren Z, Goldman N . Traditional acupuncture triggers a local increase in adenosine in human subjects. J Pain. 2012; 13(12):1215-23. PMC: 3587733. DOI: 10.1016/j.jpain.2012.09.012. View

Guo Z, Longhurst J . Activation of reciprocal pathways between arcuate nucleus and ventrolateral periaqueductal gray during electroacupuncture: involvement of VGLUT3. Brain Res. 2010; 1360:77-88. PMC: 2962589. DOI: 10.1016/j.brainres.2010.08.102. View

Shi J, Wu X, Surma M, Vemula S, Zhang L, Yang Y . Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell Death Dis. 2013; 4:e483. PMC: 3734810. DOI: 10.1038/cddis.2013.10. View

Vickers A, Cronin A, Maschino A, Lewith G, MacPherson H, Foster N . Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med. 2012; 172(19):1444-53. PMC: 3658605. DOI: 10.1001/archinternmed.2012.3654. View

DAVIES S, Reddy H, Caivano M, Cohen P . Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000; 351(Pt 1):95-105. PMC: 1221339. DOI: 10.1042/0264-6021:3510095. View

10.

Zhao Z . Neural mechanism underlying acupuncture analgesia. Prog Neurobiol. 2008; 85(4):355-75. DOI: 10.1016/j.pneurobio.2008.05.004. View

11.

Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S . ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996; 392(2):189-93. DOI: 10.1016/0014-5793(96)00811-3. View

12.

Hong S, Jeon Y, Lee H, Kim J, Baek J, Lee J . Activation of RhoA and FAK induces ERK-mediated osteopontin expression in mechanical force-subjected periodontal ligament fibroblasts. Mol Cell Biochem. 2009; 335(1-2):263-72. DOI: 10.1007/s11010-009-0276-1. View

13.

Hirano T, Zeredo J, Kimoto M, Moritaka K, Nasution F, Toda K . Disinhibitory involvement of the anterior cingulate cortex in the descending antinociceptive effect induced by electroacupuncture stimulation in rats. Am J Chin Med. 2008; 36(3):569-77. DOI: 10.1142/S0192415X08005989. View

14.

Langevin H, Churchill D, Wu J, Badger G, Yandow J, Fox J . Evidence of connective tissue involvement in acupuncture. FASEB J. 2002; 16(8):872-4. DOI: 10.1096/fj.01-0925fje. View

15.

Abraham T, Chen M, Ma S . TRPV1 expression in acupuncture points: response to electroacupuncture stimulation. J Chem Neuroanat. 2011; 41(3):129-36. PMC: 3117662. DOI: 10.1016/j.jchemneu.2011.01.001. View

16.

Riento K, Ridley A . Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003; 4(6):446-56. DOI: 10.1038/nrm1128. View

17.

Davis R, Churchill D, Badger G, Dunn J, Langevin H . A new method for quantifying the needling component of acupuncture treatments. Acupunct Med. 2012; 30(2):113-9. PMC: 3375586. DOI: 10.1136/acupmed-2011-010111. View

18.

Mi W, Mao-Ying Q, Wang X, Li X, Yang C, Jiang J . Involvement of spinal neurotrophin-3 in electroacupuncture analgesia and inhibition of spinal glial activation in rat model of monoarthritis. J Pain. 2011; 12(9):974-84. DOI: 10.1016/j.jpain.2011.03.002. View

19.

Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W . Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci. 2010; 13(7):883-8. PMC: 3467968. DOI: 10.1038/nn.2562. View

20.

Park J, Cho S, Lee S, Ryu Y, Jang J, Kim S . Peripheral ERK modulates acupuncture-induced brain neural activity and its functional connectivity. Sci Rep. 2021; 11(1):5128. PMC: 7933175. DOI: 10.1038/s41598-021-84273-y. View