Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

doi:10.3390/cells9122725

Review

. 2020 Dec 21;9(12):2725.

doi: 10.3390/cells9122725.

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

Ti-Yen Yeh¹, I-Wei Luo², Yu-Lin Hsieh^{3

4

5}, To-Jung Tseng^{6

7}, Hao Chiang⁸, Sung-Tsang Hsieh^{1

9

10

11}

Affiliations

¹ Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
² Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
³ Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁴ School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Medical Research, Kaohsiung Medical University Hostpital, Kaohsiung 80708, Taiwan.
⁶ Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
⁷ Department of Medical Education, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁸ Akouos, Inc., Boston, MA 02210, USA.
⁹ Department of Neurology, National Taiwan University Hospital, Taipei 10002, Taiwan.
¹⁰ Graduate Institute of Brian and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
¹¹ Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei 10055, Taiwan.

PMID: 33371371
PMCID: PMC7767346
DOI: 10.3390/cells9122725

Review

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

Ti-Yen Yeh et al. Cells. 2020.

. 2020 Dec 21;9(12):2725.

doi: 10.3390/cells9122725.

Authors

Ti-Yen Yeh¹, I-Wei Luo², Yu-Lin Hsieh^{3

4

5}, To-Jung Tseng^{6

7}, Hao Chiang⁸, Sung-Tsang Hsieh^{1

9

10

11}

Affiliations

¹ Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
² Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
³ Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁴ School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Medical Research, Kaohsiung Medical University Hostpital, Kaohsiung 80708, Taiwan.
⁶ Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
⁷ Department of Medical Education, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁸ Akouos, Inc., Boston, MA 02210, USA.
⁹ Department of Neurology, National Taiwan University Hospital, Taipei 10002, Taiwan.
¹⁰ Graduate Institute of Brian and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
¹¹ Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei 10055, Taiwan.

PMID: 33371371
PMCID: PMC7767346
DOI: 10.3390/cells9122725

Abstract

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment.

Keywords: dorsal root ganglia; neuropathic pain; peripheral sensitization; post-translational modification; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Schematic diagram illustrating the peripheral sensitization in resiniferatoxin (RTX)-induced neuropathic pain model. Thermal hypoalgesia and mechanical allodynia were observed after 1 week of RTX treatment. After RTX exposure, several dorsal root ganglia (DRG) profiles were changed including the increase of purinergic receptor P2X3 (P2X3)(+)/activating transcription factor 3 (ATF3)(+) neurons and the decrease of transient receptor potential vanilloid subtype 1 (TRPV1)(+)/calcitonin gene-related peptide (CGRP)(+) neurons. At the terminal ending of nerve, the phenotype of dermal nerve also had similar changes as the DRG. The number of CGRP(+) and P2X3(+) nerve were decreased and increased respectively.

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References

1. Van Hecke O., Austin S.K., Khan R.A., Smith B.H., Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain. 2014;155:654–662. doi: 10.1016/j.pain.2013.11.013. - DOI - PubMed
1. Colloca L., Ludman T., Bouhassira D., Baron R., Dickenson A.H., Yarnitsky D., Freeman R., Truini A., Attal N., Finnerup N.B., et al. Neuropathic pain. Nat. Rev. Dis. Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2. - DOI - PMC - PubMed
1. Hansson P.T., Attal N., Baron R., Cruccu G. Toward a definition of pharmacoresistant neuropathic pain. Eur. J. Pain. 2009;13:439–440. doi: 10.1016/j.ejpain.2009.02.008. - DOI - PubMed
1. Omori S., Isose S., Misawa S., Watanabe K., Sekiguchi Y., Shibuya K., Beppu M., Amino H., Kuwabara S. Pain-related evoked potentials after intraepidermal electrical stimulation to Adelta and C fibers in patients with neuropathic pain. Neurosci. Res. 2017;121:43–48. doi: 10.1016/j.neures.2017.03.007. - DOI - PubMed
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[1] Van Hecke O., Austin S.K., Khan R.A., Smith B.H., Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain. 2014;155:654–662. doi: 10.1016/j.pain.2013.11.013. - DOI - PubMed

[2] Van Hecke O., Austin S.K., Khan R.A., Smith B.H., Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain. 2014;155:654–662. doi: 10.1016/j.pain.2013.11.013. - DOI - PubMed

[3] Colloca L., Ludman T., Bouhassira D., Baron R., Dickenson A.H., Yarnitsky D., Freeman R., Truini A., Attal N., Finnerup N.B., et al. Neuropathic pain. Nat. Rev. Dis. Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2. - DOI - PMC - PubMed

[4] Colloca L., Ludman T., Bouhassira D., Baron R., Dickenson A.H., Yarnitsky D., Freeman R., Truini A., Attal N., Finnerup N.B., et al. Neuropathic pain. Nat. Rev. Dis. Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2. - DOI - PMC - PubMed

[5] Hansson P.T., Attal N., Baron R., Cruccu G. Toward a definition of pharmacoresistant neuropathic pain. Eur. J. Pain. 2009;13:439–440. doi: 10.1016/j.ejpain.2009.02.008. - DOI - PubMed

[6] Hansson P.T., Attal N., Baron R., Cruccu G. Toward a definition of pharmacoresistant neuropathic pain. Eur. J. Pain. 2009;13:439–440. doi: 10.1016/j.ejpain.2009.02.008. - DOI - PubMed

[7] Omori S., Isose S., Misawa S., Watanabe K., Sekiguchi Y., Shibuya K., Beppu M., Amino H., Kuwabara S. Pain-related evoked potentials after intraepidermal electrical stimulation to Adelta and C fibers in patients with neuropathic pain. Neurosci. Res. 2017;121:43–48. doi: 10.1016/j.neures.2017.03.007. - DOI - PubMed

[8] Omori S., Isose S., Misawa S., Watanabe K., Sekiguchi Y., Shibuya K., Beppu M., Amino H., Kuwabara S. Pain-related evoked potentials after intraepidermal electrical stimulation to Adelta and C fibers in patients with neuropathic pain. Neurosci. Res. 2017;121:43–48. doi: 10.1016/j.neures.2017.03.007. - DOI - PubMed

[9] Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26:173–188. doi: 10.1002/mus.10181. - DOI - PubMed

[10] Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26:173–188. doi: 10.1002/mus.10181. - DOI - PubMed

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Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

Affiliations

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

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