Differences in Neural-Immune Gene Expression Response in Rat Spinal Dorsal Horn Correlates with Variations in Electroacupuncture Analgesia

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Abstract

Background

Electroacupuncture (EA) has been widely used to alleviate diverse pains. Accumulated clinical experiences and experimental observations indicated that significant differences exist in sensitivity to EA analgesia for individuals of patients and model animals. However, the molecular mechanism accounting for this difference remains obscure.

Methodology/Principal Findings

We classified model male rats into high-responder (HR; TFL changes >150) and non-responder (NR; TFL changes ≤0) groups based on changes of their pain threshold detected by tail-flick latency (TFL) before and after 2 Hz or 100 Hz EA treatment. Gene expression analysis of spinal dorsal horn (DH) revealed divergent expression in HR and NR after 2 Hz/100 Hz EA. The expression of the neurotransmitter system related genes was significantly highly regulated in the HR animals while the proinflammation cytokines related genes were up-regulated more significantly in NR than that in HR after 2 Hz and 100 Hz EA stimulation, especially in the case of 2 Hz stimulation.

Conclusions/Significance

Our results suggested that differential regulation and coordination of neural-immune related genes might play an important role for individual variations in analgesic effects responding to EA in DH. It also provided new candidate genes related to EA responsiveness for future investigation.

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Most cited references 40

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Neural mechanism underlying acupuncture analgesia.

Zhi-Qi Zhao (2008)

Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific "acupuncture points" (acupoints) on the patient's body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Abeta, Adelta and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Abeta- and part of Adelta-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (mu-, delta- and kappa-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-kappaB, c-fos and c-jun play important roles in EA analgesia.

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Central mechanisms of pathological pain.

Rohini Kuner (2010)

Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.

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The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy.

Joyce DeLeo, N Nutile-McMenemy, F Y Tanga (2005)

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and point-mutant) mice after L5 nerve transection. In a complementary study, TLR4 antisense oligodeoxynucleotide (ODN) was administered intrathecally to L5 spinal nerve injured rats to reduce the expression of spinal TLR4. Both the genetically altered mice and the rats treated with TLR4 antisense ODN displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines as compared with their respective control groups. This finding shows that TLR4 contributes to the initiation of CNS neuroimmune activation after L5 nerve transection. Further understanding of this early, specific, innate CNS/microglial response and how it leads to sustained glial/neuronal hypersensitivity may point to new therapies for the prevention and treatment of neuropathic pain syndromes.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 3 August 2012

Volume: 7

Issue: 8

Electronic Location Identifier: e42331

Affiliations

[1 ]Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and National Engineering Research Center for Biochip at Shanghai, Shanghai, China

[2 ]Neuroscience Research Institute; Department of Neurobiology, Peking University Health Science Center; Key Laboratory of Neuroscience of the Ministry of Education and the Ministry of Public Health; Peking University, Beijing, China

[3 ]Department of Genetics and Center of Alcohol Studies, Piscataway, New Jersey, United States of America

[4 ]Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, China

University of Pecs Medical School, Hungary

Author notes

* E-mail: clcui@ 123456bjmu.edu.cn (CC); qinghua_zhang@ 123456shbiochip.com (QZ); gpzhao@ 123456sibs.ac.cn (GZ)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: CC GZ QZ. Performed the experiments: KW RZ LL XX XP. Analyzed the data: KW RZ FH LY JH. Wrote the paper: KW RZ CC GZ.

Article

Publisher ID: PONE-D-12-08523

DOI: 10.1371/journal.pone.0042331

PMC ID: 3411776

PubMed ID: 22879942

SO-VID: 60fa0174-a6d5-45b6-8623-32737afc974a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 23 March 2012

Date accepted : 3 July 2012

Page count

Pages: 13

Funding

This work was supported by the National Basic Research Program of China (No. 973-2007CB512501), China Postdoctoral Science Foundation (No. 20100480643), and National Natural Science Foundation of China (No. 30801491). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Differences in Neural-Immune Gene Expression Response in Rat Spinal Dorsal Horn Correlates with Variations in Electroacupuncture Analgesia

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

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PLOS: COVID-19 pandemic

Most cited references 40

Neural mechanism underlying acupuncture analgesia.

Central mechanisms of pathological pain.

The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy.

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