scholarly journals Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1007 ◽  
Author(s):  
Hodaya Leibovich ◽  
Nahum Buzaglo ◽  
Shlomo Tsuriel ◽  
Liat Peretz ◽  
Yaki Caspi ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Dorsal Root ◽  
Pain Sensitivity ◽  
Spared Nerve Injury ◽  
Drg Neurons ◽  
Nociceptive Neurons ◽  
Peripheral Innervation ◽  
Innervation Patterns

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique—PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats’ paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.

scholarly journals The Role of TMEM16A/ERK/NK-1 Signaling in Dorsal Root Ganglia Neurons in the Development of Neuropathic Pain Induced by Spared Nerve Injury (SNI)

2021 ◽  
Author(s):  
Qinyi Chen ◽  
Liangjingyuan Kong ◽  
Zhenzhen Xu ◽  
Nan Cao ◽  
Xuechun Tang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Dorsal Root ◽  
Electrophysiological Recording ◽  
Erk Pathway ◽  
Spared Nerve Injury ◽  
Positive Interaction ◽  
Nociceptive Neurons ◽  
Nociceptive Responses

AbstractIncreasing evidence suggests that transmembrane protein 16A (TMEM16A) in nociceptive neurons is an important molecular component contributing to peripheral pain transduction. The present study aimed to evaluate the role and mechanism of TMEM16A in chronic nociceptive responses elicited by spared nerve injury (SNI). In this study, SNI was used to induce neuropathic pain. Drugs were administered intrathecally. The expression and cellular localization of TMEM16A, the ERK pathway, and NK-1 in the dorsal root ganglion (DRG) were detected by western blot and immunofluorescence. Behavioral tests were used to evaluate the role of TMEM16A and p-ERK in SNI-induced persistent pain and hypersensitivity. The role of TMEM16A in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. The results show that TMEM16A, p-ERK, and NK-1 are predominantly expressed in small neurons associated with nociceptive sensation. TMEM16A is colocalized with p-ERK/NK-1 in DRG. TMEM16A, the MEK/ERK pathway, and NK-1 are activated in DRG after SNI. ERK inhibitor or TMEM16A antagonist prevents SNI-induced allodynia. ERK and NK-1 are downstream of TMEM16A activation. Electrophysiological recording showed that CaCC current increases and intrathecal application of T16Ainh-A01, a selective TMEM16A inhibitor, reverses the hyperexcitability of DRG neurons harvested from rats after SNI. We conclude that TMEM16A activation in DRG leads to a positive interaction of the ERK pathway with activation of NK-1 production and is involved in the development of neuropathic pain after SNI. Also, the blockade of TMEM16A or inhibition of the downstream ERK pathway or NK-1 upregulation may prevent the development of neuropathic pain.

scholarly journals Lack of efficacy of a partial adenosine A1 receptor agonist in neuropathic pain models in mice

2021 ◽  
Author(s):  
Katharina Metzner ◽  
Tilman Gross ◽  
Annika Balzulat ◽  
Gesine Wack ◽  
Ruirui Lu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Partial Agonist ◽  
Pharmacological Intervention ◽  
Spared Nerve Injury ◽  
Drg Neurons ◽  
Behavioral Experiments ◽  
Nociceptive Neurons ◽  
Electrophysiological Properties

AbstractPrevious studies suggest that adenosine A1 receptors (A1R) modulate the processing of pain. The aim of this study was to characterize the distribution of A1R in nociceptive tissues and to evaluate whether targeting A1R with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of A1R in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found A1R to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03–1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full A1R agonist. Despite expression of A1R in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial A1R agonists might be a valuable approach for the treatment of neuropathic pain.

Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain

Neuroscience ◽  
2012 ◽  
Vol 227 ◽  
pp. 370-380 ◽  
Author(s):  
M. Cachemaille ◽  
C.J. Laedermann ◽  
M. Pertin ◽  
H. Abriel ◽  
R.-D. Gosselin ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Ubiquitin Ligase ◽  
Dorsal Root ◽  
Spared Nerve Injury ◽  
Injury Model ◽  
Neuronal Expression

scholarly journals Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

2016 ◽  
Vol 32 (1) ◽  
pp. 27-40 ◽  
Author(s):  
Liying Bai ◽  
Xinru Wang ◽  
Zhisong Li ◽  
Cunlong Kong ◽  
Yonghui Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spared Nerve Injury ◽  
Chemokine Cxcl12

scholarly journals Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury

2018 ◽  
Vol 14 ◽  
pp. 174480691876580 ◽  
Author(s):  
Xue-Jing Kang ◽  
Ye-Nan Chi ◽  
Wen Chen ◽  
Feng-Yu Liu ◽  
Shuang Cui ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Calcium Channels ◽  
Nerve Injury ◽  
Spared Nerve Injury ◽  
Drg Neurons

scholarly journals Changes in Cytokine Expression after Electroacupuncture in Neuropathic Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Myeoung Hoon Cha ◽  
Taick Sang Nam ◽  
Yongho Kwak ◽  
Hyejung Lee ◽  
Bae Hwan Lee
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Dorsal Root ◽  
Interleukin 1 ◽  
Cytokine Expression ◽  
Sprague Dawley ◽  
Expression Levels ◽  
Sprague Dawley Rats ◽  
Necrosis Factor

The production of proinflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α) plays a key role in chronic pain such as neuropathic pain. We investigated changes in cytokine expression in injured peripheral nerves and dorsal root ganglia (DRG) following electroacupuncture (EA) treatment. Neuropathic pain was induced by peripheral nerve injury to the left hind limb of Sprague-Dawley rats under pentobarbital anesthesia. Two weeks later, the nerve-injured rats were treated by EA for 10 minutes. The expression levels of IL-1β, IL-6, and TNF-αin peripheral nerves and DRG of neuropathic rats were significantly increased in nerve-injured rats. However, after EA, the cytokine expression levels were noticeably decreased in peripheral nerves and DRG. These results suggest that EA stimulation can reduce the levels of proinflamtory cytokines elevated after nerve injury.

scholarly journals BKCa Channel Inhibition by Peripheral Nerve Injury Is Restored by the Xanthine Derivative KMUP-1 in Dorsal Root Ganglia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 949
Author(s):  
Kuang-I Cheng ◽  
Kan-Ting Yang ◽  
Chien-Lun Kung ◽  
Yu-Chi Cheng ◽  
Jwu-Lai Yeh ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Patch Clamp ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Dorsal Root ◽  
Bkca Channel ◽  
Mrna Levels ◽  
Drg Neurons ◽  
Perforated Patch Clamp

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BKCa current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BKCa currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BKCa. Real-time PCR was used to measure BKCa mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BKCa currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BKCa channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BKCa-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BKCa mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BKCa current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain.

scholarly journals Melatonin inhibits the up-regulation of N-type calcium channel in neuropathic pain by activating the MT2 receptor in rats

2021 ◽  
Author(s):  
JUN-JIE TIAN ◽  
YING-YING ZHANG ◽  
ZHAO-YANG TAN ◽  
NAN CAO ◽  
ZU-WEI QU ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Calcium Channel ◽  
Dorsal Root ◽  
The Other ◽  
Spared Nerve Injury ◽  
Drg Neurons ◽  
Activation Curve ◽  
Inactivation Curve ◽  
Whole Cell Patch Clamp ◽  
Behavioral Studies

The aim of the study was to clarify the effect of melatonin on neuropathic pain by N-type calcium channel (Cav2.2) inhibition in dorsal root ganglion (DRG) neurons after spared nerve injury (SNI) surgery. Immunofluorescence was used to identify the co-expression of Cav2.2 and the MT2 receptor and detect the changes in Cav2.2 expression in DRG neurons. Western-blot was also performed to detect the expression of Cav2.2 in DRG neurons. The action potential and current of Cav2.2 channels in DRG neurons were detected using whole-cell patch clamp analysis. Behavioral studies were conducted using thermal stimulation and acetone after melatonin was injected intraperitoneally. The results revealed that Cav2.2 and the MT2 receptor were co-expressed in medium and small sized DRG neurons, and the intensity of Cav2.2 increased after SNI. Injection of melatonin activated the MT2 receptor and relieved nociceptive pain through decreased the Cav2.2 expression and current in DRG neurons. Melatonin can significantly decrease the increase in Cav2.2 current density and excitability after SNI. In addition, the Cav2.2 activation curve shifted to the left after SNI, but there was no change in inactivation. 10 μM melatonin significantly inhibited the excitability of DRG neurons and Cav2.2 current, the inactivation curve of Cav2.2 current shifted significantly to the left. However, the MT2 receptor antagonist 4-P-PDOT reversed the inhibition of melatonin on Cav2.2 current. We conclude that melatonin inhibits the increased Cav2.2 expression and current; on the other hand, it reduces the excitability of DRG neurons after SNI surgery via the MT2 receptor pathway.

scholarly journals Thiamine Suppresses Thermal Hyperalgesia, Inhibits Hyperexcitability, and Lessens Alterations of Sodium Currents in Injured, Dorsal Root Ganglion Neurons in Rats

2009 ◽  
Vol 110 (2) ◽  
pp. 387-400 ◽  
Author(s):  
Xue-Song Song ◽  
Zhi-Jiang Huang ◽  
Xue-Jun Song
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Dorsal Root ◽  
Thermal Hyperalgesia ◽  
B Vitamins ◽  
Drg Neurons ◽  
Na Currents

Background B vitamins can effectively attenuate inflammatory and neuropathic pain in experimental animals, while their efficacy in treating clinical pain syndromes remains unclear. To understand possible mechanisms underlying B vitamin-induced analgesia and provide further evidence that may support the clinical utility of B vitamins in chronic pain treatment, this study investigated effects of thiamine (B1) on the excitability and Na currents of dorsal root ganglion (DRG) neurons that have been altered by nerve injury. Methods Nerve injury was mimicked by chronic compression of DRG in rats. Neuropathic pain was evidenced by the presence of thermal hyperalgesia. Intracellular and patch-clamp recordings were made in vitro from intact and dissociated DRG neurons, respectively. Results (1) In vivo intraperitoneal administration of B1 (66 mg/kg/day, 10-14 doses) significantly inhibited DRG compression-induced neural hyperexcitability, in addition to suppressing thermal hyperalgesia. (2) In vitro perfusion of B1 (0.1, 1 and 10 mM) resulted in a dose-dependent inhibition of DRG neuron hyperexcitability. In addition, the DRG neurons exhibited size-dependent sensitivity to B1 treatment, i.e., the small and the medium-sized neurons, compared to the large neurons, were significantly more sensitive. (3) Both in vitro (1 mM) and in vivo application of B1 significantly reversed DRG compression-induced down-regulation of tetrodotoxin-resistant but not tetrodotoxin-sensitive Na current density in the small neurons. B1 at 1 mM also reversed the compression-induced hyperpolarizing shift of the inactivation curve of the tetrodotoxin-resistant currents and the upregulated ramp currents in small DRG neurons. Conclusion Thiamine can reduce hyperexcitability and lessen alterations of Na currents in injured DRG neurons, in addition to suppressing thermal hyperalgesia.

scholarly journals 17β-Estradiol Attenuates Neuropathic Pain Caused by Spared Nerve Injury by Upregulating CIC-3 in the Dorsal Root Ganglion of Ovariectomized Rats

2019 ◽  
Vol 13 ◽  
Author(s):  
Zhen-Zhen Xu ◽  
Qin-Yi Chen ◽  
Shi-Yu Deng ◽  
Meng Zhang ◽  
Chao-Yang Tan ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Dorsal Root ◽  
Ovariectomized Rats ◽  
Spared Nerve Injury ◽  
17Β Estradiol
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