Molecular Changes in the Dorsal Root Ganglion during the Late Phase of Peripheral Nerve Injury–induced Pain in Rodents: A Systematic Review

2021 ◽  
Author(s):  
Mehrman Chalaki ◽  
Luis J. Cruz ◽  
Sabien G. A. van Neerven ◽  
Joost Verhaagen ◽  
Albert Dahan ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Current Knowledge ◽  
Late Phase ◽  
Molecular Changes ◽  
Genomic Changes ◽  
Protein Levels ◽  
Fundamental Understanding ◽  
Sequencing Studies

The dorsal root ganglion is widely recognized as a potential target to treat chronic pain. A fundamental understanding of quantitative molecular and genomic changes during the late phase of pain is therefore indispensable. The authors performed a systematic literature review on injury-induced pain in rodent dorsal root ganglions at minimally 3 weeks after injury. So far, slightly more than 300 molecules were quantified on the protein or messenger RNA level, of which about 60 were in more than one study. Only nine individual sequencing studies were performed in which the most up- or downregulated genes varied due to heterogeneity in study design. Neuropeptide Y and galanin were found to be consistently upregulated on both the gene and protein levels. The current knowledge regarding molecular changes in the dorsal root ganglion during the late phase of pain is limited. General conclusions are difficult to draw, making it hard to select specific molecules as a focus for treatment.

Role of Asic3, Nav1.7 and Nav1.8 in Electroacupuncture-Induced Analgesia in a Mouse Model of Fibromyalgia Pain

2018 ◽  
Vol 36 (2) ◽  
pp. 110-116 ◽  
Author(s):  
Liang-Ta Yen ◽  
Yu-Chan Hsu ◽  
Jaung-Geng Lin ◽  
Ching-Liang Hsieh ◽  
Yi-Wen Lin
Keyword(s):  
Spinal Cord ◽  
Side Effects ◽  
Dorsal Root Ganglion ◽  
Mouse Model ◽  
Dorsal Root ◽  
Mechanical Hyperalgesia ◽  
Protein Levels ◽  
The Us ◽  
Preventive Effects

Background The mechanisms underlying fibromyalgia (FM) pain are not understood. The US Food and Drug Administration has recommended three drugs for treating FM—namely, pregabalin, duloxetine and milnacipran; however, these medications are associated with severe side effects. Objective To create a mouse model of FM pain using dual injections of acidic saline to cause mechanical hyperalgesia and test whether ASIC3, Nav1.7 and Nav1.8 are involved in this process and whether electroacupuncture (EA) can reverse these phenomena. Methods The FM model was established by injecting acidic saline twice into 40 ICR mice. The mice were assigned to subgroups (n=8 each) treated with different EA frequencies (2, 15 and 50 Hz). ASIC3, Nav1.7 and Nav1.8 expression levels were measured by Western blotting and immunohistochemistry. Results Significant mechanical hyperalgesia was induced on day 8 in FM mice, which was reversed by 2, 15 and 50 Hz EA. ASIC3, Nav1.7 and Nav1.8 protein levels increased significantly in both the dorsal root ganglion and in the spinal cord of FM model mice. These changes were further attenuated by 2, 15 and 50 Hz EA. Conclusion Reduced nociceptive ASIC3, Nav1.7 and Nav1.8 proteins are involved in the preventive effects of EA against FM, and this series of molecules may represent targets for FM treatment.

scholarly journals Gene Knockdown of the N -Methyl-d-Aspartate Receptor NR1 Subunit with Subcutaneous Small Interfering RNA Reduces Inflammation-induced Nociception in Rats

2010 ◽  
Vol 112 (6) ◽  
pp. 1482-1493 ◽  
Author(s):  
Ping-Heng Tan ◽  
Yuan-Yi Chia ◽  
Lok-Hi Chow ◽  
Jieh-Jie Chen ◽  
Lin-Cheng Yang ◽  
...  
Keyword(s):  
Nervous System ◽  
Dorsal Root Ganglion ◽  
Subcutaneous Injection ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Complete Freund’S Adjuvant ◽  
Aspartate Receptor ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant

Background Spinal N-methyl-D-aspartate receptors have been demonstrated to play an important role in the facilitation and maintenance of nociception. To avoid adverse effects of blocking N-methyl-D-aspartate receptors in the central nervous system, blocking N-methyl-D-aspartate receptor in peripheral nervous system is an ideal alternative. Transfection of small interfering RNAs (siRNAs) into cells has been revealed to provide potent silencing of specific genes. In this study, the authors examined the effect of subcutaneous injection of siRNA targeting the NR1 subunit of the N-methyl-D-aspartate receptor on silencing NR1 gene expression and subsequently abolishing inflammatory nociception in rats. Methods Male Sprague-Dawley rats received intradermal injection of NR1 siRNA and underwent injection of formalin or complete Freund's adjuvant. The flinch response and mechanical hypersensitivity by von Frey filaments were assessed. Then the messenger RNA and protein of NR1 in skin and dorsal root ganglion were analyzed. Results The results revealed that subcutaneous injection of 1 nmol NR1 siRNA effectively diminished the nociception induced by formalin and complete Freund's adjuvant stimuli and attenuated the level of NR1 messenger RNA and protein in skin and ipsilateral dorsal root ganglion. The antinociception effect and the inhibition of NR1 expression persisted for about 7 days after administration of NR1 siRNA. Conclusions The data of this study suggest that NR1 siRNA has potential therapeutic value in the treatment of inflammatory pain induced or maintained by peripheral nociceptor activity and support the potential application of this method to the study of nociceptive processes and target the validation of pain-associated genes.

scholarly journals 5-Hydroxytryptamine Type 3 Receptor Modulates Opioid-induced Hyperalgesia and Tolerance in Mice

2011 ◽  
Vol 114 (5) ◽  
pp. 1180-1189 ◽  
Author(s):  
De-Yong Liang ◽  
XiangQi Li ◽  
J. David Clark
Keyword(s):  
Spinal Cord ◽  
Dorsal Root Ganglion ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Intrathecal Injection ◽  
Tail Flick ◽  
Intraplantar Injection ◽  
Morphine Administration ◽  
Opioid Induced Hyperalgesia ◽  
Type 3

Background Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxytryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems. Methods C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail-flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA concentrations by real-time polymerase chain reaction or immunochemistry analysis. Results The results showed that (1) systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection; (2) systemic or intrathecal injection of ondansetron prevented and reversed tolerance; and (3) ondansetron blocked morphine-induced increases of multiple genes relevant to OIH and tolerance in dorsal root ganglion and spinal cord. Conclusions Morphine acts via a 5-HT3-dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use.

Short Hairpin RNA–mediated Selective Knockdown of NaV1.8 Tetrodotoxin-resistant Voltage-gated Sodium Channel in Dorsal Root Ganglion Neurons

2005 ◽  
Vol 103 (4) ◽  
pp. 828-836 ◽  
Author(s):  
Maya Mikami ◽  
Jay Yang
Keyword(s):  
Dorsal Root Ganglion ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Short Hairpin Rna ◽  
Dorsal Root Ganglion Neurons ◽  
Hairpin Rna ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Short Hairpin ◽  
Ganglion Neurons

Background Voltage-gated sodium channels comprise a family of closely related proteins, each subserving different physiologic and pathologic functions. NaV1.8 is an isoform of voltage-gated sodium channel implicated in the pathogenesis of inflammatory and neuropathic pain, but currently, there is no isoform-specific inhibitor of any voltage-gated sodium channels. The authors explored the possibility of short hairpin RNA-mediated selective knockdown of NaV1.8 expression. Methods DNA constructs designed to transcribe short hairpin RNA targeting NaV1.8 were created and incorporated into recombinant lentiviruses. The virus-induced selective knockdown of NaV1.8 was examined at the protein, messenger RNA, and functional levels using Western blot, immunohistochemistry, reverse-transcription polymerase chain reaction, and patch clamp electrophysiology. Results Transduction of HEK293 cells stably expressing NaV1.8 or primary dorsal root ganglion neurons with lentivirus expressing short hairpin RNA resulted in the knockdown of NaV1.8 protein and messenger RNA concentrations. Whole cell patch clamp recordings confirmed decrease in the NaV1.8-mediated current density without changes in other biophysical properties. Conclusions A selective knockdown of NaV1.8 expression in dorsal root ganglion neurons can be attained by short hairpin RNA delivered with lentivirus. This method may provide a new gene therapy approach to controlling neuronal hyperexcitability and pathologic pain.

scholarly journals Modulation of Spinal GABAergic Inhibition and Mechanical Hypersensitivity following Chronic Compression of Dorsal Root Ganglion in the Rat

2015 ◽  
Vol 2015 ◽  
pp. 1-12
Author(s):  
Moon Chul Lee ◽  
Taick Sang Nam ◽  
Se Jung Jung ◽  
Young S. Gwak ◽  
Joong Woo Leem
Keyword(s):  
Dorsal Root Ganglion ◽  
Early Phase ◽  
Dorsal Root ◽  
Neuronal Excitability ◽  
Late Phase ◽  
Gabaergic Inhibition ◽  
Mechanical Sensitivity ◽  
Gaba A ◽  
Mechanical Hypersensitivity ◽  
Injured Side

Chronic compression of dorsal root ganglion (CCD) results in neuropathic pain. We investigated the role of spinal GABA in CCD-induced pain using rats with unilateral CCD. A stereological analysis revealed that the proportion of GABA-immunoreactive neurons to total neurons at L4/5 laminae I–III on the injured side decreased in the early phase of CCD (post-CCD week 1) and then returned to the sham-control level in the late phase (post-CCD week 18). In the early phase, the rats showed an increase in both mechanical sensitivity of the hind paw and spinal WDR neuronal excitability on the injured side, and such increase was suppressed by spinally applied muscimol (GABA-A agonist, 5 nmol) and baclofen (GABA-B agonist, 25 nmol), indicating the reduced spinal GABAergic inhibition involved. In the late phase, the CCD-induced increase in mechanical sensitivity and neuronal excitability returned to pre-CCD levels, and such recovered responses were enhanced by spinally applied bicuculline (GABA-A antagonist, 15 nmol) and CGP52432 (GABA-B antagonist, 15 nmol), indicating the regained spinal GABAergic inhibition involved. In conclusion, the alteration of spinal GABAergic inhibition following CCD and leading to a gradual reduction over time of CCD-induced mechanical hypersensitivity is most likely due to changes in GABA content in spinal GABA neurons.

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

2013 ◽  
Vol 304 (4) ◽  
pp. G311-G321 ◽  
Author(s):  
Shufen Hu ◽  
Ying Xiao ◽  
Liyan Zhu ◽  
Lin Li ◽  
Chuang-Ying Hu ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Sodium Channel ◽  
Dorsal Root ◽  
Maternal Deprivation ◽  
Male Rats ◽  
Drg Neurons ◽  
Protein Levels ◽  
Leftward Shift ◽  
Enhanced Expression ◽  
Ganglion Neurons

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain in association with altered bowel movements. The underlying mechanisms of visceral hypersensitivity remain elusive. This study was designed to examine the role for sodium channels in a rat model of chronic visceral hyperalgesia induced by neonatal maternal deprivation (NMD). Abdominal withdrawal reflex (AWR) scores were performed on adult male rats. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch-clamp configurations. The expression of NaV1.8 was analyzed by Western blot and quantitative real-time PCR. NMD significantly increased AWR scores, which lasted for ∼6 wk in an association with hyperexcitability of colon DRG neurons. TTX-resistant but not TTX-sensitive sodium current density was greatly enhanced in colon DRG neurons in NMD rats. Compared with controls, activation curves showed a leftward shift in NMD rats whereas inactivation curves did not differ significantly. NMD markedly accelerated the activation time of peak current amplitude without any changes in inactivation time. Furthermore, NMD remarkably enhanced expression of NaV1.8 at protein levels but not at mRNA levels in colon-related DRGs. The expression of NaV1.9 was not altered after NMD. These data suggest that NMD enhances TTX-resistant sodium activity of colon DRG neurons, which is most likely mediated by a leftward shift of activation curve and by enhanced expression of NaV1.8 at protein levels, thus identifying a specific molecular mechanism underlying chronic visceral pain and sensitization in patients with IBS.

scholarly journals Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain

2019 ◽  
Vol 20 (4) ◽  
pp. 811 ◽  
Author(s):  
Mei Kwan ◽  
Anthony Choo ◽  
Taleen Hanania ◽  
Afshin Ghavami ◽  
Jose Beltran ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Rat Model ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Caspase 3 ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Oral Dosing ◽  
Protein Levels

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.

Oxaliplatin Regulates Chemotherapy Induced Peripheral Neuropathic Pain in the Dorsal Horn and Dorsal Root Ganglion via the Calcineurin/NFAT Pathway

2018 ◽  
Vol 18 (8) ◽  
pp. 1197-1207 ◽  
Author(s):  
Wan Huang ◽  
Jingxiu Huang ◽  
Yu Jiang ◽  
Xuanwei Huang ◽  
Wei Xing ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Dorsal Horn ◽  
Rat Model ◽  
Dorsal Root ◽  
Mrna Level ◽  
Control Group ◽  
Activated T Cells ◽  
Withdrawal Threshold ◽  
Protein Levels

Objective: The aim of this study was to investigate the mechanism of oxaliplatin in the induction of neuropathic pain as a symptom of Chemotherapy-Induced Peripheral Neuropathy (CIPN). Methods: The CIPN rat model was induced with a one-time injection of oxaliplatin, and the paw withdrawal response was determined using von Frey filaments. The Paw Withdrawal Threshold (PWT) value was recorded and the Dorsal Horn (DH) and Dorsal Root Ganglion (DRG) tissues were collected. The mRNA and protein levels of Calcineurin (CaN), Nuclear Factor of Activated T cells (NFAT), and other relevant cytokines were determined. CaN and NFAT inhibition reagents, FK506 and 11R-VIVIT, were applied in order to investigate the functions of the CaN/NFAT pathway in the neuropathic pain processes. The levels of the downstream inflammatory cytokines, TNF-α and IL-1β, were assessed by ELISA. Results: The application of oxaliplatin reduced the value of PWT by 4 times on days 7（4±1.33）and 14（5.13±3.07）compared with the control group(14±0.91; 13.67±0.76). After treatment, the CaN mRNA level decreased and that of NFAT increased in DH and DRG tissues (P<0.05). However, treatment with FK506 and 11R-VIVIT decreased the value of PWT that had increased after oxaliplatin treatment. The expression of downstream cytokines related to the CaN/NFAT pathway increased, including CCR2, COX2, p-ERK, and p-P38 (all p<0.05). In addition, when the CaN/NFAT pathway was activated, the concentration of TNFα increased to 40pg/mg in DH tissues and 60pg/mg in DRG tissues compared with the control group, while the concentration of IL-1β increased to over 60pg/mg in DH and DRG tissues. Conclusion: It was the first time to prove that oxaliplatin-induced neuropathic pain was correlated to the activation of the CaN/NFAT pathway in our rat model. This finding can provide a new direction to explore the mechanism of oxaliplatin-induced neuropathic pain.

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

2020 ◽  
Vol 12 (569) ◽  
pp. eaba9188 ◽  
Author(s):  
Juliette Hordeaux ◽  
Elizabeth L. Buza ◽  
Brianne Jeffrey ◽  
Chunjuan Song ◽  
Tahsin Jahan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dorsal Root Ganglion ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Transgene Expression ◽  
Target Cells ◽  
Drg Neurons ◽  
Gene Therapies ◽  
Endogenous Expression

Delivering adeno-associated virus (AAV) vectors into the central nervous system of nonhuman primates (NHPs) via the blood or cerebral spinal fluid is associated with dorsal root ganglion (DRG) toxicity. Conventional immune-suppression regimens do not prevent this toxicity, possibly because it may be caused by high transduction rates, which can, in turn, cause cellular stress due to an overabundance of the transgene product in target cells. To test this hypothesis and develop an approach to eliminate DRG toxicity, we exploited endogenous expression of microRNA (miR) 183 complex, which is largely restricted to DRG neurons, to specifically down-regulate transgene expression in these cells. We introduced sequence targets for miR183 into the vector genome within the 3′ untranslated region of the corresponding transgene messenger RNA and injected vectors into the cisterna magna of NHPs. Administration of unmodified AAV vectors resulted in robust transduction of target tissues and toxicity in DRG neurons. Consistent with the proposal that immune system activity does not mediate this neuronal toxicity, we found that steroid administration was ineffective in alleviating this pathology. However, including miR183 targets in the vectors reduced transgene expression in, and toxicity of, DRG neurons without affecting transduction elsewhere in the primate’s brain. This approach might be useful in reducing DRG toxicity and the associated morbidity and should facilitate the development of AAV-based gene therapies for many central nervous system diseases.

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