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Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway., (© 2024 Federation of American Societies for Experimental Biology.)

Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAG CamkIIα+ neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAG CamkIIα+ neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAG CamkIIα+ neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in alleviating these symptoms. Nevertheless, EA combined with chemogenetic activation failed to further relieve allodynia and anxiety-like behaviors. Artificial inhibition of vlPAG CamkIIα+ neurons abolished the analgesic and anxiolytic effects of EA. Overall, our study reveals a novel mechanism of neuropathic pain-induced anxiety and shows that EA may relieve comorbid chronic neuropathic pain and anxiety by activating vlPAG CamkIIα+ neurons., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Zhu et al.)

Chronic neuropathic pain and comorbid depression syndrome (CDS) is a major worldwide health problem that affects the quality of life of patients and imposes a tremendous socioeconomic burden. More than half of patients with chronic neuropathic pain also suffer from moderate or severe depression. Due to the complex pathogenesis of CDS, there are no effective therapeutic drugs available. The lack of research on the neural circuit mechanisms of CDS limits the development of treatments. The purpose of this article is to provide an overview of the various circuits involved in CDS. Notably, activating some neural circuits can alleviate pain and/or depression, while activating other circuits can exacerbate these conditions. Moreover, we discuss current and emerging pharmacotherapies for CDS, such as ketamine. Understanding the circuit mechanisms of CDS may provide clues for the development of novel drug treatments for improved CDS management.

Background: Stimulation of dorsal root ganglion (DRG) is an ideal neuromodulative intervention, providing pain relief in localized chronic pain conditions because γ-band oscillations reflect the intensity of ongoing chronic pain in patients affected., Objective: We aimed to observe the role of cortical γ-band power associated with the relief of chronic neuropathic pain through DRG stimulation (DRGS)., Materials and Methods: We examined nine patients (two women, mean age 56.8 years; range, 36-77 years) diagnosed with chronic neuropathic pain who underwent DRGS therapy. We used the numeric rating scale (NRS) on the painful limb and simultaneously recorded the electroencephalography to assess the broadband γ power. Assessments were conducted on the first day and on the seventh day after implantation of the DRGS system and then compared and correlated with the results of the NRS., Results: The NRS scores showed a significant decrease from the first day to the seventh day (p = 0.007). The resting-state γ power revealed a significant decrease (p = 0.021) between 30 and 45 Hz, recorded through the central electrode contralateral to the painful limb from the first day (mean [M] = 0.46, SD = 0.25) to the seventh day (M = 0.31, SD = 0.12) after DRGS. There was no significant change in the resting-state γ-band power recorded through the central electrode ipsilateral to the painful limb. However, we found a positive correlation in the γ-band power (r s  = 0.628, p = 0.005) with the NRS rating., Conclusions: A lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system., Competing Interests: Conflict of Interest Matthias Hubert Morgalla has been a speaker for Abbott. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos + neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors. Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine- N -oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

Background: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD., Methods: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1., Results: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin., Conclusion: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP., Methods: We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p., Results: The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats., Conclusion: Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP., (© 2024. The Author(s).)

Objectives: Tropisetron is an alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist and is a commonly used antiemetic clinically. α7nAChRs activation modulating nociception transmissions and cholinergic anti-inflammation may decrease neuropathic pain. This study was set to investigate the effects of tropisetron on neuropathic pain and neuroinflammation as well as the underlying mechanisms in rats., Methods: Neuropathic pain behavior was assessed in rats using the paw mechanical withdrawal threshold and paw thermal withdrawal latency before and after the establishment of a spared nerve injury (SNI) pain model in rats treated with tropisetron treatment in the presence or absence of the α7nAChR antagonist methyllycaconitine (MLA) through intrathecal injection. Their spinal cords were then harvested for inflammatory cytokines, the α7nAChR, p38 mitogen-activated protein kinase (p-p38MAPK) and cAMP-response element binding protein (CREB) measurement., Results: Tropisetron effectively alleviated mechanical allodynia and thermal hyperalgesia; decreased IL-6, IL-1ß and TNF-a; and down-regulated the phosphorylation of p38MAPK and CREB. Pre-treatment with MLA abolished these effects of tropisetron., Conclusion: Our data indicate that tropisetron alleviates neuropathic pain may through inhibition of the p38MAPK-CREB pathway via α7nAChR activation. Thus, tropisetron may be a potential new therapeutic strategy for chronic neuropathic pain.

Background and Aims: The dysgranula parts of the posterior insular cortex (PIC) stimulation (PICS) has been investigated as a new putative cortical target for nonpharmacologic therapies in patients with chronic and neuropathic pain (NP). This work investigates the neural bases of insula neurostimulation-induced antinociception and glutamatergic neurochemical mechanisms recruited by the PICS in animals with neuropathy., Materials and Methods: Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham procedure ("false operated"). Either the Cascade Blue 3000 MW lysine-fixable dextran (CBD) or the biotinylated dextran amine 3000 MW (BDA) neural tract tracer was microinjected into the PIC. The electrical PICS was performed at a low frequency (20 μA, 100 Hz) for 15 seconds by a deep brain stimulation device. PIC N-methyl-D-aspartate (NMDA) receptors (NMDAR) blockade with the selective antagonist LY235959 (at 2, 4, and 8 nmol/200 nL) followed by PICS was investigated in rats with CCI., Results: PIC sends projections to the caudal pontine reticular nucleus, alpha part of the parvicellular reticular nucleus, dorsomedial tegmental area, and secondary somatosensory cortex (S 2 ). PICS decreased both mechanical and cold allodynia in rats with chronic NP. Blockade of NMDAR in the PIC with LY235959 at 8 nmol attenuated PICS-produced antinociception., Conclusion: Neuroanatomic projections from the PIC to pontine reticular nuclei and S 2 may contribute to chronic NP signaling. PICS attenuates the chronic NP, and the NMDA glutamatergic system in the PIC may be involved in PICS-induced antinociception in rodents with NP conditions., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Aims: Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety-like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated., Methods: The effects of EA stimulation on mechanical allodynia and anxiety-like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACC Glu ) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety-like behaviors in SNI mice., Results: Electroacupuncture significantly alleviated both mechanical allodynia and anxiety-like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACC Glu -DRN projections attenuated both mechanical allodynia and anxiety-like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACC Glu -DRN pathway did not induce mechanical allodynia and anxiety-like behaviors under physiological conditions, but inhibiting this pathway produced anxiety-like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACC Glu -DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACC Glu -DRN pathway., Conclusions: The role of rACC Glu -DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACC Glu -DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety-like behaviors., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 μA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl 2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl 2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Spinal arachnoid cysts (SACs) arise either intra- or extradurally and are usually solitary, while cases of multiple SACs have been scarcely reported in the literature. Herein, we report on a rare case of multiple and recurring intradural spinal arachnoid cysts (SACs) causing severe spinal cord compression and neuropathic radicular pain, in a 35-year-old female with a 10-year follow-up. Two separate attempts at surgery were performed but only provided temporary relief since the cysts recurred and new ones formed along the entirety of the spinal cord. Finally, a conservative approach with physiotherapy and a combination of analgesic medications was pursued., (© 2023. The Author(s).)

Depression has a high rate of comorbidity with neuropathic pain. This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the Acanthoscurria gomesiana spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive-like behavior) tests. BDA neural tract tracer-labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N-methyl-D-aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive-like effects, and the NMDA agonist reversed these effects., (© 2023 Wiley Periodicals LLC.)

Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dou, Chen, Yang, Dai, Long, Sun and Lin.)

Astrocyte activation in the spinal dorsal horn may play an important role in the development of chronic neuropathic pain, but the mechanisms involved in astrocyte activation and their modulatory effects remain unknown. The inward rectifying potassium channel protein 4.1 (Kir4.1) is the most important background K + channel in astrocytes. However, how Kir4.1 is regulated and contributes to behavioral hyperalgesia in chronic pain is unknown. In this study, single-cell RNA sequencing analysis indicated that the expression levels of both Kir4.1 and Methyl-CpG-binding protein 2 (MeCP2) were decreased in spinal astrocytes after chronic constriction injury (CCI) in a mouse model. Conditional knockout of the Kir4.1 channel in spinal astrocytes led to hyperalgesia, and overexpression of the Kir4.1 channel in spinal cord relieved CCI-induced hyperalgesia. Expression of spinal Kir4.1 after CCI was regulated by MeCP2. Electrophysiological recording in spinal slices showed that knockdown of Kir4.1 significantly up-regulated the excitability of astrocytes and then functionally changed the firing patterns of neurons in dorsal spinal cord. Therefore, targeting spinal Kir4.1 may be a therapeutic approach for hyperalgesia in chronic neuropathic pain., Competing Interests: Competing interests The authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To investigate the role of DNA methylation in modulating chronic neuropathic pain (NPP), identify possible target genes of DNA methylation involved in this process, and preliminarily confirm the medicinal value of the DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AZA) in NPP by targeting gene methylation. Two rat NPP models, chronic constriction injury (CCI) and spinal nerve ligation (SNL), were used. The DNA methylation profiles in the lumbar spinal cord were assayed using an Arraystar Rat RefSeq Promoter Array. The underlying genes with differential methylation were then identified and submitted to Gene Ontology and pathway analysis. Methyl-DNA immunoprecipitation quantitative PCR (MeDIP-qPCR) and quantitative reverse transcription-PCR (RT-qPCR) were used to confirm gene methylation and expression. The protective function of 5-AZA in NPP and gene expression were evaluated via behavioral assays and RT-qPCR, respectively. Analysis of the DNA methylation patterns in the lumbar spinal cord indicated that 1205 differentially methylated fragments in CCI rats were located within DNA promoter regions, including 638 hypermethylated fragments and 567 hypomethylated fragments. The methylation levels of Grm4, Htr4, Adrb2, Kcnf1, Gad2, and Pparg, which are associated with long-term potentiation (LTP) and glutamatergic synapse pathways, were increased with a corresponding decrease in their mRNA expression, in the spinal cords of CCI rats. Moreover, we found that the intraperitoneal injection of 5-AZA (4 mg/kg) attenuated CCI- or SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, the mRNA expression of hypermethylated genes such as Grm4, Htr4, Adrb2, Kcnf1, and Gad2 was reversed after 5-AZA treatment. CCI induced widespread methylation changes in the DNA promoter regions in the lumbar spinal cord. Intraperitoneal 5-AZA alleviated hyperalgesia in CCI and SNL rats, an effect accompanied by the reversed expression of hypermethylated genes. Thus, DNA methylation inhibition represents a promising epigenetic strategy for protection against chronic NPP following nerve injury. Our study lays a theoretical foundation for 5-AZA to become a clinical targeted drug., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathic pain is a common chronic condition, which remains poorly understood. Many patients receiving treatment continue to experience severe pain, due to limited diagnostic/treatment management programmes. The development of objective clinical diagnostic/treatment strategies requires identification of robust biomarkers of neuropathic pain. To this end, we looked to identify biomarkers of chronic neuropathic pain by assessing gene expression profiles in an animal model of neuropathic pain, and differential gene expression in patients to determine the potential translatability. We demonstrated cross-species validation of several genes including those identified through bioinformatic analysis by assessing their expression in blood samples from neuropathic pain patients, according to conservative assessments of significance measured using Bonferroni-corrected p-values. These include CASP5 (p = 0.00226), CASP8 (p = 0.00587), CASP9 (p = 2.09 × 10 -9 ), FPR2 (p = 0.00278), SH3BGRL3 (p = 0.00633), and TMEM88 (p = 0.00038). A ROC analysis revealed several combinations of genes to show high levels of discriminatory power in the comparison of neuropathic pain patients and control participants, of which the combination SH3BGRL3, TMEM88, and CASP9 achieved the highest level (AUROC = 0.923). The CASP9 gene was found to be common in five combinations of three genes revealing the highest levels of discriminatory power. In contrast, the gene combination PLAC8, ROMO1, and A3GALT2 showed the highest levels of discriminatory power in the comparison of neuropathic pain and nociceptive pain (AUROC = 0.919), when patients were grouped by S-LANSS scores. Molecules that demonstrate an active role in neuropathic pain have the potential to be developed into a biological measure for objective diagnostic tests, or as novel drug targets for improved pain management., (© 2022. The Author(s).)

Neuropathic pain is a risk factor for cognitive defects. The ubiquitous expression of AQP4 in astrocytes throughout the central nervous system is altered in the neurodegenerative disease. However, the exact role of AQP4 in cognitive impairment induced by chronic neuropathic pain remains unclear. In this study, we discovered that AQP4 protein and mRNA expression decreased time-dependently in the model of chronic neuropathic pain-induced cognitive disorder. AQP4 overexpression recovered mice from cognitive impairment. Furthermore, the concentration of Aβ1-42 in the serum and hippocampus reduced in mice with AQP4 overexpression adeno-associated virus injection. In conclusion, AQP4 in astrocytes is important in mitigating cognitive impairment caused by chronic neuropathic pain., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Neuropathic pain is a complication after groin hernia surgery. Triple neurectomy of the iliohypogastric nerve, ilioinguinal nerve and genitofemoral nerve is an efficient treatment modality, with several surgical approaches. The minimally invasive endoscopic method to neurectomy was specifically investigated in this meta-analysis. Our aim is to determine the efficacy of this method in the treatment of chronic neuropathic pain posthernia repair surgery., Methods: A systematic review was conducted using four databases to search for the keywords ("endoscopic retroperitoneal neurectomy" and "laparoscopic retroperitoneal neurectomy"). The NCBI National Library of Medicine, Cochrane Library, MEDLINE Complete and BioMed Central were last searched on 26 May 2022. Randomised control trials and retrospective or prospective papers involving endoscopic retroperitoneal neurectomy operations after inguinal hernia repair were included. All other surgeries, procedures and study designs were excluded. The internal quality of included studies was assessed using the Newcastle-Ottawa Scale. The percentage of patients who had reduction in pain ("positive treatment outcome") was used to assess the procedure's effectiveness in each analysis., Results: Five comparable endoscopic retroperitoneal neurectomy studies with a total of 142 patients were analysed. Both the Wald test (Q (6) = 1.79, = .775) and the probability ratio test (Q (6) = 4.24, = .374) provide similar findings (0.000, 0.0% [0.0%; 78%]). The meta-analysis' key finding is that the intervention was up to 78% effective (95% confidence interval, 71%; 84%)., Conclusion: Endoscopic retroperitoneal neurectomy can be an effective treatment option for postoperative neuropathic pain relief following surgical hernia repair. Although there is limited reported experience with this technique, it may provide a clinical benefit to the patient. We recommend further prospective data and long-term follow-up studies be conducted to confirm and expand on these outcomes., (© 2023. The Author(s).)

In neuropathic pain clinical trials, the patient's perspective is often insufficiently reflected focusing mainly on pain intensity. Comparability of outcome assessment is limited due to heterogenous patient reported outcome measures (PROMs). The MEDLINE, CENTRAL, and Embase databases and reference lists of published meta-analyses were searched. Randomized controlled studies assessing treatment efficacy of drugs for chronic neuropathic pain were included. PROMs were assigned to recommended IMMPACT/NeuPSIG domains: pain intensity, pain other aspects, physical functioning, emotional functioning, global improvement and satisfaction, adverse events, participant disposition. Domains and PROMs were compared regarding the publication year and methodological quality of the studies. Within the 251 included studies 200 PROMs were used with 27 being recommended by IMMPACT/NeuPSIG. The number of domains was higher in high/moderate quality studies. The (sub-) domains 'physical functioning', 'global improvement and satisfaction', and 'neuropathic pain quality' were assessed more frequently in high/moderate quality studies and those published after 2011. Recent studies and those of better quality more often used the recommended PROMs. Although neuropathic assessment via PROMs has improved, there is still a high heterogeneity. A standardized core set of outcome domains and should be defined to improve neuropathic pain treatment and to achieve better comparability of clinical trials. Perspective: This systematic literature review assesses the use of patient reported outcome measures (PROMs) in chronic neuropathic pain. The results show that there is still a high heterogeneity, highlighting the need for a standardized core set of outcome domains and PROMs to improve comparability of clinical trials and neuropathic pain treatment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic neuropathic pain often leads to cognitive impairment, but the exact mechanism remains unclear. Gamma-aminobutyric acid A receptors (GABA A Rs) are the major inhibitory receptors in the brain, of which the α5-containing GABA A Rs (GABA A Rs-α5) are implicated in a range of neuropsychiatric disorders with cognitive deficits. However, whether GABA A Rs-α5 are involved in chronic neuropathic pain-related cognitive impairment remains unknown. In this study, the rats with chronic neuropathic pain induced by right sciatic nerve ligation injury (SNI) exhibited cognitive impairment with declined spontaneous alternation in Y-maze test and discrimination index in novel object recognition test. The GABA A Rs-α5 expressing on parvalbumin and somatostatin interneurons increased remarkably in hippocampus, resulting in decreased mean frequency of spontaneous inhibitory postsynaptic currents in hippocampal pyramidal neurons. Significantly, antagonizing the GABA A Rs-α5 by L655708 rescued weakened inhibitory synaptic transmission and cognitive impairment induced by chronic neuropathic pain. Taken together, these data suggest that the GABA A Rs-α5 play a crucial role in chronic neuropathic pain-induced cognitive impairment by weakening inhibitory synaptic transmission, which may provide insights into the pharmacologic treatment of chronic neuropathic pain-related cognitive impairment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate the impact of Mindfulness-Based Stress Reduction (MBSR) on gray matter volume (GMV) in female breast cancer survivors who suffer from chronic neuropathic pain (CNP)., Methods: Voxel-based morphometry (VBM) was used to explore differences in GMV in 13 MBSR trainees and 10 waitlisted controls, with MRI scans and self-report measures completed pre- and post-8 weeks of training., Results: Compared to controls, the MBSR group had greater GMV in the angular gyrus and middle frontal gyrus post-training. The MBSR group's right parahippocampal gyrus GMV increased from pre- to post-training, whereas the control group's left parahippocampal gyrus, precuneus, middle temporal gyrus, and right cuneus GMV decreased over the same time period. Pain interference was significantly reduced and mindfulness was significantly increased following MBSR for the intervention group only., Conclusions: MBSR was associated with increased GMV in regions where GMV is known to (1) increase with mindfulness and reorientation of attention and (2) decrease with the experience of chronic neuropathic pain. By contrast, the control group's decreases in GMV may be due to the negative effects of CNP which potentially may be reduced with MBSR, though further research is needed., Implications for Cancer Survivors: Given the poor efficiency of pharmacotherapies in a high percentage of women with neuropathic pain following breast cancer treatment, adjunct methods are required. MBSR may affect the brain to help alter attention and perception of pain, thus playing a potentially important role in the path to wellness for breast cancer survivors., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Current treatments for chronic neuropathic pain often fall short. A small-molecular compound ZL006 can suppress N-Methyl-d-aspartate receptor (NMDAR)-mediated neuropathic pain behaviors without blocking essential NMDAR function and brings new hope for neuropathic pain therapy. The persistent nature of neuropathic pain mandates the long-term treatment. However, similar to existing analgesics, ZL006 has only a short duration of action. To unleash the therapeutic potential of ZL006, the stability of ZL006 in aqueous solutions is investigated, and a ZL006-incorporated P407-based thermoresponsive injectable hydrogel is developed. The computational analysis is performed to help achieve the desired ZL006-loaded hydrogel system and elucidate the gelation mechanism. The hydrogel matrix can be loaded with ZL006 in an aqueous phase at room temperature without costly specialized equipment and no organic solvent, where the sol is formed and injectable. On subcutaneous administration and subsequent rapid warming to physiological temperature, the sol is converted to a gel. The thermoresponsive hydrogel at body temperature enables the extended release of encapsulated ZL006, and therefore a single subcutaneous injection of ZL006-hydrogel produces a prolonged and stable analgesic action in mice with spinal nerve ligation. The study provides a practical chronic neuropathic pain therapy and a new perspective on future applications of ZL006., (© 2022 Wiley-VCH GmbH.)

Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The management of chronic neuropathic pain remains a challenge, because pain is subjective, and measuring it objectively is usually out of question. However, neuropathic pain is also a signal provided by maladaptive neuronal activity. Thus, the integral management of chronic neuropathic pain should not only rely on the subjective perception of the patient, but also on objective data that measures the evolution of neuronal activity. We will discuss different objective and subjective methods for the characterization of neuropathic pain. Additionally, the gaps and proposals for an integral management of chronic neuropathic pain will also be discussed. The current management that relies mostly on subjective measures has not been sufficient, therefore, this has hindered advances in pain management and clinical trials. If an integral characterization is achieved, clinical management and stratification for clinical trials could be based on both questionnaires and neuronal activity. Appropriate characterization may lead to an increased effectiveness for new therapies, and a better quality of life for neuropathic pain sufferers., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Dorsal root ganglion stimulation (DRGS) is able to relieve chronic neuropathic pain. There seems evidence that DRGS might achieve this by gradually influencing pain pathways. We used laser-evoked potentials (LEP) to verify our hypothesis that the recovery of the LEP may reflect DRGS-induced changes within the nociceptive system., Methods: Nine patients (mean age 56.8 years, range 36-77 years, two females) diagnosed with chronic neuropathic pain in the knee or groin were enrolled in the study. We measured each patient's LEP at the painful limb and contralateral control limb on the first, fourth, and seventh day after implantation of the DRGS system. We used the numeric rating scale (NRS) for the simultaneous pain assessment., Results: The LEP amplitude of the N2-P2 complex showed a significant increase on day 7 when compared to day 1 (Z = -2.666, p = 0.008) and to day 4 (Z = -2.547, p = 0.011), respectively. There was no significant difference in the N2-P2 complex amplitude between ON and OFF states during DRGS. The patients' NRS significantly decreased after 1 day (p = 0.007), 4 days (p = 0.007), and 7 days (p = 0.007) when compared to the baseline., Conclusions: The results show that with DRGS, the LEP recovered gradually within 7 days in neuropathic pain patients. Therefore, reduction of the NRS in patients with chronic neuropathic pain might be due to DRGS-induced processes within the nociceptive system. These processes might indicate neuroplasticity mediated recovery of the LEP., (© 2021 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Background: Motor cortex stimulation (MCS) is proper as a non-pharmacological therapy for patients with chronic and neuropathic pain (NP)., Aims: This work aims to investigate if the MCS in the primary motor cortex (M 1 ) produces analgesia and how the MCS could interfere in the MCS-induced analgesia. Also, to elucidate if the persistent activation of N-methyl-d-aspartic acid receptor (NMDAr) in the periaqueductal grey matter (PAG) can contribute to central sensitisation of the NP., Methods: Male Wistar rats were submitted to the von Frey test to evaluate the mechanical allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve. The MCS was performed with low-frequency (20 μA, 100 Hz) currents during 15 s by a deep brain stimulation (DBS) device. Moreover, the effect of M 1 -treatment with an NMDAr agonist (at 2, 4, and 8 nmol) was investigated in CCI rats. The PAG dorsomedial column (dmPAG) was pretreated with the NMDAr antagonist LY 235959 (at 8 nmol), followed by MCS., Results: The MCS decreased the mechanical allodynia in rats with chronic NP. The M 1 -treatment with an NMDA agonist at 2 and 8 nmol reduced the mechanical allodynia in CCI rats. In addition, dmPAG-pretreatment with LY 235959 at 8 nmol attenuated the mechanical allodynia evoked by MCS., Conclusion: The M 1 cortex glutamatergic system is involved in the modulation of chronic NP. The analgesic effect of MCS may depend on glutamate signaling recruitting NMDAr located on PAG neurons in rodents with chronic NP., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To observe the effect of electroacupuncture (EA) on the expression of Toll like receptor 4(TLR4)and heat shock protein 90(HSP90) in the spinal cord of rats with chronic constriction injury (CCI) of sciatic nerve, so as to explore the mechanism of spinal cord TLR4 and HSP90 in alleviating chronic neuropathic pain by EA., Methods: Male Wistar rats were randomized into control, model, EA, HSP90 inhibitor (inhibitor) and EA+ inhibitor groups ( n =10 in each group). The neuropathic pain model was established by ligature of the right sciatic nerve to induce CCI. EA (1 mA，2 Hz/15 Hz)was applied at bilateral "Zusanli"(ST36) and "Yanglingquan"(GB34) for 30 min, once daily for 5 days. Rats of the inhibitor and EA+inhibitor groups were given a subcutaneous injection of HSP90 inhibitor geldanamycin (50 μg/kg) at the neck before daily EA. The paw withdrawal latency (PWL) of the bilateral hind-limbs was detected by using an algesia-detector. The contents of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the lumbar spinal cord (L2-L4) tissue were detected by enzyme-linked immunosorbent assay. The relative expression levels of HSP90 and TLR4 proteins in the lumbar spinal cord (L2-L4) were detected using Western blot and immunofluorescence double labeling, respectively., Results: Following CCI, a strong thermal hyperalgesia, an apparent up-regulation of expression of HSP90 and TLR4 proteins and TLR4 in microglia, and increasing levels of IL-1β and TNF-α in the spinal cord were induced in the model group relevant to the control group ( P <0.01， P <0.05). Five sessions of EA intervention or inhibitor injection significantly attenuated hyperalgesia, reversed the increase of IL-1β and TNF-α, and down-regulated the expression of TLR4 in microglia ( P <0.05). Compared with the model group, the expression of HSP90 was further increased ( P <0.05), and those of TLR4 in microglia and neurons were significantly decreased and increased, respectively in the EA group ( P <0.05). Compared with the EA group, the levels of PWLD,TLR4 and HSP90 expression, and the proportions of neuronal nuclei antigen（NeuN） and TLR4, and ionized calcium binding adapter molecule （Iba1） and TLR4 co-expressed cells were significantly decreased in the inhibitor group and EA+inhibitor group ( P <0.05). The proportion of NeuN and TLR4 co-expression cells in the EA+inhibitor group was significantly higher than that of the inhibitor group ( P <0.05)., Conclusion: EA stimulation of ST36 and GB34 can alleviate thermal hyperalgesia in CCI rats, which is closely associated with its effect in regulating the expression of TLR4 in the spinal cord neurons and microglia. HSP90 in the spinal cord may be a co-stimulatory molecule for EA induced relief of neuropathic pain by regulating TLR4.

The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl 2 ), and the treatment of the PrL cortex with cannabidiol (CBD), the CB 1 receptor antagonist AM251 and the 5-HT 1A receptor antagonist WAY-100635 were also investigated. Our results showed that CoCl 2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB 1 cannabinoid receptors and 5-HT 1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Breast cancer continues to be the most commonly diagnosed cancer among Canadian women, with as many as 25-60% of women suffering from chronic neuropathic pain (CNP) as a pervasive consequence of treatment. While pharmacological interventions have shown limited efficacy for the management of CNP to date, psychological interventions, such as mindfulness-based stress reduction (MBSR), may be a promising alterative for improving pain-related problems. The purpose of this study was to use brain imaging methods to investigate this potential., Methods: Resting-state fMRI was used in female breast cancer survivors with CNP before and after an 8-week MBSR course (n = 13) and compared with a waitlist control group (n = 10)., Results: Focusing on the default mode network, the most significant results show greater posterior cingulate connectivity with medial prefrontal regions post-MBSR intervention. Moreover, this change in connectivity correlated with reduced pain severity for the MBSR group., Conclusions: These results provide empirical evidence of a change in the brain following MBSR intervention associated with changes in the subjective experience of pain., Implications for Cancer Survivors: This study gives hope for a non-invasive method of easing the struggle of CNP in women following breast cancer treatment., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain., Methods: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry., Results: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential., Conclusion: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.

Objectives: Traumatic peripheral nerve injuries (PNI) often result in severe neuropathic pain which typically becomes chronic, is recalcitrant to common analgesics, and is associated with sleep disturbances, anxiety, and depression. Pharmacological treatments proven to be effective against neuropathic pain are not well tolerated due to side effects. Neuromodulative interventions such as peripheral nerve or spinal cord stimulation have generated mixed results and may be limited by reduced somatotopic specificity. Dorsal root ganglion (DRG) stimulation may be more effective in this etiology., Materials and Methods: Twenty-seven patients were trialed with a DRG neurostimulation system for PNI; trial success (defined as ≥50% pain relief) was 85%, and 23 patients received a permanent stimulator. However, 36-month outcome data was only available for 21 patients. Pain, quality of life, mental and physical function, and opioid usage were assessed at baseline and at 3-, 6-, 12-, 18-, 24-, and 36 months post-permanent implant. Implant-related complications were also documented., Results: Compared to baseline, we observed a significant pain relief (p < 0.001) at 3 (58%), 12 (66%), 18 (69%), 24 (71%), and 36 months (73%) in 21 patients (52.5 ± 14.2 years; 12 female), respectively. Mental and physical function showed immediate and sustained improvements. Participants reported improvements in quality of life. Opioid dosage reduced significantly (p < 0.001) at 3 (30%), 12 (93%), 18 (98%), 24 (99%), and 36 months (99%), and 20 of 21 patients were completely opioid-free after 36 months. There were five lead migrations and two electrode fractures (corrected by surgical intervention) and one wound infection (conservatively managed)., Conclusions: DRG neuromodulation appears to be a safe, effective, and durable option for treating neuropathic pain caused by PNI. The treatment allows cessation of often ineffective pharmacotherapy (including opioid misuse) and significantly improves quality of life., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain., Competing Interests: JB and RF are named inventors on patent applications covering the use of TNFR2 agonists. RF is a named inventor on patent applications covering the TNFR2 agonist technology., (Copyright © 2021 Bethea and Fischer.)

While numerous studies and patient experiences have demonstrated the efficacy of spinal cord stimulation as a treatment for chronic neuropathic pain, the exact mechanism underlying this therapy is still uncertain. Recent studies highlighting the importance of microglial cells in chronic pain and characterizing microglial activation transcriptomes have created a focus on microglia in pain research. Our group has investigated the modulation of gene expression in neurons and glial cells after spinal cord stimulation (SCS), specifically focusing on transcriptomic changes induced by varying SCS stimulation parameters. Previous work showed that, in rodents subjected to the spared nerve injury (SNI) model of neuropathic pain, a differential target multiplexed programming (DTMP) approach provided significantly better relief of pain-like behavior compared to high rate (HRP) and low rate programming (LRP). While these studies demonstrated the importance of transcriptomic changes in SCS mechanism of action, they did not specifically address the role of SCS in microglial activation. The data presented herein utilizes microglia-specific activation transcriptomes to further understand how an SNI model of chronic pain and subsequent continuous SCS treatment with either DTMP, HRP, or LRP affects microglial activation. Genes for each activation transcriptome were identified within our dataset and gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations indicated that DTMP yields the highest significant correlations to expression levels found in the healthy animals across all microglial activation transcriptomes. In contrast, HRP or LRP yielded weak or very weak correlations for these transcriptomes. This work demonstrates that chronic pain and subsequent SCS treatments can modulate microglial activation transcriptomes, supporting previous research on microglia in chronic pain. Furthermore, this study provides evidence that DTMP is more effective than HRP and LRP at modulating microglial transcriptomes, offering potential insight into the therapeutic efficacy of DTMP.

Background and Purpose: The cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive., Experimental Approach: Male rats and wild-type and TRPV1 knockout mice with peripheral nerve injury - sciatic nerve axotomy and spinal nerve ligation in rats; chronic constriction injury (CCI) in mice - provided models of chronic neuropathic pain. Ipsilateral lumbar (L)4-5 DRGs were assayed for activin C expression. Chronic neuropathic pain animals were treated with intrathecal or locally pre-administered activin C or the vehicle. Nociceptive behaviours and pain-related markers in L4-5 DRGs and spinal cord were evaluated. TRPV1 channel modulation by activin C was measured., Key Results: Following peripheral nerve injury, expression of activin βC subunit mRNA and activin C protein was markedly up-regulated in L4-5 DRGs of animals with axotomy, SNL or CCI. [Correction added on 26 November 2020, after first online publication: The preceding sentence has been corrected in this current version.] Intrathecal activin C dose-dependently inhibited neuropathic pain in spinal nerve ligated rats. Local pre-administration of activin C decreased neuropathic pain, macrophage infiltration into ipsilateral L4-5 DRGs and microglial reaction in L4-5 spinal cords of mice with CCI. In rat DRG neurons, activin C enhanced capsaicin-induced TRPV1 currents. Pre-treatment with activin C reduced capsaicin-evoked acute hyperalgesia and normalized capsaicin-evoked persistent hypothermia in mice. Finally, the analgesic effect of activin C was abolished in TRPV1 knockout mice with CCI., Conclusion and Implications: Activin C inhibits neuropathic pain by modulating TRPV1 channels, revealing potential analgesic applications in chronic neuropathic pain therapy., (© 2020 The British Pharmacological Society.)

Purpose: The present study explores the benefits of an 8-week mindfulness-based stress reduction (MBSR) program to white matter integrity among breast cancer survivors experiencing chronic neuropathic pain (CNP)., Methods: Twenty-three women were randomly assigned to either a MBSR treatment group (n = 13) or a waitlist control group (n = 10). Participants were imaged with MRI prior to and post-MBSR training using diffusion tensor imaging., Results: Compared with controls, the MBSR group showed a significant increase in fractional anisotropy (FA), particularly in the left subcortical regions including the uncinate fasciculus, amygdala, and hippocampus, as well as in the external capsule and in the left sagittal stratum. No decreases to FA were found in any brain regions following MBSR training. The FA values also negatively correlated with the pain severity and pain interference scores from the BRIEF pain questionnaire., Conclusions: The present findings demonstrate that MBSR training may enhance the integrity of cerebral white matter that coincides with a reduction in pain perception. Further research with a larger sample size is required., Implications for Cancer Survivors: This study highlights the potential for MBSR, as a non-pharmacological intervention, to provide both brain health improvement and pain perception relief for female breast cancer survivors experiencing CNP.

Because environmental elements modify chronic pain development and endogenous mechanisms of pain control are still a great therapeutic source, we investigated the effects of an early exposure to environmental enrichment (EE) in a translational model of neuropathic pain. Young male rats born and bred in an enriched environment, which did not count on running wheel, underwent chronic constriction injury (CCI) of sciatic nerve. EE abolished neuropathic pain behavior 14 days after CCI. Opioid receptors' antagonism reversed EE-analgesic effect. β-endorphin and met-enkephalin serum levels were increased only in EE-CCI group. Blockade of glucocorticoid receptors did not alter EE-analgesic effect, although corticosterone circulating levels were increased in EE animals. In the spinal cord, EE controlled CCI-induced serotonin increase. In DRG, EE blunted the expression of ATF-3 after CCI. Surprisingly, EE-CCI group showed a remarkable preservation of sciatic nerve fibers compared to NE-CCI group. This work demonstrated global effects induced by an EE protocol that explain, in part, the protective role of EE upon chronic noxious stimulation, reinforcing the importance of endogenous mechanisms in the prevention of chronic pain development., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain., Methods: Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed., Results: Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively; p < 0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively; p < 0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation: p = 0.73, and at 60 min stimulation; p = 0.42)., Conclusions: Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain., (© 2019 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Aim: The medial prefrontal context (mPFC) plays pivotal roles in initiation, development, and maintenance of chronic pain, whereas the underlying molecular mechanisms remain elusive, which invited investigation of potential involvement of MKP1 in mPFC in mice in neuropathic pain, and its cellular and molecular mechanisms. Materials and methods: Neuropathic pain model was established in adult male Kunming mice via chronic constrictive injury (CCI) of the sciatic nerve. Paw withdrawal latency (PWL) was measured at the plantar area by radiant heat test. Stereotaxic microinjection was applied in mice as per the atlas of Mouse Brain in Stereotaxic Coordinates. mRNA levels of MKP1 in mPFC in CCI mice were assessed by RT-PCR; protein expressions of MKP1, p-p38, p-JNK and p-ERK in mPFC in CCI mice were analyzed by Western blotting, and expressions of the c-Fos in mPFC in CCI mice evaluated by immunohistochemistry. Moreover, Lenti-MKP1 particles or BCI treatment was employed to inhibit MKP1 in mPFC contralateral to the injury. Results: MKP1 was activated and persistently upregulated in mPFC neurons in CCI mice. Inhibition of MKP1 in the mPFC contralateral to the injury could reverse CCI-induced pain behavior and neuronal activity either via employment of Lenti-MKP1 particles or BCI treatment. MKP1 in the mPFC modulated neuropathic pain via dephosphorization of p38 and JNK1/2. Conclusion: The findings demonstrated that MKP1 in mPFC could play a paramount role in the modulation of neuropathic pain, which might be associated to the increased neuronal excitability in the mPFC and downregulated p-p38 and p-JNK expression.

Objective: Invasive motor cortex stimulation (iMCS) has been proposed as a treatment for intractable neuropathic pain syndromes. Although the mechanisms underlying the analgesic effect of iMCS remain largely elusive, several studies found iMCS-related changes in regional cerebral blood flow (rCBF) in neuropathic pain patients. The aim of this study was to meta-analyze the findings of neuroimaging studies on rCBF changes to iMCS., Methods: PubMed, Embase, MEDLINE, Google Scholar, and the Cochrane Library were systematically searched for retrieval of relevant scientific papers. After initial assessment of relevancy by screening title and abstract by two investigators, independently, predefined inclusion and exclusion criteria were used for final inclusion of papers. Descriptive results were statistically assessed, whereas coordinates were pooled and meta-analyzed in accordance with the activation likelihood estimation (ALE) methodology., Results: Six studies were included in the systematic narrative analysis, suggesting rCBF increases in the cingulate gyrus, thalamus, insula, and putamen after switching the MCS device "ON" as compared to the "OFF" situation. Decreases in rCBF were found in for example the precentral gyrus and different occipital regions. Two studies did not report stereotactic coordinates and were excluded from further analysis. ALE meta-analysis showed that, after switching the iMCS electrode "ON," increased rCBF occurred in the (1) anterior cingulate gyrus; (2) putamen; (3) cerebral peduncle; (4) precentral gyrus; (5) superior frontal gyrus; (6) red nucleus; (7) internal part of the globus pallidus; (8) ventral lateral nucleus of the thalamus; (9) medial frontal gyrus; (10) inferior frontal gyrus; and (11) claustrum, as compared to the "OFF" situation. Reductions in rCBF were found in the posterior cingulate gyrus when the iMCS electrode was turned "OFF.", Conclusions: These findings suggested that iMCS induces changes in principal components of the default mode-, the salience-, and sensorimotor network., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Objectives: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS., Methods: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner., Results: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas., Conclusions: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst., (© 2020 World Institute of Pain.)

Experimental treatments for treating neuropathic pain include transcranial magnetic stimulation (TMS) and invasive electric motor cortex stimulation (iMCS) of the primary motor cortex (M1). Mechanisms of action of both methods, however, remain largely elusive. Within this paper, we focus on animal-based experiments in order to investigate the biological mechanisms that are involved in alleviating pain by use of TMS and/or iMCS. Therefore, this paper systematically reviewed the animal-based evidence on these mechanisms. Multiple online databases were systematically searched and retrieved articles were assessed using predefined inclusion and exclusion criteria. Twenty-three suitable articles were included; six on TMS and seventeen on iMCS. In general, iMCS and TMS were found to impact the primary motor cortex structure and function in animals. Furthermore, structural and functional changes within the thalamus, striatum, periaqueductal grey, rostral ventromedial medulla and dorsal horn were reported to occur. Although widespread, all areas in which structural and functional changes occurred after TMS and iMCS have been found to be interconnected anatomically. This could provide a rationale for future investigations of treating neuropathic pain by use of neuromodulation., Competing Interests: Declaration of Competing Interest The authors declare that they have had no conflict of interest in the conduction of this research., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: A sex-difference in susceptibility to chronic pain is well-known. Although recent studies have begun to reveal the sex-dependent mechanisms of nerve injury-induced pain sensitization, sex differences in the affective and cognitive brain dysfunctions associated with chronic pain have not been investigated. Therefore, we tested whether chronic pain leads to affective and cognitive disorders in a mouse neuropathic pain model and whether those disorders are sexually dimorphic., Methods: Chronic neuropathic pain was induced in male and female mice by L5 spinal nerve transection (SNT) injury. Pain sensitivity was measured with the von Frey test. Affective behaviors such as depression and anxiety were assessed by the forced swim, tail suspension, and open field tests. Cognitive brain function was assessed with the Morris water maze and the novel object location and novel object recognition tests., Results: Mechanical allodynia was induced and maintained for up to 8 weeks after SNT in both male and female mice. Depressive- and anxiety-like behaviors were observed 8 weeks post-SNT injury regardless of sex. Chronic pain-induced cognitive deficits measured with the Morris water maze and novel object location test were seen only in male mice, not in female mice., Conclusions: Chronic neuropathic pain is accompanied by anxiety- and depressive-like behaviors in a mouse model regardless of sex, and male mice are more vulnerable than female mice to chronic pain-associated cognitive deficits.

Objective: To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action., Materials and Methods: Rats were implanted with a four-contact cylindrical mini-lead and randomly assigned to two control (no-pain and pain model) and five test groups featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms. Mechanical and cold allodynia were assessed to measure efficacy. The ipsilateral dorsal quadrant of spinal cord adjacent to the lead was harvested post-stimulation and processed to determine gene expression via real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Gene expression, SCS intensity (mA), and behavioral score as percent of baseline (BSPB) were statistically analyzed and used to generate correlograms using R-Studio. Statistical analysis was performed using SPSS22.0, and p < 0.05 was considered significant., Results: As expected, BSPB was significantly lower for the pain model group compared to the no-pain group. BSPB was significantly improved post-stim compared to pre-stim using cathodic, anodic, symmetric biphasic, or asymmetric biphasic 1:2 waveforms; however, BSPB was not restored to Sham levels. RT-PCR analysis showed that eight genes demonstrated a significant difference between the pain model and SCS waveforms and between waveforms. Correlograms reveal a linear correlation between regulation of expression of a given gene in relation to mA, BSPB, or other genes., Conclusions: Our results exhibit that specific SCS waveforms differentially modulate several key transcriptional pathways that are relevant in chronic pain conditions. These results have significant implications for SCS: whether to move beyond traditional paradigm of neuronal activation to focus also on modulating immune-driven processes., (© 2019 International Neuromodulation Society.)

Spinal cord stimulation is a proven effective therapy for treating chronic neuropathic pain. Previous work in our laboratory demonstrated that spinal cord stimulation based on a differential target multiplexed programming approach provided significant relief of pain-like behavior in rodents subjected to the spared nerve injury model of neuropathic pain. The relief was significantly better than obtained using high rate and low rate programming. Furthermore, transcriptomics-based results implied that differential target multiplexed programming modulates neuronal-glial interactions that have been perturbed by the pain process. Although differential target multiplexed programming was developed to differentially target neurons and glial cells, our previous work did not address this. This work presents transcriptomes, specific to each of the main neural cell populations (neurons, microglia, astrocytes, and oligodendrocytes), obtained from spinal cord subjected to continuous spinal cord stimulation treatment with differential target multiplexed programming, high rate programming, or low rate programming compared with no spinal cord stimulation treatment, using the spared nerve injury model. To assess the effect of each spinal cord stimulation treatment on these cell-specific transcriptomes, gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations and cell population analysis indicate that differential target multiplexed programming yielded strong and significant correlations to expression levels found in the healthy animals across every evaluated cell-specific transcriptome. In contrast, high rate programming only yielded a strong correlation for the microglia-specific transcriptome, while low rate programming did not yield strong correlations with any cell types. This work provides evidence that differential target multiplexed programming distinctively targeted and modulated the expression of cell-specific genes in the direction of the healthy state thus supporting its previously established action on regulating neuronal-glial interaction processes in a pain model.

Research into potentially novel biomarkers for chronic pain development is lacking. microRNAs (miRNAs) are attractive candidates as biomarkers due to their conservation across species, stability in liquid biopsies, and variation that corresponds to a pathologic state. miRNAs can be sorted into extracellular vesicles (EVs) within the cell and released from the site of injury. EVs transfer cargo molecules between cells thus affecting key intercellular signaling pathways. The focus of this study was to determine the plasma derived EV miRNA content in a chronic neuropathic pain rat model. This was accomplished by performing either spinal nerve ligation (SNL; n = 6) or sham (n = 6) surgery on anesthetized male Sprague-Dawley rats. Mechanosensitivity was assessed and plasma derived EV RNA was isolated at baseline (BL), day 3, and 15 postnerve injury. EV extracted small RNA was sequenced followed by differentially expressed (DE) miRNAs and gene target enrichment/signaling pathway analysis performed using R packages and TargetScan/Ingenuity pathway analysis (IPA), respectively. Seven of the DE miRNAs were validated by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). The data indicated that SNL rats displayed a time-dependent threshold reduction in response to evoked stimuli from day 3 to day 15 postnerve injury. The data also revealed that 22 and 74 miRNAs at day 3 and 15, respectively, and 33 miRNAs at both day 3 and 15 were uniquely DE between the SNL and sham groups. The key findings from this proposal include (1) the majority of the DE EV miRNAs, which normally function to suppress inflammation, were downregulated, and (2) several of the plasma derived DE EV miRNAs reflect previously observed changes in the injured L5 nerve. The plasma derived DE EV miRNAs regulate processes important in the development and maintenance of neuropathic pain states and potentially serve as key regulators, biomarkers, and targets in the progression and treatment of chronic neuropathic pain. PERSPECTIVE: This article describes the DE miRNA content of plasma derived EVs, comparing neuropathic pain to normal conditions. This data indicates that EV miRNAs may be important in nociception and may also serve as biomarkers for chronic pain. These results encourage further research on EV miRNAs in chronic neuropathic pain sufferers., (Published by Elsevier Inc.)

Objective : Despite the application of dexmedetomidine (DEX) as a perioperative adjuvant in local analgesia, the exact analgesic mechanism underpinning chronic neuropathic pain (CNP) awaits our elucidation. Methods : We investigated the molecular mechanisms of the anti-nociceptive effect of DEX on neuropathic pain in a mouse model induced by chronic constriction injury (CCI). Results : DEX administration significantly increased the paw withdrawal latency (PWL) values 0.5 to 2 h post-injection in CCI-induced CNP mice at day 5 to 21 versus dimethyl sulfoxide (DMSO)-treated mice, confirming its analgesic effect. The c-Fos expression was significantly elevated in CCI mice versus the sham-operated group, whereas the elevation was mitigated by DEX injection. Subsequently, the involvement of MKP1 and MKP3 in the pathogenesis of chronic neuropathic pain was evaluated. Western blotting analyses revealed significant decrease in both MKP1 and MKP3 in the spinal cord in CCI group versus the sham group. DEX markedly elevated the MKP3 expression and modestly reduced the MKP1 expression, with insignificant difference in the latter. Co-injection of BCI (an MKP3 inhibitor) and DEX evidently reduced the PWL values in CCI mice. Furthermore, DEX significantly downregulated the phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2, down-stream effector of MKP3 in CCI mice, whereas the downregulation was reversed by BCI. Conclusion: We confirmed that DEX exerts the analgesic effect on chronic neuropathic pain via the regulation of MKP3/ERK1/2 signaling pathway, which may contribute to clarification of the molecular mechanism and novel therapy for chronic neuropathic pain.

Background: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRG STIM ), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways., Methods: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRG STIM using PANTHER™ pathway enrichment analysis tool., Results: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRG STIM . Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated., Conclusions: In our sub-group analysis of L4-DRG STIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00011267.

Objectives: Dorsal root ganglion stimulation (DRGS) has been used successfully against localized neuropathic pain. Nevertheless, the effects of DRGS on pain processing, particularly at the cortical level, remain largely unknown. In this study, we investigated whether positive responses to DRGS treatment would alter patients' laser-evoked potentials (LEP)., Methods: We prospectively enrolled 12 adult patients with unilateral localized neuropathic pain in the lower limbs or inguinal region and followed them up for six months. LEPs were assessed at baseline, after one month of DRGS, and after six months of DRGS. Clinical assessment included the Numerical Rating Scale (NRS), Brief Pain Inventory (BPI), SF-36, and Beck Depression Inventory (BDI). For each patient, LEP amplitudes and latencies of the N2 and P2 components on the deafferented side were measured and compared to those of the healthy side and correlated with pain intensity, as measured with the NRS., Results: At the one- and six-month follow-ups, N2-P2 amplitudes were significantly greater and NRS scores were significantly lower compared with baseline (all p's < 0.01). There was a negative correlation between LEP amplitudes and NRS scores (r s = -0.31, p < 0.10)., Conclusions: DRGS is able to restore LEPs to normal values in patients with localized neuropathic pain, and LEP alterations are correlated with clinical response in terms of pain intensity., (© 2018 International Neuromodulation Society.)