The role of orphan G protein-coupled receptors in pain.

G protein-coupled receptors (GPCRs), which form the largest family of membrane protein receptors in humans, are highly complex signaling systems with intricate structures and dynamic conformations and locations. Among these receptors, a specific subset is referred to as orphan GPCRs (oGPCRs) and has garnered significant interest in pain research due to their role in both central and peripheral nervous system function. The diversity of GPCR functions is attributed to multiple factors, including allosteric modulators, signaling bias, oligomerization, constitutive signaling, and compartmentalized signaling. This review primarily focuses on the recent advances in oGPCR research on pain mechanisms, discussing the role of specific oGPCRs including GPR34, GPR37, GPR65, GPR83, GPR84, GPR85, GPR132, GPR151, GPR160, GPR171, GPR177, and GPR183. The orphan receptors among these receptors associated with central nervous system diseases are also briefly described. Understanding the functions of these oGPCRs can contribute not only to a deeper understanding of pain mechanisms but also offer a reference for discovering new targets for pain treatment.

Curcumin analogue NL04 inhibits spinal cord central sensitization in rats with bone cancer pain by inhibiting NLRP3 inflammasome activation and reducing IL-1ß production.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 µg/kg and 489.6 µg/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dose-dependently lowered spinal IL-1ß and IL-18 levels and significantly reduced the expression of IKKß genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKKß expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1ß production, potentially ameliorating pain management in BCP.

LncRNA 51325 Alleviates Bone Cancer Induced Hyperalgesia Through Inhibition of Pum2.

Background: Bone cancer pain (BCP) represents one of the most challenging comorbidities associated with cancer metastasis. Long non-coding RNAs (lncRNAs) have garnered attention as potential therapeutic agents in managing neuropathic pain. However, their role in the regulation of nociceptive information processing remains poorly understood. In this study, we observed a significant down-regulation of the spinal lncRNA ENSRNOG00000051325 (lncRNA51325) in a rat model of bone cancer pain. Our study sought to elucidate the potential involvement of lncRNA51325 in the development of BCP by modulating the expression of molecules associated with pain modulation. Methods: We established the BCP model by injecting Walker 256 cells into the tibial plateau of rats. We conducted tests on the pain behaviors and anxiety-like responses of rats through von-Frey test, Gait analysis, and Open Field Test. Spinal lumbar expansion was harvested for molecular biology experiments to explore the relationship between lncRNA51325 and Pumilio RNA binding family member 2 (Pum2). Results: Notably, the overexpression of lncRNA51325 effectively attenuated mechanical allodynia in rats afflicted with BCP, whereas the knockdown of lncRNA51325 induced pain behaviors and anxiety-like responses in naïve rats. Additionally, we observed a time-dependent increase in the expression of Pum2 in BCP-afflicted rats, and intrathecal injection of Pum2-siRNA alleviated hyperalgesia. Furthermore, our investigations revealed that lncRNA51325 exerts a negative modulatory effect on Pum2 expression. The overexpression of lncRNA51325 significantly suppressed Pum2 expression in BCP rats, while the knockdown of lncRNA51325 led to elevated Pum2 protein levels in the spinal cord of naïve rats. Subsequent treatment with Pum2-siRNA mitigated the downregulation of lncRNA51325-induced mechanical allodynia in naïve rats. Conclusion: Our findings indicate that lncRNA51325 plays a role in regulating bone cancer pain by inhibiting Pum2 expression, offering a promising avenue for novel treatments targeting nociceptive hypersensitivity induced by bone metastatic cancer.

Progress in Radiofrequency Therapy for Zoster-Associated Pain About Parameters, Modes, Targets, and Combined Therapy: A Narrative Review.

Zoster-associated pain (ZAP) is a painful condition that significantly impacts a patient's quality of life, often leading to postherpetic neuralgia (PHN). Over 30% of patients with herpes probably experience PHN. However, the understanding and treatment of ZAP remain inadequate. Common interventional treatments include radiofrequency therapy, nerve blocks, epidural block, and spinal cord electrical stimulation. Among these, radiofrequency therapy is widely used for pain control in ZAP, but the standard pulsed radiofrequency technique can still be improved. Researchers have explored different radiofrequency parameters, modes, targets, and combined treatments to enhance the therapeutic effect. In this paper, we review the latest research findings and incorporate our own departmental investigations. We conclude that high-voltage, long-duration pulsed radiofrequency and radiofrequency thermocoagulation therapy have shown improved therapeutic outcomes, despite some remaining limitations. Emphasis is placed on safety in intercostal nerve and extracranial nerve radiofrequency treatments. Combination therapy is also safe and effective; however, many studies have a low grade of evidence. Further high-quality research and systematic reviews are needed.

Pre-oxygenation with high-flow oxygen through the nasopharyngeal airway compared to facemask on carbon dioxide clearance in emergency adults: a prospective randomized non-blinded clinical trial.

INTRODUCTION: Before tracheal intubation, it is essential to provide sufficient oxygen reserve for emergency patients with full stomachs. Recent studies have demonstrated that high-flow nasal oxygen (HFNO) effectively pre-oxygenates and prolongs apneic oxygenation during tracheal intubation. Despite its effectiveness, the use of HFNO remains controversial due to concerns regarding carbon dioxide clearance. The air leakage and unknown upper airway obstruction during HFNO therapy cause reduced oxygen flow above the vocal cords, possibly weaken the carbon dioxide clearance. METHODS: Patients requiring emergency surgery who had fasted < 8 h and not drunk < 2 h were randomly assigned to the high-flow group, who received 100% oxygen at 30-60 L/min through nasopharyngeal airway (NPA), or the mask group, who received 100% oxygen at 8 L/min. PaO2 and PaCO2 were measured immediately before pre-oxygenation (T0), anesthesia induction (T1), tracheal intubation (T2), and mechanical ventilation (T3). The gastric antrum's cross-sectional area (CSA) was measured using ultrasound technology at T0, T1, and T3. Details of complications, including hypoxemia, reflux, nasopharyngeal bleeding, postoperative pulmonary infection, postoperative nausea and vomiting (PONV), and postoperative nasopharyngeal pain, were recorded. The primary outcomes were PaCO2 measured at T1, T2, and T3. The secondary outcomes included PaO2 at T1, T2, and T3, CSA at T1 and T3, and complications happened during this trial. RESULTS: Pre-oxygenation was administered by high-flow oxygen through NPA (n = 58) or facemask (n = 57) to 115 patients. The mean (SD) PaCO2 was 32.3 (6.7) mmHg in the high-flow group and 34.6 (5.2) mmHg in the mask group (P = 0.045) at T1, 45.0 (5.5) mmHg and 49.4 (4.6) mmHg (P < 0.001) at T2, and 47.9 (5.1) mmHg and 52.9 (4.6) mmHg (P < 0.001) at T3, respectively. The median ([IQR] [range]) PaO2 in the high-flow and mask groups was 404.5 (329.1-458.1 [159.8-552.9]) mmHg and 358.9 (274.0-413.3 [129.0-539.1]) mmHg (P = 0.007) at T1, 343.0 (251.6-428.7 [73.9-522.1]) mmHg and 258.3 (162.5-347.5 [56.0-481.0]) mmHg (P < 0.001) at T2, and 333.5 (229.9-411.4 [60.5-492.4]) mmHg and 149.8 (87.0-246.6 [51.2-447.5]) mmHg (P < 0.001) at T3, respectively. The CSA in the high-flow and mask groups was 371.9 (287.4-557.9 [129.0-991.2]) mm2 and 386.8 (292.0-537.3 [88.3-1651.7]) mm2 at T1 (P = 0.920) and 452.6 (343.7-618.4 [161.6-988.1]) mm2 and 385.6 (306.3-562.0 [105.5-922.9]) mm2 at T3 (P = 0.173), respectively. The number (proportion) of complications in the high-flow and mask groups is shown below: hypoxemia: 1 (1.7%) vs. 9 (15.8%, P = 0.019); reflux: 0 (0%) vs. 0 (0%); nasopharyngeal bleeding: 1 (1.7%) vs. 0 (0%, P = 1.000); pulmonary infection: 4 (6.9%) vs. 3 (5.3%, P = 1.000); PONV: 4 (6.9%) vs. 4 (7.0%, P = 1.000), and nasopharyngeal pain: 0 (0%) vs. 0 (0%). CONCLUSIONS: Compared to facemasks, pre-oxygenation with high-flow oxygen through NPA offers improved carbon dioxide clearance and enhanced oxygenation prior to tracheal intubation in patients undergoing emergency surgery, while the risk of gastric inflation had not been ruled out. TRIAL REGISTRATION: This trial was registered prospectively at the Chinese Clinical Research Registry on 26/4/2022 (Registration number: ChiCTR2200059192).

miR-199a-3p mediates bone cancer pain through upregulation of dnmt3a expression in spinal dorsal horn neurons.

Due to its complex pathological mechanisms, bone cancer pain (BCP) has become an increasingly challenging clinical issue, there is an urgent need to identify the underlying mechanisms of BCP. In our present study, we found that decreased expression of miR-199a-3p in spinal dorsal horn (SDH) neurons contributed to BCP hypersensitivity. Intrathecal administration of miR-199a-3p agomir alleviated the initiation of tumor inoculation induced pain hypersensitivity and suppressed the expression of DNMT3A. Subsequently, luciferase assays confirmed direct binding between miR-199a-3p and Dnmt3a mRNA. AAV-DNMT3A-shRNA microinjection relieved mechanical hyperalgesia and upregulated the expression of Nrf2 levels in BCP. In naïve rats, Overexpression of DNMT3A yielded the opposite effects. Finally, increase of DNMT3A by lentiviral vector abolished miR-199a-3p-mediated alleviation hypersensitivity effects on BCP progression. Taken these together, our findings highlighted a novel contribution of miR-199a-3p to BCP and provided a fresh outlook on potential mechanism research for BCP.

Effect of Dexmedetomidine on Postoperative Plasma Neurofilament Light Chain in Elderly Patients Undergoing Thoracoscopic Surgery: A Prospective, Randomized Controlled Trial.

Purpose: Dexmedetomidine exerts a neuroprotective effect, however, the mechanism underlying this effect remains unclear. This study aimed to explore whether dexmedetomidine can reduce the increase in neurofilament light chain (NfL) protein concentration to play a neuroprotective role during thoracoscopic surgery. Patients and Methods: Patients aged ≥60 years undergoing general anesthesia for thoracoscopic surgery were randomly assigned to receive dexmedetomidine (group D) or not receive dexmedetomidine (group C). Patients in group D received a loading dose of dexmedetomidine 0.5 µg/kg before anesthesia induction and a continuous infusion at 0.5 µg·kg-1·h-1 until the end of the surgery. Dexmedetomidine was not administered in group C. The primary outcome was the NfL concentration on postoperative day 1. The concentrations of procalcitonin (PCT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were detected preoperatively and on postoperative day 1. In addition, the numerical rating scale (NRS) and quality of recovery-40 (QoR-40) scores were evaluated. Results: A total of 38 patients in group D and 37 in group C were included in the analysis. No differences were observed between the groups in terms of the plasma concentration of NfL preoperatively and on postoperative day 1 (11.17 [8.86, 13.93] vs 13.15 [10.76, 15.56] pg/mL, P > 0.05; 16.70 [12.23, 21.15] vs 19.48 [15.25, 22.85] pg/mL, P > 0.05, respectively). However, the postoperative plasma NfL concentration was significantly higher than the preoperative value in both groups (both P < 0.001). The groups exhibited no differences in PCT, SAA, hs-CRP, NRS, and QoR-40 (all P > 0.05). Conclusion: Intraoperative administration of dexmedetomidine at a conventional dose does not appear to significantly reduce the increase in postoperative plasma NfL concentration in elderly patients undergoing thoracoscopic surgery. This finding suggests that the neuroprotective effect of dexmedetomidine at a conventional dose was not obvious during general anesthesia.

JAG-1/Notch signaling axis in the spinal cord contributes to bone cancer pain in rats.

Notch signal plays an important role in regulating cell-cell interactions with the adjacent cells. However, it remains unknown whether Jagged1 (JAG-1) mediated Notch signaling regulates bone cancer pain (BCP) via the spinal cell interactions mechanism. Here, we showed that intramedullary injection of Walker 256 breast cancer cells increased the expression of JAG-1 in spinal astrocytes and knockdown of JAG-1 reduced BCP. The supplementation of exogenous JAG-1 to the spinal cord induced BCP-like behavior and promoted expression of c-Fos and hairy and enhancer of split homolog-1 (Hes-1) in the spinal cord of the naïve rats. These effects were reversed when the rats were administered intrathecal injections of N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). The intrathecal injection of DAPT reduced BCP and inhibited Hes-1 and c-Fos expression in the spinal cord. Furthermore, our results showed that JAG-1 up-regulated Hes-1 expression by inducing the recruitment of Notch intracellular domain (NICD) to the RBP-J/CSL-binding site located within the Hes-1 promoter sequence. Finally, the intrathecal injection of c-Fos-antisense oligonucleotides (c-Fos-ASO) and administration of sh-Hes-1 to the spinal dorsal horn also alleviated BCP. The study indicates that inhibition of the JAG-1/Notch signaling axis may be a potential strategy for the treatment of BCP.

CXCL13 contributes to chronic pain of a mouse model of CRPS-I via CXCR5-mediated NF-κB activation and pro-inflammatory cytokine production in spinal cord dorsal horn.

BACKGROUND: Complex regional pain syndrome type-I (CRPS-I) causes excruciating pain that affect patients' life quality. However, the mechanisms underlying CRPS-I are incompletely understood, which hampers the development of target specific therapeutics. METHODS: The mouse chronic post-ischemic pain (CPIP) model was established to mimic CRPS-I. qPCR, Western blot, immunostaining, behavioral assay and pharmacological methods were used to study mechanisms underlying neuroinflammation and chronic pain in spinal cord dorsal horn (SCDH) of CPIP mice. RESULTS: CPIP mice developed robust and long-lasting mechanical allodynia in bilateral hindpaws. The expression of inflammatory chemokine CXCL13 and its receptor CXCR5 was significantly upregulated in ipsilateral SCDH of CPIP mice. Immunostaining revealed CXCL13 and CXCR5 was predominantly expressed in spinal neurons. Neutralization of spinal CXCL13 or genetic deletion of Cxcr5 (Cxcr5-/-) significantly reduced mechanical allodynia, as well as spinal glial cell overactivation and c-Fos activation in SCDH of CPIP mice. Mechanical pain causes affective disorder in CPIP mice, which was attenuated in Cxcr5-/- mice. Phosphorylated STAT3 co-expressed with CXCL13 in SCDH neurons and contributed to CXCL13 upregulation and mechanical allodynia in CPIP mice. CXCR5 coupled with NF-κB signaling in SCDH neurons to trigger pro-inflammatory cytokine gene Il6 upregulation, contributing to mechanical allodynia. Intrathecal CXCL13 injection produced mechanical allodynia via CXCR5-dependent NF-κB activation. Specific overexpression of CXCL13 in SCDH neurons is sufficient to induce persistent mechanical allodynia in naïve mice. CONCLUSIONS: These results demonstrated a previously unidentified role of CXCL13/CXCR5 signaling in mediating spinal neuroinflammation and mechanical pain in an animal model of CRPS-I. Our work suggests that targeting CXCL13/CXCR5 pathway may lead to novel therapeutic approaches for CRPS-I.

Upregulation of LncRNA71132 in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain.

ABSTRACT: Bone cancer pain (BCP) is a pervasive clinical symptom which impairs the quality life. Long noncoding RNAs (lncRNAs) are enriched in the central nervous system and play indispensable roles in numerous biological processes, while its regulatory function in nociceptive information processing remains elusive. Here, we reported that functional modulatory role of ENSRNOT00000071132 (lncRNA71132) in the BCP process and sponging with miR-143 and its downstream GPR85-dependent signaling cascade. Spinal lncRNA71132 was remarkably increased in the rat model of bone cancer pain. The knockdown of spinal lncRNA71132 reverted BCP behaviors and spinal c-Fos neuronal sensitization. Overexpression of spinal lncRNA71132 in naive rat generated pain behaviors, which were accompanied by increased spinal c-Fos neuronal sensitization. Furthermore, it was found that lncRNA71132 participates in the modulation of BCP by inversely regulating the processing of miR-143-5p. In addition, an increase in expression of spinal lncRNA71132 resulted in the decrease in expression of miR-143 under the BCP state. Finally, it was found that miR-143-5p regulates pain behaviors by targeting GPR85. Overexpression of miR-143-5p in the spinal cord reverted the nociceptive behaviors triggered by BCP, accompanied by a decrease in expression of spinal GPR85 protein, but no influence on expression of gpr85 mRNA. The findings of this study indicate that lncRNA71132 works as a miRNA sponge in miR-143-5p-mediated posttranscriptional modulation of GPR85 expression in BCP. Therefore, epigenetic interventions against lncRNA71132 may potentially work as novel treatment avenues in treating nociceptive hypersensitivity triggered by bone cancer.

Efficacy and safety of sympathetic radiofrequency thermocoagulation in the treatment of cold hypersensitivity.

Background: Cold hypersensitivity (CH) is a sensation of cold in the limbs and (or) body of a patient in an environment that is not considered cold by unaffected people, or a strong feeling of cold at a relatively low temperature. However, the currently available treatments are limited and often unsatisfactory. This study aimed to evaluate the clinical efficacy and safety of the sympathetic radiofrequency thermocoagulation (RF-TC) technique in patients with CH disorder. Methods: The study is a retrospective analysis. A total of 71 were entered into the final analysis and all patients underwent computed tomography-guided thoracic (lumbar) sympathetic nerve RF-TC on an elective basis. The values of terminal temperature (T) and perfusion index (PI) of patients before and after treatment were recorded. Patients were followed up clinically at regular intervals and their Visual Analog Scale (VAS) and Pittsburgh Sleep Quality Index (PSQI) scores were recorded to detect postoperative complications and assess patient satisfaction with the treatment. Results: All patients completed the radiofrequency treatment. Compared with the preoperative period, VAS and PSQI scores were significantly lower at all postoperative time periods (P < 0.001). Patients had significantly higher postoperative terminal temperatures and perfusion indices on the right and left sides than before surgery (P < 0.001). The overall patient satisfaction score was 4 (3-5) at 3 years of postoperative follow-up. There were 20 recurrences (28.2%). The main postoperative complications were postoperative local pain and compensatory hyperhidrosis. No other adverse events or deaths were observed. Conclusion: RF-TC for CH could be a feasible, effective, and safe treatment option to improve patients' symptoms of cold sensation. Yet, more researches are needed to verify this potentially efficient and standardized treatment.

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation.

Chronic, inflammatory pain is an international health concern that severely diminishes individuals' quality of life. Catalpol is an iridoid glycoside derived from the roots of Rehmannia glutinosa that possesses anti-inflammatory, antioxidant, and neuroprotective properties for the treating multiple kinds of disorders. Nevertheless, catalpol's impacts on inflammatory pain and its potential methods of action are still unclear. The purpose of this investigation is to determine the mechanism of catalpol to reduce the inflammatory pain behaviors in a rat model with complete Freund's adjuvant (CFA). Catwalk, Von-Frey, and open field testing were performed for behavioral assessment. Western blot analysis and real-time quantitative PCR (RT-PCR) were employed to identify variations in molecular expression, while immunofluorescence was utilized to identify cellular localization. Catalpol effectively reduced CFA-induced mechanical allodynia and thermal hyperalgesia when injected intrathecally. Moreover, catalpol can regulate the HDAC4/PPAR-γ-signaling pathway in CFA rat spinal cord neurons. Meanwhile catalpol significantly decreased the expression of the NF-κB/NLRP3 inflammatory axis in the spinal cord of CFA rats. In addition, both in vivo and in vitro research revealed that catalpol treatment inhibited astrocyte activation and increase inflammatory factor expression. Interestingly, we also found that catalpol could alleviate peripheral pain by inhibiting tissue inflammation. Taken together, the findings declared that catalpol may inhibit inflammatory pain in CFA rats by targeting spinal cord and peripheral inflammation.

Risk Factors Affecting the Outcomes of CT-Guided Radiofrequency Thermocoagulation of Thoracic Sympathetic Nerve in the Treatment of Primary Palm Hyperhidrosis.

BACKGROUND: Primary palm hyperhidrosis (PPH) is a chronic disease characterized by uncontrolled palm-sweating exceeding physiological needs. It negatively impacts the quality of life of the patients and can lead to different degrees of psychological problems. Currently, there are a variety of treatment options for PPH, of which thoracotomy is a first-line treatment that has shown good efficacy. However, since it is an invasive procedure requiring general anesthesia and is often associated with high costs and serious complications, better alternatives should be explored. Computed tomography (CT)-guided percutaneous puncture of radiofrequency thermocoagulation (RF-TC) of the thoracic sympathetic nerve is a promising alternative treatment. It is a minimally invasive procedure that can be performed under local anesthesia and is associated with rapid recovery. However, the factors affecting the duration of the surgery-related benefits and outcomes of CT-guided percutaneous RF-TC of the thoracic sympathetic nerve are unclear. OBJECTIVES: To investigate the factors influencing the outcomes of CT-guided percutaneous RF-TC of the thoracic sympathetic nerve in patients with PPH. STUDY DESIGN: A retrospective study. SETTING: This study was conducted at the Pain Department of Jiaxing University Affiliated Hospital (Jiaxing, China). METHODS: After approval by the Ethics Committee of the Affiliated Hospital of Jiaxing College, the data of 232 corresponding patients were assessed. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify factors associated with PPH and to construct a nomogram for predicting postoperative recurrence. Time-independent receiver operating characteristic (ROC) curve analyses were performed to assess the nomogram's predictive capacity. RESULTS: In the one-year survival analysis model, gender (HR = 1.573, 95%CI: 0.844 to 2.934), age (HR = 0.965, 95%CI: 0.915 to 1.018), disease course (HR = 0.960, 95%CI: 0.908 to 1.015), palm temperature difference (HR = 0.377, 95%CI: 0.287 to 0.495), perfusion index difference (HR = 0.590, 95%CI: 0.513 to 0.680) and hyperhidrosis disease severity scale (HR = 1.963, 95%CI: 0.769 to 5.011) were identified as statistically significant factors in univariate analysis, while palm temperature difference (HR = 0.589, 95%CI: 0.369 to 0.941) and perfusion index difference (HR = 0.357, 95%CI: 0.588 to 0.968) were the independent factors in the multivariate Cox proportional hazards risk model. In the 2-year survival analysis model, palm temperature difference (HR = 0.353, 95%CI: 0.261 to 0.478), perfusion index difference (HR = 0.589, 95%CI: 0.510 to 0.680) and hyperhidrosis disease severity scale (HR = 1.964, 95%CI: 0.771 to 5.006) were the statistically significant factors while palm temperature difference (HR = 0.507, 95%CI: 0.321 to 0.799) and perfusion index difference (HR = 0.789, 95%CI: 0.625 to 0.995) were the independent factors. LIMITATIONS: This single-center retrospective study was limited by its small sample size, short follow-up time, and the possibility of bias resulting from the non-random patient selection. CONCLUSION: Palm temperature difference and perfusion index difference were independent risk factors associated with prolonging the surgical benefits and reducing postoperative recurrence of CT-guided RF-TC of the sympathetic nerves in patients with PPH.

CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats.

Bone cancer pain (BCP) is a clinically intractable mixed pain, involving inflammation and neuropathic pain, and its mechanisms remain unclear. CXC chemokine receptor 1 (CXCR1, IL-8RA) and 2 (CXCR2, IL-8RB) are high-affinity receptors for interleukin 8 (IL8). According to previous studies, CXCR2 plays a crucial role in BCP between astrocytes and neurons, while the role of CXCR1 remains unclear. The objective of this study was to investigate the role of CXCR1 in BCP. We found that CXCR1 expression increased in the spinal dorsal horn. Intrathecal injection of CXCR1 siRNA effectively attenuated mechanical allodynia and pain-related behaviors in rats. It was found that CXCR1 was predominantly co-localized with neurons. Intrathecal injection of CXCR1-siRNA reduced phosphorylated JAK2/STAT3 protein levels and the NLRP3 inflammasome (NLRP3, caspase1, and IL-1ß) levels. Furthermore, in vitro cytological experiments confirmed this conclusion. The study results suggest that the spinal chemokine receptor CXCR1 activation mediates BCP through JAK2/STAT3 signaling pathway and NLRP3 inflammasome (NLRP3, caspase1, and IL-1ß).

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain.

BACKGROUND: Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. METHODS: The miRNA-155-5p levels and cellular distribution were determined by RNA sequencing, fluorescent in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Immunoblotting, qPCR, dual-luciferase reporter gene assays, immunofluorescence, recombinant overexpression adeno-associated virus, small interfering RNA, intraspinal administration, and behavioral tests were utilized for exploring the downstream signaling pathway. RESULTS: The miR-155-5p high expression in spinal neurons contributes to BCP maintenance. The miR-155-5p blockage via the intrathecal injection of miR-155-5p antagomir alleviated the pain behavior; in contrast, upregulating miR-155-5p by agomir induced pain hypersensitivity. The miR-155-5p bounds directly to TCF4 mRNA's 3' UTR. BCP significantly reduced protein expression of TCF4 versus the Sham group. The miR-155-5p inhibition relieved the spinal TCF4 protein's down-expression level, while miR-155-5p upregulation by miR-155-5p agomir intrathecal injection decreased TCF4 protein expression in naïve rats. Additionally, TCF4 overexpression in BCP rats could increase Kv1.1. Moreover, TCF4 knockdown inhibited Kv1.1 expression in BCP rats. Indeed, TCF4 and Kv1.1 were co-expressed in BCP spinal cord neurons. CONCLUSION: The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155-5p could be a promising target in treating BCP.

Efficacy of Percutaneous Radiofrequency Sympathectomy Versus Percutaneous Ethanol Sympatholysis in the Treatment of Primary Hyperhidrosis.

BACKGROUND: At present, there are many surgical treatments for primary hyperhidrosis (PH), but their medium- and long-term effects remain unclear. OBJECTIVES: To evaluate and compare the efficacy of radiofrequency sympathectomy (RFS) and percutaneous ethanol sympatholysis (PES) in the treatment of PH. STUDY DESIGN: A retrospective study. SETTING: This study was performed at the Affiliated Hospital of Jiaxing University, China. METHODS: Patients who underwent RFS and PES at The First Affiliated Hospital of Jiaxing University for PH were retrospectively reviewed from January 2016 through December 2018 and were divided into an RFS group and a PES group. The Hyperhidrosis Disease Severity Scale  was evaluated at the following time points: before the operation, immediately after the operation, 12 months and 24 months after the operation. The effective rate, patient satisfaction, and compensatory hyperhidrosis were also evaluated. RESULTS: A total of 94 patients diagnosed with primary hyperhidrosis were included (RFS group, n = 45; PES group, n = 49). RFS yielded a postprocedure 24-month effective rate of 53.33% in treating hyperhidrosis compared to PES (24.49%, P < 0.05). There were no significant differences between the 2 groups regarding patient satisfaction (P = 0.927) and compensatory hyperhidrosis (P = 0.711). LIMITATIONS: This was a single-center study. CONCLUSION: This is the first clinical study to evaluate the efficacy of RFS and compare it with PES in treating primary hyperhidrosis. RFS significantly decreased hyperhidrosis and had a higher 2-year effective rate compared to PES.

Correlation Between Electromyography and Severity and Prognosis of Upper Limb Herpes Zoster.

BACKGROUND: There are differences in the clinical treatment schemes for patients with different severities of herpes zoster (HZ). Therefore, effective and accurate evaluation of disease severity is of great significance for the formulation of treatment plans. Postherpetic neuralgia (PHN) with long-term chronic pain leads to anxiety, depression, and even suicidal thoughts, which place a heavy burden on society and the family. Therefore, identifying risk factors and taking early intervention to reduce the occurrence of PHN is meaningful. Electromyography (EMG) can provide technical support for the early diagnosis of peripheral neuropathy. However, the application of EMG in HZ and PHN has rarely been reported. The purpose of this study was to compare the detection indices of EMG in patients with different severities and prognoses of HZ and to analyze the application of EMG in severity and prognosis of HZ. OBJECTIVE: This study aimed to explore the relationship between EMG and severity and prognosis of upper limb HZ. STUDY DESIGN: A retrospective, observational study. SETTING: The study was carried out in the Pain Department of the affiliated Hospital of Jiaxing College in Jiaxing, China. METHODS: A total of 91 patients with upper limb HZ at the First Hospital of Jiaxing between January 2015 and August 2021 were enrolled. The patients were divided into mild, moderate, and severe HZ groups according to their numeric rating scale (NRS) scores. The occurrence of PHN was defined as a poor prognosis. The patients were divided into non-PHN and PHN groups according to the occurrence of PHN. Motor and sensory conduction indices of the median nerve were measured in each group. Spearman's correlation analysis was used to analyze the relationship between the EMG-related data of the median nerve and the NRS score and muscle strength. Univariate and multivariate logistic regression analyses were used to determine the independent influencing factors of PHN in patients with upper limb HZ, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of EMG-related data in patients with upper limb HZ. RESULTS: Among 91 patients, there were 29 patients in the mild HZ group, 31 in the moderate HZ group, and 31 in the severe HZ group. The sensory nerve action potential (SNAP) amplitude of the median nerve in the severe and moderate HZ groups was lower than that in the mild HZ group, and that in the severe HZ group was lower than that in the moderate HZ group (F = 22.192, P < 0.05). Through Spearman's correlation analysis, it was found that the compound muscle action potential (CMAP) and SNAP amplitudes of the median nerve on the affected limb were negatively correlated with the NRS score (r = -0.266, P = 0.011; r = -0.778, P < 0.001), and there was no significant correlation between each index and muscle strength (P > 0.05). Among 91 patients, 44 and 47 were in the non-PHN and PHN groups, respectively. Univariate and multivariate logistic regression analyses showed that the CMAP amplitude of the median nerve on the affected limb (OR = 0.241, 95% CI: 0.098-0.567, P = 0.001) and SNAP amplitude (OR = 0.268, 95% CI: 0.110-0.628, P = 0.002) were independent influencing factors of PHN. Through the analysis of the ROC curve, it was found that the CMAP and SNAP amplitudes of the median nerve on the affected limb had a high predictive value for PHN (AUC = 0.657, P = 0.010; AUC = 0.773, P < 0.001). The cutoff values were 5.45 mV and 10.80 mV, respectively; and the predictive value of the 2 indices combined was the highest (AUC = 0.785, P < 0.001). LIMITATIONS: The nonrandomized, single-center, small sample size, and retrospective design are major limitations of this study. CONCLUSION: The CMAP and SNAP amplitudes of the median nerve on the affected limb were related to the degree of pain in patients with upper limb HZ. The CMAP and SNAP amplitudes of the median nerve on the affected limb can be used as prognostic factors for patients with upper limb HZ, and CMAP amplitude combined with SNAP amplitude is more valuable in predicting prognosis.

Comparison of Efficacy and Safety of Lumbar Sympathetic Radiofrequency Thermocoagulation Versus Chemical Lumbar Sympathectomy in the Treatment of Cold Hypersensitivity in the Hands and Feet: A Retrospective Study.

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a disease characterized by abnormal cold in the limbs with limited treatment options. Compared to traditional drug therapy, lumbar sympathectomy is a new minimally invasive surgical method for treating CHHF. OBJECTIVES: The present study aimed to compare the efficacy and safety of lumbar sympathetic radiofrequency thermocoagulation (RFT) and chemical lumbar sympathectomy (CLS) in treating CHHF. STUDY DESIGN: A single-center, retrospective, observational study. SETTING: Department of Anesthesiology and Pain Medicine, Jiaxing, China. METHODS: A total of 102 patients with CHHF who underwent lumbar sympathectomy from January 2016 to April 2020 were included in this study. According to the mode of operation, the patients were divided into 2 groups: CLS (n = 56) and RFT (n = 46). All patients were treated under the guidance of computed tomography (CT). The foot temperature (T) and peripheral perfusion index (PI) were compared between the 2 groups before and after treatment. The 2 groups' visual analog scale (VAS) scores were evaluated before the operation and 1 day, 1 month, 3 months, 6 months, and 1 year after the treatment. The postoperative recurrence rate of the 2 groups was observed 1 year after treatment. The short and long-term complications during the postoperative follow-up were recorded. RESULTS: All patients completed the operation successfully. No significant difference was noted in the gender, age, course of the disease, preoperative T and PI, and postoperative T and PI between the 2 groups (P > 0.05). The postoperative T and PI were significantly increased compared to preoperative in both groups (P < 0.05). No significant difference was observed in T and PI between the 2 groups (P > 0.05), and no significant difference was recorded in VAS scores between the 2 groups 1 day and 1 month after the treatment (P > 0.05). The VAS scores at 3 months, 6 months, and 1 year after the treatment were significantly lower in the RFT group compared to the CLS group (P < 0.05). During the 1-year follow-up, patients who received CLS had a higher risk of recurrence than RFT treatment (P < 0.05). The RFT group treatment of CHHF showed better long-term outcomes than the CLS group. About 12.5% of patients in the CLS group and 6.5% in the RFT group had postoperative complications, including pain at the puncture site and genitofemoral neuralgia. However, no severe complications or deaths were observed in either of the 2 groups. LIMITATIONS: The was a single-center, retrospective, non-randomized study, which is a major limitation of this study. CONCLUSIONS: Lumbar sympathetic RFT had better long-term efficacy, lower recurrence, and fewer complications than the chemical lumbar sympathectomy when treating CHHF.

Association between the Risk of Relapse and the Type of Surgical Procedure for Herpes Zoster-related Pain.

BACKGROUND: Pulsed radiofrequency (PRF) on the dorsal root ganglion (DRG) is a common minimally invasive surgery for herpes zoster (HZ)-related pain, including acute zoster pain and postherpetic neuralgia (PHN); however, some patients still have no obvious pain relief, a high recurrence rate, and short-term recurrence. Radiofrequency thermocoagulation (RF-TC) has a higher temperature; however, it is still unknown whether the degree of complete damage will affect the recurrence rate and if there is any difference compared with the effect of PRF. OBJECTIVES: This study mainly aimed to explore whether there was a difference in the recurrence rate following CT-guided PRF and RF-TC for HZ-related pain. This is also a preliminary exploration of RF-TC for treatment of HZ-related pain. STUDY DESIGN: A retrospective cohort study. SETTING: The study was carried out in the Affiliated Hospital of Jiaxing University in Jiaxing, China. METHODS: We included a total of 134 patients who underwent CT-guided PRF or RF-TC for HZ-related pain in the pain department. Medical records related to relapse, numerical rating scale scores (NRSs), Pittsburgh sleep quality index (PSQI), adverse events, and satisfaction were reviewed. The Kaplan-Meier analysis was used to estimate the cumulative survival rates of the surgical procedures. After controlling for related confounders, the relationship of surgical procedure and recurrence rate was analyzed by interval-censored multivariable Cox regression. A time-independent receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. A nomogram was used to predict postoperative recurrence. Multiple imputations was used to deal with the randomly missing data. Repeated-measures analysis of variance (ANOVA) was applied to analyze NRSs and PSQI at each time interval, and multiple comparisons were made. RESULTS: In 134 patients with HZ-related pain, the ratio of patients receiving PRF to those receiving RF-TC was 1:1. Interval-censored multivariable Cox regression analysis demonstrated that lesion space (1-2% / ref: adjusted hazard ratio (HR), 2.075; 95% confidence intervals (CI), 1.002-4.210; > 2% / ref: adjusted HR, 3.406; 95% CI, 1.670 - 6.950), pain grade (adjusted HR, 2.249; 95% CI, 1.221 - 4.143) and surgical procedure (adjusted HR, 2.392; 95% CI, 1.308 - 4.375) were significantly associated with a higher risk of the primary outcome. There were 20 cases of recurrence in RF-TC group, while there were 30 cases in PRF group. The short-term (within 3 months) postoperative recurrence rate was 14.93% in the RF-TC group and 37.31% in the PRF group. The differences in PSQI and NRSs between 2 groups were also statistically significant. LIMITATIONS: The study uses a small sample size from a single center. The model built is not validated internally or externally. The conclusions of randomized controlled trials will be more convincing. Subgroup analysis of the disease course was not performed. CONCLUSION: In the treatment of HZ-related pain, the use of PRF is significantly associated with a high short-term recurrence rate. However, compared with RF-TC, PRF results in milder numbness and less intraoperative pain. RF-TC may be a feasible procedure if patients can accept pain relief at the cost of long periods of numbness, whether RF-TC has the value of clinical promotion still needs to be further explored.

Risk Factors Affecting the Success Rate of Radiofrequency Thermocoagulation of Lumbar Sympathetic Nerve.

BACKGROUND: Computed tomography (CT)-guided radiofrequency thermocoagulation of lumbar sympathetic nerve has been gradually applied to the treatment of many autonomic nerve disorders, such as plantar hyperhidrosis (PH) and diabetic peripheral neuropathy (DPN). The difference in the success rate of operation between the left and right sides is not yet studied. OBJECTIVE: This study aimed to explore a statistically significant difference between the success rate of left and right CT-guided radiofrequency thermocoagulation of lumbar sympathetic nerve and screen the risk factors affecting the success rate of the right surgery. STUDY DESIGN: This is a single-center retrospective cohort study. SETTING: The study was carried out in the Pain Department of the affiliated Hospital of Jiaxing College in Jiaxing, China. METHODS: A total of 86 patients who received CT-guided radiofrequency thermocoagulation of lumbar sympathetic nerve were included in this study approved by the Ethics Committee of the affiliated Hospital of Jiaxing University. Nonparametric and chi-square tests were used to compare the operation times, CT scan times, and success rate on the left and right sides. Binary multivariate logistic regression analysis was applied to screen the risk factors on the outcome variable. RESULTS: The bilateral operation time, CT scan times, and success rate differed significantly between the left and right sides (P < 0.05). After univariate analysis, 6 covariates (gender, body mass index, treatment history, operation time, CT scan times, and puncture needle type) were selected. Finally, the multivariate regression model screened out 2 risk factors: the operation time and puncture needle type. LIMITATIONS: We look forward to increasing the sample size in follow-up studies and exploring relevant conclusions in randomized controlled trials. CONCLUSION: This study proved that in CT-guided radiofrequency thermocoagulation of the lumbar sympathetic nerve, the difficulty of operation on the right side was significantly high, and the success rate was also lower than that on the contralateral side. Multivariate logistic regression analysis showed that operation time and type of puncture needle were risk factors affecting the success rate of the operation. These findings laid a foundation for the accomplishment of technical improvement and innovation in the future. A preliminary exploration was carried out to reduce the risk and complications and to improve the success rate of the operation.