Dorsal root entry zone lesioning for brachial plexus avulsion - technical evolution and long-term follow-up.

BACKGROUND: Brachial plexus avulsion (BPA) injuries can cause severe deafferentation pain. This has been successfully treated with dorsal root entry zone (DREZ) lesioning. Distortions in anatomy following a BPA injury can make identifying neural structures challenging. We describe a modification to the operative technique that improves the surgical view and the advanced intraoperative neuromonitoring (IONM) employed to identify DREZ. We have analysed the long-term outcomes for pain, quality of life, and complications in patients undergoing DREZ lesioning. METHODS: This is a single-centre retrospective case series including patients who underwent DREZ lesioning with IONM for brachial plexus avulsion between 2012 and 2022. Analysed data included pre- and postoperative pain (VAS), quality of life score for chronic pain, and complications. The evolution of the surgical approach is discussed. RESULTS: 44 consecutive patients underwent a DREZ lesioning procedure with intraoperative monitoring and mapping. In these patients the mean VAS score improved from 8.9 (7-10) to 1.87 (0-6) (p < 0.0001) at the time of discharge. 31 patients were followed-up for more than 12 months with a mean duration of follow-up of 41 months and their results were as follows: the mean VAS improved from 9.0 (7-10) to 4.1 (0-9) (p < 0.0001) at the last follow-up and the mean QOL values improved from 3.7 (2-6) to 7.4 (4-10) (p < 0.0001). The long-term outcomes were 'good' in 39%, 'fair' in 29% and 'poor' in 32% of patients. 55% of the patients were able to stop or reduce pain medications. CONCLUSIONS: Modifications of surgical technique provide better exposure of DREZ, and IONM aids in identifying DREZ in the presence of severe intra-dural changes. Long-term outcomes of DREZ lesioning indicate not only a reduction in pain but also a significant improvement in quality of life.

miR-506-3p Relieves Neuropathic Pain following Brachial Plexus Avulsion via Mitigating Microglial Activation through Targeting the CCL2-CCR2 Axis.

Neuroinflammation results in neuropathic pain (NP) following brachial plexus avulsion (BPA). This research was designed for investigating the function of miR-506-3p in BPA-induced NP. A total brachial plexus root avulsion model was produced in adult rats as well as IL-1ß-treated motoneuron-like NSC-34 cells and the LPS-treated microglia cell line BV2 for in vivo and in vitro experiments, respectively. RT-PCR and Western blot were performed to detect the profiles of miR-506-3p, CCL2 and CCR2, NF-κB, FOXO3a, TNF-α, IL-1ß, and IL-6 in cells or the spinal cord close to the tBPI lesion. Neuronal apoptosis was evaluated by immunohistochemistry in vivo. CCK8, TUNEL staining, and the lactic dehydrogenase kit were adopted for the evaluation of neuronal viability or damage in vitro. RNA immunoprecipitation and dual luciferase reporter gene assays analyzed the targeted association between miR-506-3p and CCL2. As shown by the data, miR-506-3p was vigorously less expressed, while CCL2-CCR2, NF-κB TNF-α, IL-1ß, and IL-6 were upregulated in the spinal cord with tBPI. Overexpression of miR-506-3p attenuated neuronal apoptosis and microglial inflammation. Mechanistically, CCL2 was a downstream target of miR-506-3p. Upregulating miR-506-3p dampened CCL2-CCR2 and NF-κB activation in the spinal cord and microglia. miR-506-3p had neuroprotective and inflammation-fighting functions in the tBPI rat model via CCL2/CCR2/NF-κB axis.

Restoration of intrinsic hand function by superficial radial nerve: an anatomical study.

BACKGROUND: The contralateral seventh cervical (cC7) nerve root transfer represents a cornerstone technique in treating total brachial plexus avulsion injury. Traditional cC7 procedures employ the entire ulnar nerve as a graft, which inevitably compromises its restorative capacity. OBJECTIVE: Our cadaveric study seeks to assess this innovative approach aimed at preserving the motor branch of the ulnar nerve (MBUN). This new method aims to enable future repair stages, using the superficial radial nerve (SRN) as a bridge connecting cC7 and MBUN. METHODS: We undertook a comprehensive dissection of ten adult cadavers, generously provided by the Department of Anatomy, Histology, and Embryology at Fudan University, China. It allowed us to evaluate the feasibility of our proposed technique. For this study, we harvested only the dorsal and superficial branches of the ulnar nerve, as well as the SRN, to establish connections between the cC7 nerve and recipient nerves (both the median nerve and MBUN). We meticulously dissected the SRN and the motor and sensory branches of the ulnar nerve. Measurements were made from the reverse point of the SRN to the wrist flexion crease and the coaptation point of the SRN and MBUN. Additionally, we traced the MBUN from distal to proximal ends, recording its maximum length. We also measured the diameters of the nerve branches and tallied the number of axons. RESULTS: Our modified approach proved technically viable in all examined limbs. The distances from the reverse point of the SRN to the wrist flexion crease were 8.24 ± 1.80 cm and to the coaptation point were 6.60 ± 1.75 cm. The maximum length of the MBUN was 7.62 ± 1.03 cm. The average axon diameters in the MBUN and the anterior and posterior branches of the SRN were 1.88 ± 0.42 mm、1.56 ± 0.38 mm、2.02 ± 0.41 mm,respectively. The corresponding mean numbers of axons were 1426.60 ± 331.39 and 721.50 ± 138.22, and 741.90 ± 171.34, respectively. CONCLUSION: The SRN demonstrated the potential to be transferred to the MBUN without necessitating a nerve graft. A potential advantage of this modification is preserving the MBUN's recovery potential.

Functional outcome of contralateral C7 nerve transfer combined with free functional gracilis transplantation to repair total brachial plexus avulsion: a report of thirty-nine cases.

PURPOSE: Treatment of total brachial plexus avulsion (TBPA) is a challenge in the clinic, especially the restoration of hand function. The current main surgical order is from proximal to distal joints. The purpose of this study was to demonstrate the outcomes of "distal to proximal" surgical method. METHODS: Thirty-nine patients underwent contralateral C7 (CC7) nerve transfer to directly repair the lower trunk (CC7-LT) and phrenic nerve transfer to the suprascapular nerve (PN-SSN) during the first stage, followed by free functional gracilis transplantation (FFGT) for elbow flexion and finger extension. Muscle strength of upper limb, degree of shoulder abduction and elbow flexion, and Semmes-Weinstein monofilament test and static two-point discrimination of the hand were examined according to the modified British Medical Research Council (mBMRC) scoring system. RESULTS: The results showed that motor recovery reached a level of M3 + or greater in 66.7% of patients for shoulder abduction, 87.2% of patients for elbow flexion, 48.7% of patients for finger extension, and 25.6% of patients for finger flexion. The mean shoulder abduction angle was 45.5° (range 0-90°), and the average elbow flexion angle was 107.2° (range 0-142°), with 2.5 kg average flexion strength (range 0.5-5 kg). In addition, protective sensibility (≥ S2) was found to be achieved in 71.8% of patients. CONCLUSION: In reconstruction of TBPA, CC7 transfer combined with free functional gracilis transplantation is an available treatment method. It could help patients regain shoulder joint stability and the function of elbow flexion and finger extension and, more importantly, provide finger sensation and partial finger flexion function. However, the pick-up function was unsatisfied, which needed additional surgery.

Early Intervention of Cold-Water Swimming on Functional Recovery and Spinal Pain Modulation Following Brachial Plexus Avulsion in Rats.

Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS could promote functional recovery and pain modulation through the reduction of neuroinflammation and microglial overactivation in dorsal horn neurons at the early-stage of BPA. After BPA surgery was performed on rats, they were assigned to CWS or sham training for 5 min twice a day for two weeks. Functional behavioral responses were tested before and after BPA surgery, and each week during training. Results after the two-week training program showed significant improvements in BPA-induced motor and sensory loss (p < 0.05), lower inflammatory cell infiltration, and vacuole formation in injured nerves among the BPA-CWS group. Moreover, BPA significantly increased the expression of SP and IBA1 in dorsal horn neurons (p < 0.05), whereas CWS prevented their overexpression in the BPA-CWS group. The present findings evidenced beneficial rehabilitative effects of CWS on functional recovery and pain modulation at early-stage BPA. The beneficial effects are partially related to inflammatory suppression and spinal modulation. The synergistic role of CWS combined with other management approaches merits further investigation.

Contralateral C7 transfer to axillary and median nerves in rats with total brachial plexus avulsion.

BACKGROUND: Contralateral cervical 7 nerve (cC7) was used to repair two recipient nerves simultaneously for patients with total brachial plexus avulsion (TBPA). OBJECTIVE: To evaluate the effect of cC7 transfer to axillary and median nerves in rats with TBPA. METHODS: Eighty S-D rats were divided into 4 groups randomly on average. Group A: cC7-median nerve, Group B: cC7-axillary nerve, Group C: cC7-median and axillary nerves, Group D: TBPA without repair. The evaluation tools included behavioral tests, electromyogram (EMG), measurement of cross-sectional area of muscle fiber, nerve fiber count and gene expression assay. RESULTS: The effective rates of EMG were 90 and 70% in Flexor Carpi Radialis (FCR) in Group A and C, while 70 and 60% in deltoid (DEL) in Group B and C, respectively. In behavioral test, the differences of effective rates between groups were not significant. The mean cross-sectional area of FCR in Group A or C was significantly larger than that in Group D. Either the number of median or axillary nerve fibers in Group A, B or C was statistically more than that in Group D. No matter for FCR or DEL, there were no significant differences in the ratios of relative expression of Muscle Atrophy F-box(MAFBOX)and Muscle RING Finger 1(MURF1)among these groups. CONCLUSION: Compared with cC7 transfer to median nerve, cC7 transfer to both median and axillary nerves did not affect median nerve recovery. The deltoid muscle also could be restored. The recovery proportion of axillary nerve was less than that of median nerve.

Administration of Curcumin Alleviates Neuropathic Pain in a Rat Model of Brachial Plexus Avulsion.

BACKGROUND/AIMS: Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. METHODS: Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. RESULTS: After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. CONCLUSIONS: Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes.

Histone deacetylase inhibition inhibits brachial plexus avulsion-induced neuropathic pain.

INTRODUCTION: Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA-induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt)-mediated mammalian target of rapamycin (mTOR) activation. METHODS: We generated a rat BPA model; administered HDAC inhibitor tricostatin A (TSA) for 7 days postsurgery; and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation, and mTOR activation. RESULTS: TSA treatment alleviated BPA-induced mechanical hyperalgesia, suppressed Akt phosphorylation, and increased HDAC. We found suppressed proinflammatory cytokine levels, TRPV1 and TRPM8 expression, and mTOR activity in TSA-treated BPA rats. DISCUSSION: Our results suggest that altered HDAC and Akt signaling are involved in BPA-induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. Muscle Nerve 58: 434-440, 2018.

Bipolar dual-lead spinal cord stimulation between two electrodes on the ventral and dorsal sides of the spinal cord: consideration of putative mechanisms.

We have applied bipolar dual-lead spinal cord stimulation (SCS) between two cylinder-type electrodes placed on the ventral and dorsal sides of the spinal cord (dual-VD-SCS). A 36-year-old man suffered from burning pain from his right elbow down to his hand after brachial plexus avulsion. The areas with paresthesia induced by conventional SCS did not include the painful hand area. However, dual-VD-SCS completely induced paresthesia in the painful hand area. We speculate that dual-VD-SCS can be applied to stimulate deeper sites of the dorsal column and dorsal horn than conventional SCS and is useful for pain reduction.

Functional connectivity of motor cortical network in patients with brachial plexus avulsion injury after contralateral cervical nerve transfer: a resting-state fMRI study.

INTRODUCTION: The purpose of this study is to assess the functional connectivity of the motor cortical network in patients with brachial plexus avulsion injury (BPAI) after contralateral C7 nerve transfer, using resting-state functional magnetic resonance imaging (RS-fMRI). METHODS: Twelve patients with total brachial plexus root avulsion underwent RS-fMRI after contralateral C7 nerve transfer. Seventeen healthy volunteers were also included in this fMRI study as controls. The hand motor seed regions were defined as region of interests in the bilateral hemispheres. The seed-based functional connectivity was calculated in all the subjects. Differences in functional connectivity of the motor cortical network between patients and healthy controls were compared. RESULTS: The inter-hemispheric functional connectivity of the M1 areas was increased in patients with BPAI compared with the controls. The inter-hemispheric functional connectivity between the supplementary motor areas was reduced bilaterally. CONCLUSIONS: The resting-state inter-hemispheric functional connectivity of the bilateral M1 areas is altered in patients after contralateral C7 nerve transfer, suggesting a functional reorganization of cerebral cortex.

Intraoperative Neurophysiological Monitoring (Motor and Somatosensory Evoked Potentials) in Dorsal Root Entry Zone Lesioning for Brachial Plexus Avulsion Pain.

AIMS: To address the feasibility and importance of intraoperative neurophysiological monitoring (IONM) in dorsal root entry zone (DREZ) lesioning for brachial plexus avulsion pain. METHODS: Muscle motor evoked potential (mMEP) and somatosensory evoked potential (SSEP) were applied during DREZ lesioning for brachial plexus avulsion pain. RESULTS: IONM of mMEPs and SSEPs was feasible for monitoring of the spinal cord during DREZ lesioning. With the exception of 3 unrecordable mMEPs in ipsilateral arms, mMEPs were preserved and referenced to look for changes according to lesioning in 6 upper extremities (66.6%) and 8 lower extremities. All 3 patients with >50% reduction in baseline mMEP amplitude after lesioning in either the ipsilateral upper or lower extremities showed postoperative ataxia and weakness of the lower extremities (100%). Only 2 out of 9 patients (22.2%) with brachial plexus avulsion pain had discernible baseline SSEPs in the ipsilateral upper extremities. One of 2 patients with discernible SSEPs in the upper extremities showed significant SSEP events during the DREZ lesioning and experienced postoperative ataxia and weakness in the legs despite the absence of a SSEP event in the lower extremities. CONCLUSION: Significant events on IONM were common during DREZ lesioning for brachial plexus avulsion pain and were closely related to the occurrence of postoperative neurological deficits.

Outcome Comparison of Nerve Transfer with Different Donor Nerves in a Rat Model.

OBJECTIVE: The phrenic nerve and the contralateral seventh cervical (C7) nerve root are the most commonly used donor nerves in the treatment of total brachial plexus avulsion. The aim of this study was to determine if the phrenic nerve or the contralateral C7 nerve root yields a superior outcome for nerve transfer. METHODS: A total of 60 Sprague-Dawley rats were randomly assigned to 1 of 3 groups. In Group A the phrenic nerve was used as the donor nerve; in Group B the contralateral C7 nerve root nerve was used as the donor nerve; in Group C the nerve was directly sutured. The results of behavioral assessment, electrophysiology, histology, nerve fiber count and muscle weight at 24 weeks postoperatively were recorded. RESULTS: Group A showed a faster recovery time compared to Group B; however Group B showed a better functional recovery at the final outcome assessment compared to Group A. CONCLUSION: The contralateral C7 nerve root was better as the donor nerve for nerve transfer in the treatment of total brachial plexus avulsion.

Tactile feedback for relief of deafferentation pain using virtual reality system: a pilot study.

BACKGROUND: Previous studies have tried to relieve deafferentation pain (DP) by using virtual reality rehabilitation systems. However, the effectiveness of multimodal sensory feedback was not validated. The objective of this study is to relieve DP by neurorehabilitation using a virtual reality system with multimodal sensory feedback and to validate the efficacy of tactile feedback on immediate pain reduction. METHODS: We have developed a virtual reality rehabilitation system with multimodal sensory feedback and applied it to seven patients with DP caused by brachial plexus avulsion or arm amputation. The patients executed a reaching task using the virtual phantom limb manipulated by their real intact limb. The reaching task was conducted under two conditions: one with tactile feedback on the intact hand and one without. The pain intensity was evaluated through a questionnaire. RESULTS: We found that the task with the tactile feedback reduced DP more (41.8 ± 19.8 %) than the task without the tactile feedback (28.2 ± 29.5 %), which was supported by a Wilcoxon signed-rank test result (p < 0.05). CONCLUSIONS: Overall, our findings indicate that the tactile feedback improves the immediate pain intensity through rehabilitation using our virtual reality system.

Phantom pain in a patient with brachial plexus avulsion injury.

OBJECTIVE: Phantom limb pain is a painful sensation perceived in the absent limb following surgical or traumatic amputation. Phantom limb sensations, which are nonpainful, occur in nearly all amputees. Deafferentation can also produce similar symptoms. Here we report the presence of phantom pain in a deafferented limb. DESIGN: Case report. SETTING: Hospital-based outpatient clinic. PATIENT: A 65-year-old man was referred to the pain clinic for management of upper extremity pain secondary to brachial plexus avulsion (BPA) following a motor vehicle accident. Initially he noticed a feeling of growing and shrinking of his arm. Following this, the pain started gradually from his elbow extending to his fingertips covering all dermatomes. He described the pain as continuous, severe, and sharp. He also described the arm as being separate from his existing insensate arm and felt as though the fist was closed with the thumb pointing out. On physical examination, he had no sensation to fine touch or pressure below the elbow. There were no consistent areas of allodynia. He had diffuse muscle wasting in all the muscle groups of his left upper extremity, besides winging of the scapula. Electrodiagnostic studies showed a left brachial plexopathy consistent with multilevel nerve root avulsion sparing the dorsal rami. CONCLUSION: This is a report of phantom limb sensations and phantom pain following BPA in an intact but flaccid and insensate limb.

The Effects of Generally Administered Anti-Nerve Growth Factor Receptor (p75NTR) Antibody on Pain-Related Behavior, Dorsal Root Ganglia, and Spinal Glia Activation in a Rat Model of Brachial Plexus Avulsion.

PURPOSE: To investigate the effect of intraperitoneal administration of an anti-p75 neurotrophin receptor (p75NTR) antibody on reducing neuropathic pain in a rat model of brachial plexus avulsion (BPA). METHODS: We randomly assigned 40 male Wistar rats to 4 groups. In the BPA group, the C8-T1 roots were avulsed from the spinal cord at the lower trunk level, and saline was administered intraperitoneally. In the anti-p75NTR groups, 1 µL or 50 µL anti-p75NTR antibody was administered intraperitoneally after avulsion. In the sham-operated group, the lower trunk level was exposed, and saline was administered intraperitoneally. Mechanical hyperalgesia and pain-induced walking patterns were measured using von Frey filaments and CatWalk gait analysis at various time points until 15 days after administration. At 3 and 15 days after administration, sensory neurons involved in pain perception and satellite glial cells in the ipsilateral C7 dorsal root ganglia were immunolabeled with antibodies against calcitonin gene-related peptide and glial fibrillary acidic protein (GFAP), respectively. At both time points, microglial and astrocyte activation, indicative of spinal pain transmission, were immunohistochemically examined in the ipsilateral dorsal horn of the spinal cord (C7) using anti-ionized calcium-binding adaptor molecule 1 and anti-GFAP antibodies, respectively. RESULTS: The gait pattern was significantly improved in both anti-p75NTR groups compared with the BPA group. There were significantly fewer calcitonin gene-related peptide-immunoreactive (IR) neurons, neurons encircled by GFAP-IR satellite glial cells, and GFAP-IR astrocytes in both anti-p75NTR groups compared with the BPA group at both time points. Fewer ionized calcium-binding adaptor molecule 1-IR microglia were quantified in both anti-p75NTR groups compared with the BPA group, but this was only significant at 15 days after administration. CONCLUSIONS: Systemic application of the p75NTR inhibitory antibody suppressed neuropathic pain after BPA. CLINICAL RELEVANCE: p75NTR may be a potential therapeutic target for the clinical treatment of neuropathic pain in BPA injury.

End-to-side neurotization with different donor nerves for treating brachial plexus injury: an experimental study in a rat model.

INTRODUCTION: End-to-side neurotization is currently used to treat brachial plexus injury, but it is not clear which donor nerve yields the best outcome. We performed experiments to determine the optimal donor nerve. METHODS: A total of 66 male Sprague-Dawley rats were assigned to 1 of 3 groups. Group A was the control group. In Group B, the phrenic nerve was used as the donor, while the ipsilateral C7 nerve root served as the donor in Group C. The epineurial window was used in end-to-side neurorrhaphy. Behavioral observations, histology, electrophysiology, and fluorescence retrotracing were performed postoperatively. RESULTS: Fluorescence retrotracing confirmed nerve regeneration in both Groups B and C upon end-to-side neurotization. The outcome of Group B was superior to that of Group C. CONCLUSIONS: Use of the phrenic nerve as the donor nerve yielded a better outcome than use of the ipsilateral C7 nerve root.

Pneumocephalus resulting from traumatic pneumothorax and brachial plexus avulsion.

Background: Traumatic pneumocephalus is commonly encountered after basal skull fractures and rarely associated with blunt chest trauma. Here, we report a case of pneumocephalus caused by traumatic pneumothorax and brachial plexus avulsion. Case Presentation: A 20-year-old male was admitted to our hospital following a motorcycle accident with complete paralysis of the right upper limb. 2 days later, follow-up computed tomography revealed a slight right pneumothorax, pneumomediastinum around the neck, and intracranial air without skull fracture. Air migrates into the subarachnoid space through a dural tear caused by a brachial plexus avulsion. The pneumocephalus immediately improved after the insertion of a chest drain. Conclusion: Pneumothorax combined with brachial plexus avulsion could lead to pneumocephalus. Immediate chest drainage might be the best way to stop the migration of air; however, care should be taken to not worsen cerebrospinal fluid leakage.

Altered intrinsic brain activity in patients with neuropathic pain after brachial plexus avulsion.

OBJECTIVE: This study aimed to investigate brain activity changes in patients suffering from neuropathic pain (NP) following brachial plexus avulsion (BPA). METHODS: Fifteen patients with NP following BPA and eight healthy participants (HP) were recruited for this study. All participants underwent examination using resting-state functional MRI. The amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were calculated and compared between the BPA group, left-BPA subgroup, right-BPA subgroup, and the HP group using independent samples t-tests. RESULTS: In the BPA group, there were notable increases in ALFF/ReHo observed in the left rolandic operculum, insula, and supramarginal gyrus, while decreases were observed in the left paracentral lobule, fusiform gyrus, calcarine fissure and surrounding cortex, lingual gyrus, precuneus, as well as the bilateral anterior/median cingulate and paracingulate gyri, supplementary motor area, and cerebellum. In the left-BPA subgroup, elevated ALFF/ReHo levels were identified in the left middle/inferior frontal gyri, rolandic operculum, and supramarginal gyrus, with corresponding decreases in the left calcarine fissure and surrounding cortex, inferior occipital gyrus, fusiform gyrus, lingual gyrus, as well as the bilateral anterior/median cingulate and paracingulate gyri, postcentral gyri, supplementary motor area, paracentral lobules, and cerebellum. The right-BPA subgroup displayed increased ALFF/ReHo in the left frontal lobe, rolandic operculum, insula, fusiform gyrus, and lingual gyrus, as well as the right cerebellum. Conversely, decreases in ALFF/ReHo were observed in the bilateral anterior/median cingulate and paracingulate gyri, calcarine fissure and surrounding cortex, cuneus, and occipital lobes. CONCLUSIONS: The NP after BPA caused spontaneous activity changes in brain regions associated with linguistic, visual, somatosensory, and motor coordination and processing function. The majority of these abnormal areas were situated in the left cerebral hemisphere, while the effect of cingulate gyri and cerebellum seemed to be bilateral.

5-HT3a receptor contributes to neuropathic pain by regulating central sensitization in a rat with brachial plexus avulsion.

PURPOSE: As a frequently occurring complication resulting from brachial plexus avulsion (BPA), neuropathic pain significantly impacts the quality of life of patients and places a substantial burden on their families. Recent reports have suggested that the 5-HT3a receptor may play a role in the development and regulation of neuropathic pain. The current study aimed to explore the involvement of the 5-HT3a receptor in neuropathic pain resulting from BPA in rats. METHODS: A rat model of neuropathic pain was induced through brachial plexus avulsion (BPA). The pain thresholds of the rats were measured after BPA. The spinal dorsal horn (SDH) of rats was collected at day 14 after surgery, and the expression and distribution of the 5-HT3a receptor were analyzed using immunohistochemistry and western blotting. The expression levels of various factors related to central sensitization were measured by western blot, including c-Fos, GFAP, IBA-1, IL-1ß and TNF-α. The effects of 5-HT3a receptor antagonists on hyperalgesia were assessed through behavioral tests after intrathecal administration of ondansetron. Additionally, at 120 min postinjection, the SDH of rats was acquired, and the change of expression levels of protiens related to central sensitization were measured by western blot. RESULTS: BPA induced mechanical and cold hypersensitivity in rats. The 5-HT3a receptor was increased and mainly distributed on neurons and microglia in the SDH after BPA, and the level of central sensitization and expression of inflammatory factors, such as c-Fos, GFAP, IBA-1, IL-1ß and TNF-α, were also increased markedly. Ondansetron, which is a selective 5-HT3a receptor antagonist, reversed the behavioral changes caused by BPA. The antagonist also decreased the expression of central sensitization markers and inflammatory factors. CONCLUSION: The results suggested that the 5-HT3a receptor is involved in neuropathic pain by regulating central nervous system sensitization in a rat brachial plexus avulsion model. Targeting the 5-HT3a receptor may be a promising approach for treating neuropathic pain after brachial plexus avulsion.

Ferroptosis Regulated by 5-HT3a Receptor via Calcium/Calmodulin Signaling Contributes to Neuropathic Pain in Brachial Plexus Avulsion Rat Models.

Neuropathic pain is a prevalent complication following brachial plexus avulsion (BPA). Ferroptosis has been implicated in various nervous system disorders. However, the association between ferroptosis and neuropathic pain induced by BPA remains unclear. This study aimed to investigate the role of ferroptosis in BPA-induced neuropathic pain. A rat model of neuropathic pain was established via BPA induction. Pain thresholds of rats were measured after BPA surgery and intraperitoneal injection of Fer-1. On day 14 postsurgery, spinal dorsal horn (SDH) samples were collected for Western blotting, biochemical analysis, and immunohistochemistry to analyze the expression and distribution of ferroptosis-related markers. The relationships among 5-HT3a receptor, calcium/calmodulin (CaM) pathway, and ferroptosis were assessed via Western blotting, biochemical analysis, and lipid peroxidation assays, including iron and calcium content, reactive oxygen species, glutathione peroxidase 4 (GPX4), ACSL, and CaM expression. BPA-induced neuropathic pain was associated with iron accumulation, increased lipid peroxidation, dysregulated expression of Acyl-CoA synthetase long-chain family member 4, and GPX4, and changes in transferrin receptor, divalent metal transporter 1, and ferroportin-1 (FPN1). Intraperitoneal administration of Fer-1 reversed all of these alterations and mitigated mechanical and cold hypersensitivity. Inhibition of the 5-HT3a receptor reduced the extent of ferroptosis. Furthermore, the 5-HT3a receptor can regulate the calcium/CaM pathway via L-type calcium channels (LTCCs), and blocking LTCCs with nifedipine also alleviated ferroptosis in the SDH of BPA rats. Taken together, in rats with BPA, the development of neuropathic pain involves ferroptosis, which is regulated by the 5-HT3a receptor through the LTCCs and the calcium/CaM signaling pathway in the SDH.