[Progress of intraosseous basivertebral nerve ablation for symptomatic Modic alterations].

Chronic lumbar and back pain caused by degenerative vertebral endplates presents a challenging issue for patients and clinicians. As a new minimally invasive spinal treatment method, radiofrequency ablation of vertebral basal nerve in bone can denature the corresponding vertebral basal nerve through radiofrequency ablation of degenerative vertebral endplate. It blocks the nociceptive signal transmission of the vertebral base nerve, thereby alleviating the symptoms of low back pain caused by the degenerative vertebral endplate. At present, many foreign articles have reported the operation principle, operation method, clinical efficacy and related complications of radiofrequency ablation of the vertebral basal nerve. The main purpose of this paper is to conduct a comprehensive analysis of the current relevant research, and provide a reference for the follow-up clinical research.

Review of craniofacial pain syndromes involving the greater occipital nerve: relevant anatomy, clinical findings, and interventional management.

Craniofacial pain syndromes exhibit a high prevalence in the general population, with a subset of patients developing chronic pain that significantly impacts their quality of life and results in substantial disabilities. Anatomical and functional assessments of the greater occipital nerve (GON) have unveiled its implication in numerous craniofacial pain syndromes, notably through the trigeminal-cervical convergence complex. The pathophysiological involvement of the greater occipital nerve in craniofacial pain syndromes, coupled with its accessibility, designates it as the primary target for various interventional procedures in managing craniofacial pain syndromes. This educational review aims to describe multiple craniofacial pain syndromes, elucidate the role of GON in their pathophysiology, detail the relevant anatomy of the greater occipital nerve (including specific intervention sites), highlight the role of imaging in diagnosing craniofacial pain syndromes, and discuss various interventional procedures such as nerve infiltration, ablation, neuromodulation techniques, and surgeries. Imaging is essential in managing these patients, whether for diagnostic or therapeutic purposes. The utilization of image guidance has demonstrated an enhancement in reproducibility, as well as technical and clinical outcomes of interventional procedures. Studies have shown that interventional management of craniofacial pain is effective in treating occipital neuralgia, cervicogenic headaches, cluster headaches, trigeminal neuralgia, and chronic migraines, with a reported efficacy of 60-90% over a duration of 1-9 months. Repeated infiltrations, neuromodulation, or ablation may prove effective in selected cases. Therefore, reassessment of treatment response and efficacy during follow-up is imperative to guide further management and explore alternative treatment options. Optimal utilization of imaging, interventional techniques, and a multidisciplinary team, including radiologists, will ensure maximum benefit for these patients.

Turmeric Bioactive Compounds Alleviate Spinal Nerve Ligation-Induced Neuropathic Pain by Suppressing Glial Activation and Improving Mitochondrial Function in Spinal Cord and Amygdala.

This study examined the effects of turmeric bioactive compounds, curcumin C3 complex® (CUR) and bisdemethoxycurcumin (BDMC), on mechanical hypersensitivity and the gene expression of markers for glial activation, mitochondrial function, and oxidative stress in the spinal cord and amygdala of rats with neuropathic pain (NP). Twenty-four animals were randomly assigned to four groups: sham, spinal nerve ligation (SNL, an NP model), SNL+100 mg CUR/kg BW p.o., and SNL+50 mg BDMC/kg BW p.o. for 4 weeks. Mechanical hypersensitivity was assessed by the von Frey test (VFT) weekly. The lumbosacral section of the spinal cord and the right amygdala (central nucleus) were collected to determine the mRNA expression of genes (IBA-1, CD11b, GFAP, MFN1, DRP1, FIS1, PGC1α, PINK, Complex I, TLR4, and SOD1) utilizing qRT-PCR. Increased mechanical hypersensitivity and increased gene expression of markers for microglial activation (IBA-1 in the amygdala and CD11b in the spinal cord), astrocyte activation (GFAP in the spinal cord), mitochondrial dysfunction (PGC1α in the amygdala), and oxidative stress (TLR4 in the spinal cord and amygdala) were found in untreated SNL rats. Oral administration of CUR and BDMC significantly decreased mechanical hypersensitivity. CUR decreased CD11b and GFAP gene expression in the spinal cord. BDMC decreased IBA-1 in the spinal cord and amygdala as well as CD11b and GFAP in the spinal cord. Both CUR and BDMC reduced PGC1α gene expression in the amygdala, PINK1 gene expression in the spinal cord, and TLR4 in the spinal cord and amygdala, while they increased Complex I and SOD1 gene expression in the spinal cord. CUR and BDMC administration decreased mechanical hypersensitivity in NP by mitigating glial activation, oxidative stress, and mitochondrial dysfunction.

Superior Cluneal Nerve Entrapment Syndrome: Thought to Be Spondylolysis.

A rare but typically overlooked diagnosis in the orthopaedic surgery community is superior cluneal nerve (SCN) entrapment syndrome. The cluneal nerves function as purely sensory fibers, and the SCNs provide cutaneous innervation to the posterior parasacral, gluteal, and posterolateral thigh regions. When irritated, this syndrome can cause acute and chronic lower back pain and lower extremity symptoms. A 14-year-old adolescent girl presented to the clinic for an evaluation of pain in the right side of her lower back. The patient's physical examination showed tenderness to palpation on the right posterior iliac crest seven centimeters from the midline. Her neurologic examination demonstrated normal deep tendon reflexes, muscle strength, and sensation in the L2-S1 dermatomal distribution. Although imaging showed evidence of a left L5 spondylolysis, she responded positively to a steroid injection over the posterior iliac crest but negatively to one over the L5 pars defect. She later underwent a right SCN decompression surgery. After the procedure, she reported at least 90% improvement in her pain and rated it as a one in severity, on a scale of 0 to 10. Research regarding SCN entrapment syndrome has increased in the past several years. However, most of these studies are limited to the adult population. Therefore, more reports highlighting the potential for this syndrome in adolescents are needed as well.

Surgical management of pediatric occipital neuralgia: a single-center experience of an uncommon pathology.

OBJECTIVE: Occipital neuralgia (ON) is a rare headache disorder characterized by sharp pain in the distribution of the greater occipital nerve (GON), lesser occipital nerve, or third occipital nerve. ON is commonly associated with traumatic injury, and effective identification and diagnosis can be difficult given the infrequent presentation and similarities to other pediatric headache disorders. While GON decompression has been well described in adults for refractory pain, there is a paucity of data in the pediatric population, with no previously published series on ON. The primary aim of this study was to identify the characteristics of pediatric patients with ON prior to surgical intervention and to describe the natural history of postoperative outcomes after decompression or neurectomy in a pediatric population. METHODS: A single-center retrospective case series was performed to evaluate factors predisposing children to refractory ON and the surgical efficacy of GON decompression or neurectomy. Six patients (mean age 15.0 ± 2.2 years) were identified for inclusion from October 2021 to October 2022. All patients had refractory ON as diagnosed by a pediatric neurologist. After medical therapy and repeated occipital nerve blocks failed, the patients were referred for GON decompression. Five patients had a history of trauma. RESULTS: Six patients were identified and treated in our cohort, highlighting the infrequency of this pathology. All had at least one occipital nerve block, with 83% receiving varied relief. All underwent bilateral decompression or neurectomy of the GON and experienced relief, reporting improved visual analog scale scores (mean 8.3 ± 0.9 preoperatively to 1.0 ± 2.2 postoperatively, p = 0.0009). The patients were followed for an average of 10 months, and their mean number of medications decreased from 2.7 ± 0.5 preoperatively to 0.8 ± 0.7 postoperatively (p = 0.019). Each patient reported numbness or tingling in the GON distribution postoperatively, which spontaneously resolved over time. Two patients had recurrent pain in a delayed fashion. CONCLUSIONS: GON decompression and neurectomy are efficacious treatments of refractory ON in the pediatric population.

Anatomic description of the basivertebral nerve and meningeal branch of the spinal nerve in the dog.

PURPOSE: The existence of the basivertebral nerve and meningeal branch of the spinal nerve has not been proven in dogs to date. The objectives of this study are to 1) determine whether dogs have a meningeal branch of the spinal nerve (MBSN) and a basivertebral nerve (BVN) and to (2) describe anatomical characteristics of these two nerves. Authors also put forward a discussion on the possible clinical relevance of these findings. MATERIAL AND METHODS: Dissections were performed on six embalmed dogs at the Veterinary Faculty of Barcelona with the use of stereomicroscopy and microsurgery equipment. RESULTS: The MBSN (grossly) and BVN (grossly and histologically) were identified in the cervical, thoracic, and lumbar region in all dog specimens. In addition, other small fibers (suspected nerves) entering the vertebral body through small foramina close to the end plates were identified. Histological examination of the tissues confirmed the presence of nerve fibers (myelinated and unmyelinated) in suspected BVN samples. Results of the present study indicated that dogs have BVNs. Also, suspected nerve fibers were identified among the epidural fat, running from the intervertebral foramina, that likely represent the MBSN. CONCLUSION: These findings open up the discussion on extrapolation of treatment options employed in human medicine for "low back pain", such as BVN ablation, which is discussed in this article. Further anatomic and clinical studies of the innervation for the vertebral body, periosteum, vasculature, dorsal longitudinal ligament and anulus fibrosus are necessary to elucidate possible anatomical variants and breed differences as well as potential clinical (e.g., therapeutic) relevance.

DUSP8/TAK1 signaling mediates neuropathic pain through regulating neuroinflammation and neuron death in a spinal nerve ligation (SNL) rat model.

Nerve injury-induced neuropathic pain is a type of chronic pain associated with neuroinflammatory response and neuronal death; however the underlying molecular mechanisms are still unclear. Dual-specificity phosphatase 8 (DUSP8) can mediate numerous cellular events, but whether it's involved in neuropathic pain is unknown. In the study, we found that spinal nerve ligation (SNL) operation on rats significantly decreased DUSP8 expression levels in ipsilateral spinal cord (ISC) tissues. Consistently, lipopolysaccharide (LPS) exposure also reduced DUSP8 in murine microglial cells. Adeno-associated virus (AAV)-mediated DUSP8 over-expression was found to considerably ameliorate SNL-induced neuropathic pain in rats. Additionally, neuronal death in the ISC tissues was also attenuated by AAV-DUSP8 following SNL surgery. Moreover, SNL-triggered neuroinflammation and microglial activation were also mitigated upon DUSP8 over-expression by suppressing nuclear factor κB (NF-κB) signaling, which were validated in LPS-exposed microglial cells. Importantly, our in vitro experiments indicated that inflammatory response in microglial cells contributed to neuron death, and such effect could also be ameliorated by DUSP8 over-expression. Notably, we found that DUSP8 directly interacted with transforming growth factor ß activated kinase-1 (TAK1) in microglial cells. Both SNL and LPS led to the activation of TAK1/p38/JNK1/2 signaling, whereas being strongly abolished by DUSP8. Intriguingly, TAK1 blockage significantly diminished LPS-induced inflammation and neuron death, whereas being accelerated by DUSP8 knockdown, further indicating that DUSP8-ameliorated neuropathic pain was largely TAK1-dependent. Together, all our findings revealed that DUSP8/TAK1 signaling may be a potential target for neuropathic pain alleviation.

Single midline incision approach for decompression of greater, lesser and third occipital nerves in migraine surgery.

BACKGROUND: The traditional approach for occipital migraine surgery encompasses three separate surgical incisions in the posterior neck to decompress the greater occipital nerves (GON), lesser occipital nerves (LON), and third occipital nerves (TON). Other incisions have been investigated, including singular transverse incisions. We sought to evaluate a single, vertical midline incision approach for decompression of all six occipital nerves. METHODS: Using 10 cadaveric hemi-sides (5 fresh cadaver head and necks). Anatomic landmarks and the location of the bilateral GON, LON, and TON were marked according to previous anatomic studies. A single, midline 9-cm incision was made, and lateral skin flaps were raised to decompress or avulse all six nerves. RESULTS: Through the midline incision, the GON and TON were identified at 3.5 and 6.2 cm, respectively, inferior to a line bisecting the external auditory canal (EAC) and 1.5 cm lateral to the midline. The LON was identified as 6-cm inferior and 6.5-cm medial to a line bisecting the EAC in the plane just above the investing layer of the deep cervical fascia until the posterior border of the sternocleidomastoid was encountered. The LON had the greatest amount of variation but was identified lateral to the posterior border of the SCM. CONCLUSIONS: A single midline incision approach allows for successful identification and decompression of all six occipital nerves in migraine surgery.

HDAC6 inhibitor ACY-1215 improves neuropathic pain and its comorbidities in rats of peripheral nerve injury by regulating neuroinflammation.

The fact that neuropathic pain (NP) has no effective therapy and is frequently accompanied by psychiatric comorbidities is well established. Aberrant neuroinflammation plays an important role in the development and maintenance of NP. HDAC6 inhibitors have been demonstrated to ameliorate mechanical allodynia brought on by chemotherapy and peripheral nerve damage. However, its pharmacological mechanisms and its effects on NP-related mental disorders have not been fully elucidated. The present study was dedicated to exploring the effects of ACY-1215 (a specific HDAC6 inhibitor) on neuroinflammation and behavioral abnormalities associated with NP. In this work, spinal nerve ligation (SNL) was performed as an NP model on rats. Mechanical allodynia, cognitive impairment, and depressive-like behavior caused by SNL were attenuated by continuous intraperitoneal injection of ACY-1215. Moreover, ACY-1215 administration suppressed SNL-induced neuroinflammatory responses (including microgliosis, the elevation of pro-inflammatory factors IL-1ß and TNF-α) in ligation of the ipsilateral spinal dorsal horn (iSDH), hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, MyD88-dependent pro-inflammatory pathways (MyD88/NF-κB and MyD88/ERK) were activated in the iSDH following SNL and were inhibited by ACY-1215. Moreover, ACY-1215 enhanced the acetylation modification of MyD88 and inhibited the SNL-induced elevation of MyD88 without affecting its transcription in the iSDH. These findings suggest that pharmacological inhibition of HDAC6 can ameliorate NP and its psychiatric complications through modulating neuroinflammation, in part by blocking the MyD88-mediated pro-inflammatory pathways. The possible mechanism is that ACY-1215 prevents the elevation of MyD88 reactivity by increasing its acetylation level. Notably, neither SNL nor ACY-1215 significantly altered MyD88 expression in HPC and PFC, indicating differentiated pro-inflammatory mechanisms in the supraspinal neural regions.

Decompression of the Greater Occipital Nerve for Occipital Neuralgia and Chronic Occipital Headache Caused by Entrapment of the Greater Occipital Nerve.

BACKGROUND: Chronic entrapment of the greater occipital nerve (GON) can not only manifest in typical stabbing pain of occipital neuralgia (ON) but also lead to continuous ache and pressure-like pain in the occipital and temporal areas. However, the effect of GON decompression on these symptoms has yet to be established. We report the follow-up results of GON decompression in typical cases of ON and chronic occipital headache due to GON entrapment (COHGONE). METHODS: A 1-year follow-up study of GON decompression was conducted on 11 patients with typical ON and 39 COHGONE patients with GON entrapment. The degree of pain reduction was analyzed using the numerical rating scale-11 (NRS-11) score and percent pain relief before and 1 year after surgery. A success was defined by at least a 50% reduction in pain measured via NRS-11 during the 12-month follow-up. To assess the degree of subjective satisfaction, a 10-point Likert scale was used. Postoperative outcome was also evaluated using the Barrow Neurological Institute (BNI) pain intensity score. The difference in GON decompression between the patients with typical ON and those with COHGONE was studied. RESULTS: GON decompression was successful in 43 of 50 patients (86.0%) and percent pain relief was 72.99 ± 25.53. Subjective improvement based on a 10-point Likert scale was 7.9 ± 2.42 and the BNI grade was 2.06 ± 1.04. It was effective in both the ON and COHGONE groups, but the success rate was higher in the ON group (90.9%) than in the COHGONE group (84.6%), showing statistically significant differences in the results based on average NRS-11 score, percent pain relief, subjective improvement, and BNI grades (p < 0.05, independent t-test). CONCLUSION: GON decompression is effective in chronic occipital headache and in ON symptoms induced by GON entrapment.

A new approach for contralateral C7 nerve transfer via retrospinal route.

Anterior and posterior approaches exist for the treatment of spinal pathologies. Anatomically, the 7th cervical spinal nerve(C7)crosses the C6-C7 intervertebral foramen bilaterally, allowing contralateral prevertebral or posterior C7 nerve transfer to be used. The advantage of the posterior rather than the anterior spinal approach is that it does not require retraction of important blood vessels, nerves, or other structures. In this paper, we describe transfer of the contralateral C7 nerve using a posterior approach.

Anatomical Evaluation of Spinal Nerve and Cervical Intervertebral Foramina in Anterior Controllable Antedisplacement and Fusion Surgery: A Cadaveric and Radiologic Study.

OBJECTIVE: To achieve the anatomical evaluation of spinal nerve and cervical intervertebral foramina in anterior controllable antedisplacement and fusion (ACAF) surgery, a novel surgical technique with the wider decompression, through a cadaveric and radiologic study. METHODS: Radiographic data of consecutive 47 patients (21 by ACAF and 26 by anterior cervical corpectomy and fusion [ACCF]) who have accepted surgery for treatment of cervical ossification of the posterior longitudinal ligament(OPLL) and stenosis from March 2017 to March 2018 were retrospectively reviewed and compared between an ACAF group and ACCF group. Three postoperative radiographic parameters were evaluated: the decompression width and the satisfaction rate of decompression at the entrance zone of intervertebral foramina on computed tomography (CT), and the transverse diameter of spinal cord in the decompression levels on magnetic resonance imaging (MRI). In the anatomic study, three fresh cadaveric spines (death within 3 months) undergoing ACAF surgery were also studied. Four anatomic parameters were evaluated: the width of groove, the distance between the bilateral origins of ventral rootlets, the length of ventral rootlet from their origin to the intervertebral foramina, the descending angle of ventral rootlet. RESULTS: The groove created in ACAF surgery included the bilateral origins of ventral rootlets. The rootlets tended to be vertical from the rostral to the caudal direction as their takeoff points from the central thecal sac became higher and farther away from their corresponding intervertebral foramina gradually. No differences were identified between left and right in terms of the length of ventral rootlet from the origin to the intervertebral foramina and the descending angle of ventral rootlet. The decompression width was significantly greater in ACAF group (19.2 ± 1.2 vs 14.7 ± 1.2, 21.3 ± 2.2 vs 15.4 ± 0.9, 21.5 ± 2.1 vs 15.7 ± 1.0, 21.9 ± 1.6 vs 15.9 ± 0.8, from C3 to C6 ). The satisfactory rate of decompression at the entrance zone of intervertebral foramina tended to be better in the left side in ACAF group (significant differences were identified in the left side at C3/4 , C4/5 , C6/7 level, and in the right side at C4/5 level when compared with ACCF). And decompression width was significantly greater than the transverse diameter of spinal cord in ACAF group. Comparatively, there existed no significant difference in the ACCF group besides the C5 level. CONCLUSION: ACAF can decompress the entrance zone of intervertebral foramina effectively and its decompression width includes the origins and massive running part of bilateral ventral rootlets. Due to its wider decompression range, ACAF can be used as a revision strategy for the patients with failed ACCF.

Diagnostic Role of Selective Spinal Nerve Block in Treatment of Lumbar Spine Diseases by Percutaneous Endoscopic Technique.

AIM: To assess the role of our modified selective spinal nerve block (SSNB) procedure to predict the results of the subsequent Percutaneous endoscopic transforaminal lumbar surgeries (PETLS). MATERIAL AND METHODS: We retrospectively analyzed data of patients who underwent our modified SSNBs before PETLS from February 2013 to March 2018 Clinical outcome data were collected 3 days after PETLS and at follow-up visits. RESULTS: A total of 120 modified SSNB procedures (transforaminal-78 paravertebral-24, and interlaminar-18) in 92 patients presented positive response. The median follow-up period was 30.6 months. Based on Macnab criteria, the overall success rate (excellent and good results) was 83.7%. Fair and poor outcomes were observed in 10 and 5 patients, respectively. Patients with atypical extraforaminal herniations, and patients with two-level or multiple-level lumbar disc herniations or stenosis achieved desirable results after PETLS. There was significant improvement in the average VAS score for the leg three days after surgery (7.38±0.97 vs. 1.96 ±1.17, p < 0.05) and on follow-up visits (1.21 ± 0.83, p < 0.05). ODI was also significantly improved three days after surgery (37.20 ± 2.36 vs. 10.95 ± 2.25, p < 0.05 and at follow-up visits (8.90 ± 1.72, p < 0.05) CONCLUSION: The needle tip should be located closely near the intended compressed nerve via suitable approach combined with slowly injecting 1 ml lidocaine (1%) when performing our modified SSNB technique. It presents an alternative diagnostic procedure to identify the origin of pain of complicated lumbar diseases and to predict PETLS outcomes.

Postoperative complications of Goel-Harms C1-C2 screw-rod fixation technique for C1-C2 instability after C2 nerve sacrifice, a prospective study over two years follow up.

BACKGROUND: Atlantoaxial instability is mainly caused by trauma. C2 nerve is usually needed to be sacrificed for adequate exposure of the lateral mass and screw insertion. OBJECTIVES: This study aimed to investigate the clinical outcome of postoperative complications of C1 and C2 screw-rod fixation using the Goel-Harms technique for C1-C2 instability after sacrificing the C2 nerve root. METHODS: Amongst forty patients with C1-C2 pathology, twenty-seven cases were enrolled into the study, then variables, including age, sex, primary pathology, operation duration, postoperative pain, paresthesia, anesthesia, and other specific conditions, were documented. Data analyzed by an expert biostatistician. p-value < 0.05 was considered significant. RESULTS: Regardless of gender, the most postoperative adverse effect was occipital anesthesia (81.5%). Most of the patients (63%) had both occipital pain and anesthesia one-month post-surgery. At 3- and 6-months post-surgery, occipital pain and anesthesia were seen in 40.7% and 14.8%, respectively. CONCLUSION: The most common postoperative adverse effect of C2 nerve root scarification after C1-C2 fixation is occipital anesthesia followed by occipital paresthesia and pain, which are reduced in severity over time.

Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response.

Spinal inflammation is a pathophysiological state of neuropathic pain (NP). The subsequent microglial activation and neuroinflammatory response are contributing factors for long-lasting behavioral hypersensitivity. Valproic acid (VPA), a histone deacetylase inhibitor, has promising anti-inflammatory and neuroprotective properties for clinical use in the treatment of neurological disorders. However, the underlying mechanisms of its effects on NP have not been determined. This study aimed to clarify the possible mechanisms by which VPA alleviates NP in rat models induced by spinal nerve ligation (SNL). Intraperitoneal injection of VPA (300 mg/kg) efficiently attenuated mechanical allodynia in rats with NP. VPA exerted anti-inflammatory effects by downregulating proinflammatory cytokines (tumor necrosis factor-α, cytokines interleukin-1ß, cytokines interleukin-6; TNF-α, IL-1ß, and IL-6) and upregulating anti-inflammatory cytokines (transforming growth factor-ß, cytokines interleukin-10, cytokines interleukin-4; TGF-ß, IL-10 and IL-4). Additionally, VPA suppressed spinal microgliosis and promoted the polarization of microglia towards the M2 phenotype to further ameliorate spinal neuroinflammation. VPA also exerted neuroprotective effects by decreasing spinal cell apoptosis. The anti-inflammatory and neuroprotective effects may have depended on changes in nuclear histone deacetylase 3 (HDAC3) expression following VPA treatment. Moreover, VPA treatment inhibited nuclear factor-κB (NF-κB) p65 nuclear expression and upregulated acetylated the signal transducer and activator of transcription 1 (STAT1). In addition, VPA suppressed SNL-induced phosphorylation of Janus Kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Taken together, our results demonstrate that VPA is a promising anti-inflammatory agent suitable for NP therapy that regulates microglial function and suppresses spinal neuroinflammation via the STAT1/NF-κB and JAK2/STAT3 signaling pathways.

Electro-acupuncture Suppresses AXL Expression in Dorsal Root Ganglion Neurons and Enhances Analgesic Effect of AXL Inhibitor in Spinal Nerve Ligation Induced-Neuropathic Pain Rats.

Electro-acupuncture (EA) has been used for clinic analgesia for many years. However, its mechanisms are not fully understood. We recently reported that AXL, a tyrosine kinase receptor, contributes to the peripheral mechanism of neuropathic pain. We here aim to figure out the significance of EA on neuropathic pain mediated by AXL in dorsal root ganglion (DRG). Spinal nerve ligation (SNL) was used as a neuropathic pain model. EA was applied at ''Huantiao'' (GB-30) and ''Yanglingquan'' (GB-34) acupoints for 30 min daily from day 7 to day 10 after SNL. EA not only gradually attenuated SNL-induced mechanical allodynia, but also suppressed the expression of phosphorylated AXL (p-AXL) and AXL in injured DRGs of SNL rats examined by western blotting and immunofluorescence. Moreover, intrathecal injection of the subthreshold dose of AXL inhibitor TP0903, significantly prolonged the analgesic time of single EA treatment and enhanced the analgesic effect of repeated EA treatments, suggesting a synergic effect of EA and AXL inhibitor. These results indicate that AXL signaling underlies EA analgesia and combination of AXL inhibitor and EA might be a new strategy for clinic analgesia on neuropathic pain.

L5 Spinal Nerve Axotomy Induces Distinct Electrophysiological Changes in Axotomized L5- and Adjacent L4-Dorsal Root Ganglion Neurons in Rats In Vivo.

Peripheral neuropathic pain (PNP) is a major health problem for which effective drug treatment is lacking. Its underlying neuronal mechanisms are still illusive, but pre-clinical studies using animal models of PNP including the L5-spinal nerve axotomy (L5-SNA) model, suggest that it is partly caused by excitability changes in dorsal root ganglion (DRG) neurons. L5-SNA results in two DRG neuronal groups: (1) axotomized/damaged neurons in L5- plus some in L4-DRGs, and (2) ipsilateral L4-neurons with intact/uninjured fibers intermingling with degenerating L5-fibers. The axotomized neurons are deprived of peripherally derived trophic factors and degenerate causing neuroinflammation, whereas the uninjured L4-neuorns are subject to increased trophic factors and neuroinflammation associated with Wallerian degeneration of axotomized L5-nerve fibers. Whether these two groups of DRG neurons exhibit similar or distinct electrophysiological changes after L5-SNA remains unresolved. Conflicting evidence for this may result from some studies assuming that all L4-fibers are undamaged. Here, we recorded somatic action potentials (APs) intracellularly from C- and A-fiber L4/L5 DRG neurons in vivo, to examine our hypothesis that L5-SNA would induce distinct electrophysiological changes in the two populations of DRG neurons. Consistent with this hypothesis, we found (7 days post-SNA), in SNA rats with established pain hypersensitivity, slower AP kinetics in axotomized L5-neurons and faster AP kinetics in L4-nociceptive neurons including decreased rise time in Aδ-and Aß-fiber nociceptors, and after-hyperpolarization duration in Aß-fiber nociceptors. We also found several changes in axotomized L5-neurons but not in L4-nociceptive neurons, and some changes in L4-nociceptive but not L5-neurons. The faster AP kinetics (decreased refractory period) in L4-nociceptive neurons that are consistent with their reported hyperexcitability may lead to repetitive firing and thus provide enhanced afferent input necessary for initiating and/or maintaining PNP development. The changes in axotomized L5-neurons may contribute to the central mechanisms of PNP via enhanced neurotransmitter release in the central nervous system (CNS).

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons.

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment.

Antiallodynic effect of PhAR-DBH-Me involves cannabinoid and TRPV1 receptors.

The antiallodynic effect of PhAR-DBH-Me was evaluated on two models of neuropathic pain, and the potential roles of CB1, CB2, and TRPV1 receptors as molecular targets of PhAR-DBH-Me were studied. Female Wistar rats were submitted to L5/L6 spinal nerve ligation (SNL) or repeated doses of cisplatin (0.1 mg/kg, i.p.) to induce experimental neuropathy. Then, tactile allodynia was determined, and animals were treated with logarithmic doses of PhAR-DBH-Me (3.2-100 mg/kg, i.p.). To evaluate the mechanism of action of PhAR-DBH-Me, in silico studies using crystallized structures of CB1, CB2, and TRPV1 receptors were performed. To corroborate the computational insights, animals were intraperitoneally administrated with antagonists for CB1 (AM-251, 3 mg/kg), CB2 (AM-630, 1 mg/kg), and TRPV1 receptors (capsazepine, 3 mg/kg), 15 min before to PhAR-DBH-Me (100 mg/kg) administration. Vagal stimulation evoked on striated muscle contraction in esophagus, was used to elicited pharmacological response of PhAR-DBH-ME on nervous tissue. Systemic administration of PhAR-DBH-Me reduced the SNL- and cisplatin-induced allodynia. Docking studies suggested that PhAR-DBH-Me acts as an agonist for CB1, CB2, and TRPV1 receptors, with similar affinity to the endogenous ligand anandamide. Moreover antiallodynic effect of PhAR-DBH-Me was partially prevented by administration of AM-251 and AM-630, and completely prevented by capsazepine. Finally, PhAR-DBH-Me decreased the vagally evoked electrical response in esophagus rat. Taken together, results indicate that PhAR-DBH-Me induces an antiallodynic effect through partial activation of CB1 and CB2 receptors, as well as desensitization of TRPV1 receptors. Data also shed light on the novel vanilloid nature of the synthetic compound PhAR-DBH-Me.