C2 Dorsal Root Ganglion Research Articles

Repeat RF Ablation of C2 and Third Occipital Nerves for Recurrent Occipital Neuralgia and Cervicogenic Headaches

Objective: To address the degree and duration of pain relief from recurrent cervicogenic headaches and/or occipital neuralgia following retreatment with radiofrequency ablation of the C2 dorsal root ganglion and/or third occipital nerves; to review outcomes including duration and degree of pain relief; to evaluate procedure’s complication rate and patient’s willingness to repeat the procedure; to compare effectiveness of the most recent RF ablation to patient’s first RF ablation. Methods: This is a single-center retrospective observational study of 23 patients with recurrent cervicogenic headaches and/or occipital neuralgia treated with repeated RF ablation of the C2 dorsal root ganglion and/or third occipital nerves. All patients receiving treatment from January 2010 to July 2014 are included in this single site retrospective study. This is an IRB approved medical chart review study. Results: 22 of 23 patients underwent follow-up. An average of 86.5% of participants reported pain relief on average of 25.4 weeks at time of follow-up. 41% reported side effects including suboccipital hyperesthesia and/or ear discomfort, 95% reported willingness to repeat the procedure again if severe symptoms recurred, 59% of patients reported the most recent RF ablation had the same results as the first, 32% reported the most recent RF was the most effective, and 9% reported that the first RF was the most effective. Conclusion: Repeated RF ablation is a feasible option for recurrent cervicogenic headaches and/or occipital neuralgia. Effectiveness of repeat intervention is the same or better than the first ablation. Though there was a higher likelihood of side effects including suboccipital neuralgia and/or ear discomfort on repeat treatment, the side effects were generally well tolerated.

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

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). 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. 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. Systemic application of the p75NTR inhibitory antibody suppressed neuropathic pain after BPA. p75NTR may be a potential therapeutic target for the clinical treatment of neuropathic pain in BPA injury.

Brown Adipose Tissue Has Sympathetic-Sensory Feedback Circuits

Brown adipose tissue (BAT) is an important source of thermogenesis which is nearly exclusively dependent on its sympathetic nervous system (SNS) innervation. We previously demonstrated the SNS outflow from brain to BAT using the retrograde SNS-specific transneuronal viral tract tracer, pseudorabies virus (PRV152) and demonstrated the sensory system (SS) inflow from BAT to brain using the anterograde SS-specific transneuronal viral tract tracer, H129 strain of herpes simplex virus-1. Several brain areas were part of both the SNS outflow to, and receive SS inflow from, interscapular BAT (IBAT) in these separate studies suggesting SNS-SS feedback loops. Therefore, we tested whether individual neurons participated in SNS-SS crosstalk by injecting both PRV152 and H129 into IBAT of Siberian hamsters. To define which dorsal root ganglia (DRG) are activated by BAT SNS stimulation, indicated by c-Fos immunoreactivity (IR), we prelabeled IBAT DRG innervating neurons by injecting the retrograde tracer Fast Blue (FB) followed 1 week later by intra-BAT injections of the specific β3-adrenoceptor agonist CL316,243 in one pad and the vehicle in the contralateral pad. There were PRV152+H129 dually infected neurons across the neuroaxis with highest densities in the raphe pallidus nucleus, nucleus of the solitary tract, periaqueductal gray, hypothalamic paraventricular nucleus, and medial preoptic area, sites strongly implicated in the control of BAT thermogenesis. CL316,243 significantly increased IBAT temperature, afferent nerve activity, and c-Fos-IR in C2-C4 DRG neurons ipsilateral to the CL316,243 injections versus the contralateral side. The neuroanatomical reality of the SNS-SS feedback loops suggests coordinated and/or multiple redundant control of BAT thermogenesis.

Transduction of Neurotrophin 3 gene into peripheral nerve graft for treatment of cervical dorsal root injury

Objective To explore the therapeutic effect of the transduction of Neurotrophin 3 gene into peripheral nerve graft for treatment of cervical dorsal root injury in adult rats.Methods 24 adult male Fisher 344 rats were grouped into A (intact),B (reconstruction with PNG-GFP),and C (reconstruction with PNG-NT-3).The treatment was assessed by hot plate test,electrophysiological examination,light and electron microscopy and neurotrace labeling examinations 4 months after the nerve reconstruction.Results Four months after reconstruction,partial pain perception defects were restored.Recording of somatosensory evoked potentials,axonal regeneration and fluorescent tracer transport showed electrical and physical reconnection of the C7 dorsal root ganglion neurons to the spinal cord through the reconstructed pathway in NT-3 and GFP groups.The results of electrophysiological examination and neurotracing in the NT-3 group were superior to the GFP group and the control group (P ＜ 0.01).Conclusions Local released NT-3 by genetic engineering peripheral nerve graft could promote the regeneration of injuried central axons of C7 dorsal root ganglion neurons into the posterior horn in adult rats.Partial sensory function defects were restored. Key words: Brachial plexus ; Nerve injury ; Anastomosis,surgical; Genes ; Rats

Response of Cervicogenic Headaches and Occipital Neuralgia to Radiofrequency Ablation of the C2 Dorsal Root Ganglion and/or Third Occipital Nerve

This article investigates the degree and duration of pain relief from cervicogenic headaches or occipital neuralgia following treatment with radiofrequency ablation of the C2 dorsal root ganglion and/or third occipital nerves. It also addresses the procedure's complication rate and patient's willingness to repeat the procedure if severe symptoms recur. This is a single-center retrospective observational study of 40 patients with refractory cervicogenic headaches and or occipital neuralgia. Patients were all referred by a headache specialty clinic for evaluation for radiofrequency ablation of the C2 dorsal root ganglion and/or third occipital nerves. After treatment, patients were followed for a minimum of 6 months to a year. Patient demographics and the results of radiofrequency ablation were recorded on the same day, after 3-4 days, and at 6 months to 1 year following treatment. Thirty-five percent of patients reported 100% pain relief and 70% reported 80% or greater pain relief. The mean duration of improvement is 22.35 weeks. Complication rate was 12-13%. 92.5% of patients reported they would undergo the procedure again if severe symptoms returned. Radiofrequency ablation of the C2 dorsal root ganglion and/or third occipital nerve can provide many months of greater than 50% pain relief in the vast majority of recipients with an expected length of symptom improvement of 5-6 months.

Sensory Neuron Death After Upper Limb Nerve Injury and Protective Effect of Repair

Extensive death of sensory neurons after nerve trauma depletes the number of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neoadjuvant drugs require noninvasive in vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, magnetic resonance imaging (MRI) proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia. This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair. A 3-T clinical magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in uninjured volunteers (controls, n = 14), hand amputees (unrepaired nerve injury, n = 5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n = 4). MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. A mean 14% volume reduction was found in amputees' C7 and C8 DRG (P < .001 vs controls). Volume loss was lower in median and ulnar nerve repair patients (mean 3% volume loss, P < .01 vs amputees), and varied among patients. T1 DRG volume remained unaffected. MRI provides noninvasive in vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating a neuroprotective benefit of early repair. Volumetric MRI has potential diagnostic applications and is a quantitative tool for clinical trials of neuroprotective therapies.

Bilateral Changes of Cannabinoid Receptor Type 2 Protein and mRNA in the Dorsal Root Ganglia of a Rat Neuropathic Pain Model

Cannabinoid receptor type 2 (CB2R) plays a critical role in nociception. In contrast to cannabinoid receptor type 1 ligands, CB2R agonists do not produce undesirable central nervous system effects and thus promise to treat neuropathic pain that is often resistant to medical therapy. In the study presented here, we evaluated the bilateral distribution of the CB2R protein and messenger RNA (mRNA) in rat dorsal root ganglia (DRG) after unilateral peripheral nerve injury using immunohistochemistry, western blot, and in situ hybridization analysis. Unilateral chronic constriction injury (CCI) of the sciatic nerve induced neuropathic pain behavior and bilateral elevation of both CB2R protein and mRNA in lumbar L4-L5 as well as cervical C7-C8 DRG when compared with naive animals. CB2R protein and mRNA were increased not only in DRG neurons but also in satellite glial cells. The fact that changes appear bilaterally and (albeit at a lower level) even in the remote cervical DRG can be related to propagation of neuroinflammation alongside the neuraxis and to the neuroprotective effects of CB2R.

An Anatomical and Immunohistochemical Characterization of Afferents Innervating the C6–C7 Facet Joint After Painful Joint Loading in the Rat

This study used retrograde neuronal tracing and immunohistochemistry to identify neurons innervating the C6-C7 facet joint and those expressing calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG) of rats after painful cervical facet joint injury. The objective of this study was to characterize the innervation of the C6-C7 facet joint after painful joint injury in the rat. The cervical facet joint is a source of neck pain, and its loading can initiate persistent pain. CGRP is a nociceptive neurotransmitter; peptidergic afferents have been identified in the facet joint's capsule. Although studies suggest that facet joint injury alters CGRP expression in joint afferents, the distribution of neurons innervating the C6-C7 facet joint and their expression of CGRP after a painful joint injury have not been investigated. Holtzman rats (Harlan Sprague-Dawley, Indianapolis, IN) received an intra-articular injection of cholera toxin subunit B in the C6-C7 facet joints. After injection, subgroups underwent either a painful joint distraction or sham procedure. Mechanical sensitivity was assessed, and immunohistochemical techniques were used to quantify CGRP expression and cholera toxin subunit B labeling in the C5-C8 DRGs. Facet joint distraction-induced (P ≤ 0.0002) hypersensitivity. Neurons labeled by the joint injection were identified in the C5-C8 DRGs. Significantly, more (P ≤ 0.0001) cholera toxin subunit B-positive neurons were identified in the C7 DRG than any other level. At C7, 54.4% ± 15.3% of those neurons were also CGRP-positive, whereas only 41.5% ± 5.4% of all neurons were CGRP-positive; this difference was significant (P = 0.0084). The greatest number of afferents from the C6-C7 facet joint has cell bodies in the C7 DRG, implicating this level as the most relevant for pain from this joint. In addition, peptidergic afferents seem to have an important role in facet joint-mediated pain.

Experimental research Effects of ischemic phrenic nerve root ganglion injury on respiratory disturbances in subarachnoid hemorrhage: an experimental study

IntroductionPhrenic nerves have important roles on the management of respiration rhythm. Diaphragm paralysis is possible in phrenic nerve roots ischemia in subarachnoid hemorrhage (SAH). We examined whether there is a relationship between phrenic nerve root ischemia and respiratory disturbances in SAH.Material and methodsThis study was conducted on 5 healthy control and 14 rabbits with experimentally induced SAH by injecting autologous blood into their cisterna magna. Animals were followed up via monitors for detecting the heart and respiration rhythms for 20 days and then decapitaed by humanely. Normal and degenerated neuron densities of phrenic nerve root at the level of C4 dorsal root ganglia (C4DRG) were estimated by Stereological methods. Between the mean numerical density of degenerated neurons of C4DRG and respiratory rate/minute of groups were compared statistically.ResultsPhrenic nerve roots, artery and diaphragm muscles degeneration was detected in respiratory arrest developed animals. The mean neuronal density of C4DRG was 13272 ±1201/mm3 with a mean respiration rate of 23 ±4/min in the control group. The mean degenerated neuron density was 2.240 ±450/mm3 and respiration rhythm was 31 ±6/min in survivors. But, the mean degenerated neuron density was 5850 ±650/mm3 and mean respiration rhythm was 34 ±7/min in respiratory arrest developed animals (n = 7). A linear relationship was noticed between the degenerated neuron density of C4DRG and respiraton rate (r = –0.758; p < 0.001).ConclusionsPhrenic nerve root ischemia may be an important factor in respiration rhythms deteriorations in SAH which has not been mentioned in the literature.

Pulsed radio-frequency stimulation combined with nerve block for cervicogenic headache

Objective To observe the clinical effect on cervicogenic headache (CEH) of pulsed radiofrequency stimulation (PRF) applied to the C2 dorsal root ganglion combined with nerve block.Methods A total of 78 cases diagnosed as CEH were randomly divided into a combined treatment group,a PRF treatment group and a nerve block group.The combined treatment group was given both PRF applied to the C2 dorsal root ganglion and blocking therapy.The other two groups were given only one treatment or the other.All the treatments were once weekly for 3 weeks.Before treatment and 1,3 and 6 months after treatment,all of the patients' headaches were evaluated using a visual analogue scale (VAS).Results At 1,3 and 6 months after treatment,the average VAS scores of all three groups had decreased significantly.The VAS ratings dropped the most in the combined treatment group,followed by the PRF group and then the nerve block group.All the intergroup differences were statistically significant.The combined treatment group's cure rate (88％) was significantly better than that of the PRF group (81％),which was significantly better than that of the nerve block group (54％).Conclusion Combining PRF applied to the C2dorsal root ganglion with nerve block therapy has a synergistic effect on CEH.The curative effect of the combined treatment was better than either PRF or blocking alone. Key words: Headache; C2 dorsal root ganglia; Pulsed electrical stimulation; Radio-frequency electrical stimulation; Nerve blocking

Activating transcription factor 4, a mediator of the integrated stress response, is increased in the dorsal root ganglia following painful facet joint distraction

Chronic neck pain is one of the most common musculoskeletal disorders in the US. Although biomechanical and clinical studies have implicated the facet joint as a primary source of neck pain, specific cellular mechanisms still remain speculative. The purpose of this study was to investigate whether a mediator (activating transcription factor; 4ATF4) of the integrated stress response (ISR) is involved in facet-mediated pain. Holtzman rats underwent C6/C7 facet joint loading that produces either painful (n=16) or nonpainful (n=8) responses. A sham group (n=9) was also included as surgical controls. Behavioral sensitivity was measured and the C6 dorsal root ganglia (DRGs) were harvested on day 7 to evaluate the total and neuronal ATF4 expression. In separate groups, an intra-articular ketorolac injection was administered either immediately (D0 ketorolac) or 1 day (D1 ketorolac) after painful facet joint loading. Allodynia was measured at days 1 and 7 after injury to assess the effects on behavioral responses. ATF4 and BiP (an indicator of ISR activation) were separately quantified at day 7. Facet joint loading sufficient to elicit behavioral hypersensitivity produced a threefold increase in total and neuronal ATF4 expression in the DRG. After ketorolac treatment at the time of injury, ATF4 expression was significantly (P<0.01) reduced despite not producing any attenuation of behavioral responses. Interestingly, ketorolac treatment at day 1 significantly (P<0.001) alleviated behavioral sensitivity at day 7, but did not modify ATF4 expression. BiP expression was unchanged after either intervention time. Results suggest that ATF4-dependent activation of the ISR does not directly contribute to persistent pain, but it may sensitize neurons responsible for pain initiation. These behavioral and immunohistochemical findings imply that facet-mediated pain may be sustained through other pathways of the ISR.

Bilateral changes of IL-10 protein in lumbar and cervical dorsal root ganglia following proximal and distal chronic constriction injury of peripheral nerve

Interleukin-10 prevents transition of a physiological inflammatory reaction to a pathological state that may result in neuropathic pain. We studied bilateral changes of IL-10 protein levels in L4–L5 and C7–C8 dorsal root ganglia (DRG) after a chronic constriction injury (CCI) of either L4–L5 spinal nerves (pCCI) or the sciatic nerve (dCCI). Rats undergoing pCCI or dCCI were left to survive for 1, 3, 7 or 14 d, sham-operated rats for 3 or 14 d. After the survival time, C7–C8 and L4–L5 DRG were removed bilaterally from naïve, operated, and sham-operated rats and IL-10 protein was detected by immunohistochemical staining and measured using ELISA analysis. Unilateral pCCI and dCCI induced a transient bilateral elevation in IL-10 protein level not only in the homonymous lumbar DRG but also in the heteronymous cervical DRG nonassociated with the spinal segments of constricted nerve. Sham operations also induced bilateral elevation of IL-10 protein in both homonymous and heteronymous DRG. Our experiments revealed that the more proximal is a nerve injury the more rapid is the initial increase and slower the subsequent decrease of IL-10 protein level in DRG. Changes of IL-10 protein in DRG nonassociated with damaged nerve could be related to a general neuroinflammatory reaction of the nervous system to injury and thereby promote potential of the DRG neurons for regenerating their axons following a conditioning lesion.

Efficacy of pulsed radiofrequency application to C2 dorsal root ganglion for the treatment of cervicogenic headache

Seventy-four patients aged 26-63 yr who had suffered cervicogenic headache for 3 months-21 yr were treated with puked radiofrequency applied to C2 dorsal root ganglion, which is located in the middle of the posterior side of lateral atlantoaxial joint. A trochar was introduced percutaneously under the guidance of X-ray aiming at the target point. As it was inserted through the deep fascia, the stylet was withdrawn and a 10 cm long 22 gauge curved blunt electrode was inserted into the trochar and advanced until the patients felt radiating pain from the point of puncture to occiput. Lateral radiograph was obtained to verify the placement of electrode. The tip of the electrode was usually located in front of spinal canal at the atlantoaxial joint level. Sensory stimulation was performed with 50 Hz and 0.1-0.5 V and the patients could feel radiating pain at occiput. Motor stimulation was performed with 2 Hz and 0.4-1.0 V and regular pulsation of the patient's muscle of occiput could occur. Pulsed radiofrequency was applied at 42 ℃7 for 240 s and was performed twice on each side. VAS scores and disturbances of daily activity, mood and sleep were recorded before operation and at 1 week and 1, 3, 6, 12 and 18 months after pulsed radiofrequency treatment. Complications and recurrence within 12 and 18 months were recorded. Follow-up was lost in 22 patients. VAS scores and disturbances of daily activity, mood and sleep significantly decreased after procedure. All of the patients responded without complications like infection, spinal cord and vertebral artery injury. Some patients had transient occipital neuralgia which was usually relieved within 24 h. The recurrence rate in 12 and 18 months after operation was 19% and 31% respectively. Key words: Ganglia, spinal; Headache; Pulsed radiofrequency

Neurotrophin 3 Improves Delayed Reconstruction of Sensory Pathways After Cervical Dorsal Root Injury

Spinal root avulsion, or section, results in devastating functional sequels. Whereas reconstruction of motor pathways based on neurotization can reduce motor deficit, associated permanent limb anesthesia limits expected benefit. Sensory pathway reconstruction after dorsal root injury is limited by the inability of re-growing central sensory axons to enter the spinal cord through an injured root. To provide evidence for the reconnection of C7 DRG neurons with the central nervous system (CNS) after experimental section of the C7 dorsal root in adult rats. We assessed a new reconstruction strategy in adult rats 9 weeks after transection of C6 and C7 dorsal roots. Re-growing C7 central sensory axons were redirected to the noninjured C5 dorsal root through a nerve graft by end-to-side anastomosis that did not alter the C5 conduction properties. In a subgroup of rats, surgical reconstruction was combined with lentivirus-mediated gene transfer to the nerve graft in order to overexpress neurotrophin 3 (NT-3), a neurotrophic factor that stimulates sensory axon regeneration. Four months after reconstruction, recording of sensory evoked potentials and fluorescent tracer transport showed electrical and physical reconnection of the C7 dorsal root ganglion neurons to the spinal cord through the reconstructed pathway. Sensory perception recovery predominated on proprioception. Axonal regrowth and perception were improved when the nerve graft overexpressed neurotrophin-3 at the time of transplantation. Neurotrophin-3 overexpression did not persist 4 months after transplantation. Efficient and functional reconnection of dorsal root ganglion neurons to the spinal cord can be achieved in rats several weeks after cervical dorsal root injury. Surgical repair of sensory pathways could be considered in combination with motor nerve neurotization to treat persisting severe upper limb disability in humans.

Role of degenerated neuron density of dorsal root ganglion on anterior spinal artery vasospasm in subarachnoid hemorrhage: experimental study

The spinal arteries are innervated by several systems that contribute to the control of spinal cord blood flow. The sensory fibers of upper cervical nerves have vasodilatatory effect on the anterior spinal arteries (ASA). Subarachnoid hemorrhage (SAH) causes severe vasospasm by various neurochemical mechanisms. We examined whether there is a relationship between the neuron density of the C3 dorsal root ganglion and the severity of ASA vasospasm in SAH. This study was conducted on 20 rabbits. Four of them were used as baseline group. Experimental SAH has been applied to all of 16 animals by injecting homologous blood into cisterna magna. After 20 days of injection, ASA and C3 dorsal root ganglia (C3DRG) were examined histopathologically. ASA volume values and normal and degenerated neuron densities of C3DRG were estimated stereologically and the results were analyzed statistically. The mean ASA volume was 1.050±0.450 mm³, [corrected] and the mean neuronal density of C3DRG was 10,500 ± 850 in all animals. The mean volume value of ASA was 0.970±0.150 [corrected] mm³, and the normal neuron density of C3DRG fell to 8,600 ± 400/mm³ in slight vasospasm group. In severe vasospasm-developed animals, mean volume value of ASA was 0.540±0.90 [corrected]mm³ and the normal neuron density of C3DRG fell to 5,500 ± 360/mm³. An inverse relationship between the degenerated neuronal density of the C3DRG and ASA volume values may indicate the severity of ASA vasospasm. The neuron density of C3DRG may be an important factor on the regulation of ASA volume values and the continuation of spinal cord blood flow. Low neuron density of C3DRG may be considered as an important factor in the pathogenesis of severe ASA vasospasm in SAH.

8. Occipital Neuralgia

Occipital neuralgia is defined as a paroxysmal shooting or stabbing pain in the dermatomes of the nervus occipitalis major and/or nervus occipitalis minor. The pain originates in the suboccipital region and radiates over the vertex. A suggestive history and clinical examination with short-term pain relief after infiltration with local anesthetic confirm the diagnosis. No data are available about the prevalence or incidence of this condition. Most often, trauma or irritation of the nervi occipitales causes the neuralgia. Imaging studies are necessary to exclude underlying pathological conditions. Initial therapy consists of a single infiltration of the culprit nervi occipitales with local anesthetic and corticosteroids (2 C+). The reported effects of botulinum toxin A injections are contradictory (2 C+/-). Should injection of local anesthetic and corticosteroids fail to provide lasting relief, pulsed radio-frequency treatment of the nervi occipitales can be considered (2 C+). There is no evidence to support pulsed radio-frequency treatment of the ganglion spinale C2 (dorsal root ganglion). As such, this should only be done in a clinical trial setting. Subcutaneous occipital nerve stimulation can be considered if prior therapy with corticosteroid infiltration or pulsed radio-frequency treatment failed or provided only short-term relief (2 C+).

Role of Low-Affinity Nerve Growth Factor Receptor Inhibitory Antibody in Reducing Pain Behavior and Calcitonin Gene-Related Peptide Expression in a Rat Model of Wrist Joint Inflammatory Pain

Nerve growth factor (NGF), via the high-affinity receptor, tyrosine kinase A, has been widely reported as a mediator of pain caused by inflammation. A clinical trial has suggested that anti-NGF antibody is effective for pain caused by osteoarthritis of the knee. However, adverse events such as headache (8.9%), upper respiratory tract infection (7.3%), and paresthesia (6.8%) were reported. We hypothesized that inhibition of the low-affinity NGF receptor, p75 neurotrophin receptor (p75NTR), is also effective for joint pain and may reduce side effects. This study examined suppression of pain behavior and expression of pain-inducing neuropeptides such as calcitonin gene-related peptide (CGRP) and p75NTR in dorsal root ganglia neurons by a p75NTR inhibitory antibody in a rat model of wrist joint inflammatory pain. We injected complete Freund's adjuvant (CFA) into the wrist joint of rats and used this as a model of inflammatory pain. We applied 10 microL of saline (CFA + saline group; n = 20) or 1, 10, or 50 microL of a p75NTR inhibitory antibody (CFA + p75NTR inhibitory antibody group; n = 40) directly to the inflamed joint in the rats. Mechanical hyperalgesia was measured for 2 weeks using von Frey filaments. We assessed CGRP and p75NTR expression in C8 dorsal root ganglia immunochemically. Adverse events such as loss of weight and/or appetite, constipation, and infection were examined. p75NTR inhibitory antibody reduced mechanical hyperalgesia caused by CFA (p<.05 vs controls) in the rat model (p<.01 vs saline), without any adverse events. We found that 10 and 50 microL of a p75NTR inhibitory antibody were more effective for pain, without a significant difference between doses. CGRP and p75NTR immunoreactivity was upregulated in the CFA + saline groups compared with a control group (p<.01). However, direct p75NTR inhibitory antibody application decreased CGRP and p75NTR expression after wrist inflammation (p<.01). p75NTR inhibition may be a therapeutic target for inflamed joint pain treatment with reduced adverse events.

C1 lateral mass screw-induced occipital neuralgia: a report of two cases

C1-2 polyaxial screw-rod fixation is a relatively new technique. While recognizing the potential for inadvertent vertebral artery injury, there have been few reports in the literature outlining all the possible complications. Aim of this study is to review all cases of C1 lateral mass screws insertion with emphasis on the evaluation of potential structures at risk during the procedure. We retrospectively reviewed all patients in our unit who had C1 lateral mass screw insertion over a 2-year period. The C1 lateral mass screw was inserted as part of an atlantoaxial stabilization or incorporated into a modular occiput/subaxial construct. Outcome measures included clinical and radiological parameters. Clinical indicators included age, gender, neurologic status, surgical indication and the number of levels stabilized. Intraoperative complications including blood loss, vertebral artery injury or dural tears were recorded. Postoperative pain distribution and neurological deficit were recorded. Radiological indicators included postoperative plain radiographs to assess sagittal alignment and to check for screw malposition or construct failure. A total of 18 lateral mass screws were implanted in 9 patients. There were three male and six female patients who had C1 lateral mass screw insertion in this unit. Two patients had atlantoaxial stabilization for C2 fracture. There were four patients with rheumatoid arthritis whose C1 lateral mass screws were inserted as part of an occipitocervical or subaxial cervical stabilization. There was no vertebral artery injury, no cerebrospinal fluid leak and minimal blood loss in all patients. Three patients developed postoperative occipital neuralgia. This neuralgia was transient, in one of the patients having settled at 6-week follow-up. In the other two patients the neuralgia was unresolved at time of latest follow-up but was adequately controlled with appropriate pain management. Postoperatively no patient had radiographic evidence of construct failure and all demonstrated excellent sagittal alignment. It has been reported that the absence of threads on the upper portion of the long shank screw may protect against neural irritation. However, insertion of the C1 lateral mass screw necessitates careful caudal retraction of the C2 dorsal root ganglion. The insertion point for the C1 lateral mass screw is at the junction of the C1 posterior arch and the midpoint of the posterior inferior part of the C1 lateral mass. Two patients in our series suffered occipital neuralgia post-insertion of C1 lateral mass screws. This highlights the potential for damage to the C2 nerve root during C1 lateral mass screw placement.

Changes of Cervical Dorsal Root Ganglia Induced by Compression Injury and Decompression Procedure: A Novel Rat Model of Cervical Radiculoneuropathy

Our study aimed to establish a model of compression injury of cervical dorsal root ganglia (DRG) in the rat and to investigate the pathological changes following compression injury and decompression procedures. Thirty rats were divided into three groups: control group receiving sham surgery, compression group undergoing surgery to place a micro-silica gel on C6 DRG, and decompression group with subsequent decompression procedure. The samples harvested from the different groups were examined with light microscopy, ultrastructural analysis, and horseradish peroxidase (HRP) retrograde tracing techniques. Apoptosis of DRG neurons was demonstrated with TUNEL staining. Changes in PGE2 and PLA2 in DRG neurons were detected with enzyme-linked immunosorbent assay (ELISA). Local expression of vascular endothelial growth factor (VEGF) was monitored with immunohistochemistry. DRG neurons in the compression group became swollen with vacuolar changes in cytoplasm. Decompression procedure partially ameliorated the resultant compression pathology. Ultrastructural examination showed a large number of swollen vacuoles, demyelinated nerve root fibers, absence of Schwann cells, and proliferation in the surrounding connective tissues in the compression group. Compared to the control group, the compression group showed a significant decrease in the number of the HRP-labeled cells and a significant increase in levels of PGE2 and PLA2, in the expression of VEGF protein, and in the number of apoptotic DRG neurons. These findings demonstrate that compression results in local inflammation, followed by increased apoptosis and upregulation of VEGF. We conclude that such a model provides a tool to study the pathogenesis and treatment of cervical radiculoneuropathy.

Painful facet joint injury induces neuronal stress activation in the DRG: Implications for cellular mechanisms of pain

The cervical facet joint is implicated as one of the most common sources of chronic neck pain, owing to its rich nociceptive innervation and susceptibility to injurious mechanical loading. Injuries to the facet joint and its ligament can induce inflammation in the joint and spinal cord. Inflammatory molecules which are known to have a role in pain can also stimulate the integrated stress response (ISR). Therefore, we hypothesize that ISR is activated by facet joint injury in a rodent model of pain. To address this hypothesis, we assessed the expression of binding protein (BiP) (also known as growth-related protein 78 (GRP78)), a marker of endoplasmic reticulum stress response, in the dorsal root ganglion (DRG) after painful facet joint injury. In a rodent model of facet joint injury, dynamic distraction of the C6/C7 joint (injury, n=12) was imposed; sham procedures were performed separately (sham, n=8). Forepaw mechanical allodynia was assessed postoperatively for 7 days as a quantitative measure of pain symptoms. The C6 DRG was harvested and assessed for BiP expression using triple label immunofluorescent confocal microscopy and immunoblot analyses. BiP was significantly higher (p<0.001) in the DRG after injury than sham and was expressed predominantly in neurons. Similarly, quantification of BiP by immunoblot demonstrated a significant 2.1-fold increase (p=0.03) in injury compared to sham at day 7. Findings suggest neuronal stress activation is associated with painful facet joint injury, and that joint loading may directly mediate the behavior of DRG neurons in this class of injury.