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Background: Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors., Results: L5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase., Conclusions: There is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine β-hydroxylase (DβH)] in the spinal dorsal horn., Results: Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DβH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DβH in the spinal dorsal horn., Conclusions: The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.

Objective: The goal of this study was to elucidate the protection by and potential mechanisms of LM22A-4, a specific agonist of tyrosine kinase receptor B, against spinal cord injury (SCI)., Methods: Spinal cord trauma was induced by the application of vascular clips to the dura of mice via a four-level T7-T11 laminectomy. Thirty minutes after the injury, an abdominal injection of LM22A-4 (at dosages of 10 mg/kg and 15 mg/kg) or an equal volume of solvent was provided. Twenty-four hours after SCI, a Western blot was performed to examine the expression of p-TrkB, p-Akt, p-ERK, cleaved-caspase-3, and Bcl-2; a TUNEL assay and Nissl staining were performed to study apoptosis and the survival of neurons. In addition, another batch of mice was allowed to live for 14 days after the SCI treatment, during which the LM22A-4 was provided at the same time each day and the neurological function was assessed., Results: Spinal cord injury in mice resulted in severe trauma characterized by tissue damage and apoptosis. Treatment of the mice with LM22A-4 (10 mg/kg) significantly reduced the degree of tissue injury (histological score) and apoptosis (TUNEL staining and caspase-3 and Bcl-2 expression) compared with vehicle treated group (P < 0.05). In a separate set of experiments, chronic treatment with LM22A-4 also significantly ameliorated the recovery of limb function (P < 0.05)., Conclusion: This study provides an experimental evidence that LM22A-4 reduces the development of tissue injury associated with spinal cord trauma, and activation of the activity of TrkB may represent a novel approach for the therapy of spinal cord trauma.

Background: The histological hallmark of multiple system atrophy (MSA) is the presence of filamentous aggregations of phosphorylated α-synuclein in oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Although GCIs can occur widely in the central nervous system, accumulation of phosphorylated α-synuclein in Schwann cells has not been reported in MSA. We immunohistochemically examined the cranial and spinal nerves, peripheral ganglia and visceral autonomic nervous system of patients with MSA (n = 14) and control subjects (n = 20)., Results: In MSA, accumulation of phosphorylated α-synuclein was found in the cytoplasm of Schwann cells. These Schwann cell cytoplasmic inclusions (SCCIs) were also immunopositive for ubiquitin and p62. SCCIs were found in 12 of 14 patients with MSA (85.7 %). They were most frequent in the anterior nerve of the sacral cord and, to a lesser extent, in the cranial nerves (oculomotor, glossopharyngeal-vagus and hypoglossal nerves), and spinal and sympathetic ganglia. SCCIs were rarely found in the visceral organs. Immunoelectron microscopy demonstrated that the SCCIs consisted of abnormal filaments, 15-20 nm in diameter. No such inclusions were found in controls., Conclusion: The present findings indicate that Schwann cells are also involved in the disease process of MSA.

We report on a typical clinical course of pelvic actinomycosis: initial uncharacteristic discomfort develops into a systemic illness associated with a pelvic mass, which progresses so fast that along with the systemic infection further symptoms can be reduced to its growth rate--tiredness, abdominal pain, micturition deficiency, and leg pain. Distinction between malignancy and pelvic actinomycosis could be made only intraoperative. After hysterectomy and with antibiotics the patient recovered quickly.

Introduction: Juxtapositional tumors of the spinal nerve roots have been noted to not only interact with the roots at various vertebral levels, but also differ among patients. Therefore, the aim of the current study was to elucidate the potential for variation among the relationships of the meningeal layers at different nerve levels., Methods: In 20 unembalmed adult cadavers and five fetal specimens, the spinal nerve roots from the cervical, thoracic, and lumbar regions were harvested with their associated meningeal layers and subjected to microdissection, histological analysis, or radiological imaging using 9.4-T MRI., Results: As the nerve rootlets passed from the cord, they received their root sheath covering from the pia. After crossing the subarachnoid space to reach the apertures in the dura, they received two additional looser sheaths, an outer from the dura and an inner from the arachnoid. The pia mater always ended proximal to the arachnoid, and the pia and arachnoid layers extended more distally along the roots with caudal descent. Although the dorsal and ventral roots generally exited through separate dural openings, a single dural opening was also observed, often in the lower spinal regions. Thin intradural septations almost always separated the dorsal and ventral rootlets. The left and right sides frequently differed within individuals., Conclusions: On the basis of our study, variations of the meninges surrounding the spinal nerve roots are common, but themes do exist. Such data support surgical observations of the different interactions between tumors in these regions with surrounding neural tissues.

Guillain-Barré syndrome (GBS) is a postinfectious autoimmune neuropathy and anti-ganglioside antibodies (Abs) are strongly associated with this disorder. Several studies have implied that specific anti-ganglioside Abs induce neuropathy in patients with axonal forms of GBS. To study the mechanisms of anti-ganglioside Abs-induced neuropathy, we established a new passive transfer mouse model by L5 spinal nerve transection (L5SNT; modified Chung's model) and systemic administration of anti-ganglioside Abs. L5SNT causes degeneration of a small proportion of fibers that constitute sciatic nerve and its branches, but importantly breaks the blood-nerve barrier, which allows access to circulating Abs and inflammatory cells. Our studies indicate that, in this mouse model, anti-ganglioside Abs induce sequential nodal and axonal injury of intact myelinated nerve fibers, recapitulating pathologic features of human disease. Notably, our results showed that immune complex formation and the activating Fc gamma receptors (FcγRs) were involved in the anti-ganglioside Abs-mediated nodal and axonal injury in this model. These studies provide new evidence that the activating FcγRs-mediated inflammation plays a critical role in anti-ganglioside Abs-induced neuropathy (injury to intact nerve fibers) in GBS., (Copyright © 2015 the authors 0270-6474/15/356770-16$15.00/0.)

Objectives: To investigate whether the human sciatic nerve might have a consistent somatotopic organization according to proximal fascicle input by spinal nerves., Methods: Twelve patients (55.3 ± 15.5 years) with confirmed lesions of either the L5 or S1 spinal nerve root underwent magnetic resonance neurography of sciatic nerve fascicles including thigh and knee levels (T2-weighted sequence with fat saturation, repetition time/echo time 7,552/52 milliseconds, voxel size 0.27 × 0.27 × 3.0 mm(3)). Twenty healthy subjects and 12 additional patients with an established diagnosis of peripheral polyneuropathy served as 2 separate age- and sex-matched control groups. Two blinded readers assessed patients and controls for presence of distinct lesion patterns. Spatial maps of normalized T2 signal were rendered after segmentation and coregistration of sciatic nerve voxels to detect fascicle lesion patterns., Results: A clear somatotopic distribution of nerve fascicles was observed on cross-sections along the entire course of the sciatic nerve and was distinct between patients with L5 and those with S1 lesions. Fascicles emerging from L5 were ordered in anterolateral positions within sciatic nerve cross-sections, while fascicles emerging from S1 appeared posteromedially. Visual assessment discriminated these somatotopic lesions in all cases from both healthy and polyneuropathy controls., Conclusion: A distinct pattern of somatotopy was identified within the sciatic nerve according to proximal fascicle input by L5 and S1 spinal nerves. Knowledge of human nerve somatotopy may have clinically useful implications in imaging-aided diagnosis of neuropathies., (© 2015 American Academy of Neurology.)

Neurofibromatosis type 2 is a rare genetic disease affecting the central and peripheral nervous systems and characterized by schwannomas, meningiomas, and ependymomas. Prompt symptom recognition, diagnosis, and proper referrals can increase treatment effectiveness and decrease the mortality risk of this life-threatening disease.

Background: Transforaminal epidural steroid injection (TFESI) of corticosteroid is frequently employed to mitigate the painful and disabling symptoms of lumbar disc herniation. However, the treatment outcome of TFESI in patients with radicular pain and inflamed neural structures as assessed by contrast-enhanced magnetic resonance imaging (MRI) has not been forthcoming., Objectives: To investigate functional improvement and pain reduction following TFESI in patients found to have nerve inflammation as evidenced by gadolinium-enhanced (MRI)., Study Design: Retrospective assessment., Setting: Tertiary spinal intervention center, Daegu, Korea., Methods: Thirty-seven patients were selected by strict inclusion criteria. Patients were classified into enhancing and non-enhancing groups as evidenced by gadolinium-enhanced MRI. The enhancing group was further divided into pre-dorsal roog ganglion (DRG) only enhanced group and pre-DRG and post-DRG enhanced group. Clinical outcomes were evidenced by numeric rating scale (NRS) and Oswestry disability index (ODI) at pretreatment, one week, and 4 weeks after treatment., Results: The improvement of NRS and ODI in the enhanced group was greater than those of the non-enhanced group, at one week and 4 weeks after TFESI (P < 0.05). However there was no significant difference in improvement of NRS and ODI between pre-DRG only enhanced group and pre-DRG and post-DRG enhanced group at one week and 4 weeks after TFESI., Limitations: Retrospective chart review with a small sample size., Conclusion: The improvement of NRS and ODI in the enhanced group was significantly greater than those of the non-enhanced group after TFESI. Radicular pain and functional impairment in the presence of gadolinium enhancing spinal neural structures and lumbar disc herniation may be more responsive to TFESI than patients without enhancing neural structures.

We report a young boy who presented with progressive weakness of lower extremities associated with areflexia and abnormal electrophysiological findings initially suggestive of chronic inflammatory demyelinating polyneuropathy. Initial lumbosacral spinal magnetic resonance imaging (MRI) showed thickened descending spinal nerve roots only. Immunomodulating therapy was given but with limited clinical response. Repeated spine magnetic resonance imaging showed cauda equina and also new spinal cord extramedullary contrast enhancement. The initial extensive investigations including open biopsy did not point to any specific diagnosis. Only through pursuing a repeated biopsy, the diagnosis of the spinal peripheral primitive neuroectodermal tumor was confirmed. This case highlights the diagnostic challenges of the spinal peripheral primitive neuroectodermal tumor that could have an initial chronic inflammatory demyelinating polyneuropathy-like presentation. The literature review confirms that this is a rare condition and cauda equina origin has only been reported in adults and teenagers, and this is the first reported case in a young child., (© The Author(s) 2014.)

Background: Antidepressants are often used for the treatment of neuropathic pain, and their analgesic effects rely on increased noradrenaline and serotonin levels in the spinal cord. Clinical studies have also shown that bupropion, a dopamine and noradrenaline reuptake inhibitor, has strong efficacy in neuropathic pain; however, the role of spinal cord dopamine in neuropathic pain is unknown. We hypothesized that bupropion inhibits neuropathic pain by increasing noradrenaline and dopamine in the spinal cord. In the present study, we determined the efficacy and underlying mechanisms of intrathecal administration of bupropion in a rat model of neuropathic pain., Methods: Male Sprague-Dawley rats were anesthetized, and right L5 spinal nerve ligation (SNL) was performed to produce mechanical hyperalgesia of the hindpaw. Withdrawal threshold to a paw pressure test was measured before and after intrathecal administration of bupropion, without or with intrathecal antagonists for α2-adrenoceptors and dopamine D2 receptors. In vivo microdialysis was performed in the dorsal horn of the lumbar spinal cord to measure noradrenaline and dopamine concentrations after intrathecal injection of bupropion. We also measured the noradrenaline and dopamine contents in the ipsilateral dorsal lumbar spinal cord in normal rats and in rats 2, 3, and 4 weeks after SNL., Results: Intrathecal injection of bupropion produced a dose-dependent antihyperalgesic effect (3, 10, 30, and 100 μg, P < 0.001). The effect (30 μg) was dose-dependently reversed by intrathecal pretreatment (15 minutes before bupropion injection) with the α2-adrenoceptor antagonist idazoxan (3, 10, and 30 μg, P < 0.001) and D2 receptor antagonist sulpiride (3, 10, and 30 μg, P < 0.001). Microdialysis revealed that noradrenaline and dopamine concentrations in the spinal dorsal horn were increased after intrathecal injection of bupropion (30 μg, P < 0.001 and P = 0.001, respectively). Furthermore, the noradrenaline and dopamine contents in the spinal dorsal horn were increased 2 weeks after SNL (P < 0.001 and P = 0.044, respectively) and then decreased gradually., Conclusions: These findings suggest that plasticity of descending inhibitory pathways such as the noradrenaline and dopamine systems contributes to the maintenance of neuropathic pain and that spinal cord noradrenaline and dopamine both play an inhibitory role in neuropathic pain.

One of the most devastating injuries to the upper limb is trauma caused by the avulsion. The anatomical structure of the rabbit's brachial plexus is similar to the human brachial plexus. The aim of our study was to analyze the microanatomy and provide a detailed investigation of the rabbit's brachial plexus. The purpose of our research project was to evaluate the possibility of utilizing rabbit's plexus as a research model in studying brachial plexus injury. Studies included histomorphometric analysis of sampled ventral branches of spinal nerves C5, C6, C7, C8, and Th1, the cranial trunk, the medial part of the caudal trunk, the lateral part of the caudal trunk and peripheral nerve. Horizontal and vertical analysis was done considering following features: the axon diameter, fiber diameter and myelin sheath. The number of axons, nerve area, myelin fiber density and minimal diameter of myelin fiber, minimal axon diameter and myelin area was marked for each element. The changes between ventral branches of spinal nerves C5-Th1, trunks and peripheral nerve in which the myelin sheath, axon diameter and fiber diameter was assessed were statistically significant. It was found that the g-ratio has close value in the brachial plexus as in the peripheral nerve. The peak of these parameters was found in nerve trunks, and then decreased coherently with the nerves travelling peripherally., (© 2014 Wiley Periodicals, Inc.)

Spinal nerve L5/L6 ligation (SNL) in rats has become the standard for mechanistic studies of peripheral neuropathy and screening for novel analgesics. Conventional SNL in our hybrid mice resulted in a wide range of allodynia. Anatomical evaluation indicated that a variable number of lumbar vertebrae existed, resulting in L4/L5 or L5/L6 being ligated. Surprisingly, L4/L5 ligation did not result in ipsilateral hind limb paralysis and produced robust allodynia. Following a recent report that the mouse L4 neural segment is homologous with rat L5 we generated L4, L5 or both L4 and L5 (L4/L5) ligations in C57 mice after establishing a modified set of surgical landmarks. In contrast to rats, L4 ligation in these mice did not result in hind limb paralysis. Robust allodynia was observed in all three ligation groups. Nerve degeneration confirmed that L4 and L5, respectively, are primary contributors to the tibial and sural branches of the sciatic nerve in mice. A larger von Frey sensitive area reflected the wider distribution of Wallerian degeneration in the hindlimb of L4- compared to L5-ligated mice. Ligation of mouse L4 and L5 spinal nerves produces consistent, robust neuropathic pain behaviors and is suitable as a model for investigating mechanisms of neuropathic pain and for testing of novel analgesics. Gabapentin, used as a validation drug in neuropathic pain models and as a reference compound for novel analgesics, significantly reduced allodynia in the mice tested (L4/L5 ligations). Given the ease of surgery, robust allodynia, and larger von Frey sensitive area, we conclude that combined ligation of spinal nerves L4 and L5 optimizes the SNL model in mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: This study assessed the collateral sprouting in avulsion of the ventral branches of the C5 and C6 spinal nerves treated by coaptation of these nerves to the C7 spinal nerve on the brachial plexus of rabbits., Material and Methods: Thirty-six New Zealand rabbits were randomly divided into four groups: end-to-side coaptation (ESN) (n = 12), side-to-side coaptation (SSN) (n = 12), direct neurorrhaphy (end-to-end) (EEN) (n = 6) and no coaptation (n = 6). The operations were performed on the left brachial plexus. The contralateral, non-operated right brachial plexi were used as the control group. The groups were compared using morphological, electrophysiological and behavioral methods. The follow-up duration was 20 weeks., Results: Significant differences were observed in all parameters when the experimental groups were compared with the control group and the no coaptation group. The histology of axonal regeneration after ESN, but not after SSN, was comparable to that after EEN. There were no significant differences in the electrophysiological, behavioral assessment or G-ratio parameters between the ESN and EEN groups. There were significant differences in the behavioral assessment, G-ratio and the histomorphometric parameters between the SSN and EEN groups, which disagreed with the electrophysiological results. Sensory axon collateral sprouting was more rapid than motor axon collateral sprouting., Conclusions: The electrophysiological, histomorphometric and behavioral results obtained using end-to-side coaptation of ventral branches of the C5 and C6 spinal nerves to the C7 spinal nerve in the brachial plexi of rabbits confirm the occurrence of collateral sprouting at this level. After further research is performed to confirm the results of this study, end-to-side coaptation might emerge as an alternative method in the treatment of brachial plexus avulsion.

The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10(-4)) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44% of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10(-15)) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings-obtained in mixed tissue-show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.

Introduction: Nerves are often enlarged in chronic inflammatory demyelinating polyneuropathy (CIDP). In this investigation we studied changes with treatment over time., Methods: We retrospectively compared serial ultrasound measurements of median and ulnar nerve size with clinical and electrodiagnostic evaluations in 23 CIDP subjects. We defined remission as stable clinical improvement on low or decreasing amounts of medication., Results: Nerves were normal at last follow-up more often in subjects who achieved remission than in those who did not (10 of 13 vs. 0 of 10, P = 0.0001). Nerves were normal or smaller (>30% reduction) more often in subjects whose grip strength improved or remained strong compared those whose grip strength weakened (12 of 16 vs. 0 of 3, P = 0.04), and in subjects whose demyelinating electrodiagnostic features resolved compared with those whose demyelination persisted (7 of 7 vs. 6 of 12, P = 0.04). Over time, nerve size decreased more in subjects with baseline nerve enlargement who achieved remission than in those who did not (-41% vs. 7%, P = 0.04)., Conclusion: In CIDP, enlarged nerves normalized or decreased with remission., (© 2014 Wiley Periodicals, Inc.)

Background: Despite high prevalence of anxiety accompanying with chronic pain, the mechanisms underlying pain-related anxiety are largely unknown. With its well-documented role in pain and emotion processing, the amygdala may act as a key player in pathogenesis of neuropathic pain-related anxiety. Pain-related plasticity and sensitization of CeA (central nucleus of the amygdala) neurons have been shown in several models of chronic pain. In addition, firing pattern of neurons with spike output can powerfully affect functional output of the brain nucleus, and GABAergic neurons are crucial in the modulation of neuronal excitability. In this study, we first investigated whether pain-related plasticity (e.g. alteration of neuronal firing patterns) and sensitization of CeA neurons contribute to nerve injury-evoked anxiety in neuropathic rats. Furthermore, we explored whether GABAergic disinhibition is responsible for regulating firing patterns and intrinsic excitabilities of CeA neurons as well as for pain-related anxiety in neuropathic rats., Results: We discovered that spinal nerve ligation (SNL) produced neuropathic pain-related anxiety-like behaviors in rats, which could be specifically inhibited by intra-CeA administration of anti-anxiety drug diazepam. Moreover, we found potentiated plasticity and sensitization of CeA neurons in SNL-induced anxiety rats, of which including: 1) increased burst firing pattern and early-adapting firing pattern; 2) increased spike frequency and intrinsic excitability; 3) increased amplitude of both after-depolarized-potential (ADP) and sub-threshold membrane potential oscillation. In addition, we observed a remarkable reduction of GABAergic inhibition in CeA neurons in SNL-induced anxiety rats, which was proved to be important for altered firing patterns and hyperexcitability of CeA neurons, thereby greatly contributing to the development of neuropathic pain-related anxiety. Accordantly, activation of GABAergic inhibition by intra-CeA administration of muscimol, a selective GABAA receptors agonist, could inhibit SNL-induced anxiety-like behaviors in neuropathic rats. By contrast, suppression of GABAergic inhibition by intra-CeA administration of bicuculline, a selective GABAA receptors antagonist, produced anxiety-like behavior in normal rats., Conclusions: This study suggests that reduction of GABAergic inhibition may be responsible for potentiated plasticity and sensitization of CeA neurons, which likely underlie the enhanced output of amygdala and neuropathic pain-related anxiety in SNL rats.

Peripheral nerve injury induces neuropathic pain which is characterized by tactile allodynia and thermal hyperalgesia. N-type voltage-dependent Ca(2+) channel (VDCC) plays pivotal roles in the development of neuropathic pain, since mice lacking Cav2.2, the pore-forming subunit of N-type VDCC, show greatly reduced symptoms of both tactile allodynia and thermal hyperalgesia. Our study on gene expression profiles of the Cav2.2 knockout (KO) spinal cord after spinal nerve ligation (SNL)-injury revealed altered expression of genes known to be expressed in microglia, raising an odd idea that N-type VDCC may function in not only excitable (neurons) but also non-excitable (microglia) cells in neuropathic pain state. In the present study, we have tested this idea by using a transgenic mouse line, in which suppression of Cav2.2 expression can be achieved specifically in microglia/macrophage by the application of tamoxifen. We found SNL-operated transgenic mice exhibited greatly reduced signs of tactile allodynia, whereas the degree of thermal hyperalgesia was almost the same as that of control. Immunohistochemical analysis of the transgenic lumbar spinal cord revealed reduced accumulation of Iba1-positive cells (microglia/macrophage) around the injured neurons, indicating microglial N-type VDCC is important for accumulation of microglia at the lesion sites. Although the mechanism of its activation is not clear at present, activation of N-type VDCC expressed in non-excitable microglial cells contributes to the pathophysiology of neuropathic pain., (Copyright © 2014 Elsevier Inc. All rights reserved.)

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cervicogenic headache is pain referred to the head from a source in the cervical spine or mediated by cervical nerves. Clinical features allow for no more than a diagnosis of probable cervicogenic headache. Definitive diagnosis requires evidence of a cervical source of pain. For most treatments, the evidence is limited or poor. Many patients with probable cervicogenic headache can be managed with exercise therapy, with or without manual therapy. Intractable cervicogenic headache can be investigated with controlled diagnostic blocks of the upper cervical joints and treated with thermal radiofrequency neurotomy. Other interventions are experimental or speculative., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An 8-year-old neutered female Cavalier King Charles spaniel was evaluated for progressing right forelimb lameness. Magnetic resonance imaging revealed that the right-side radial nerves and the caudal brachial plexus were swollen. The histological and molecular biological diagnosis by partial biopsy of the C8 spinal nerve was T-cell lymphoma. Coadministration of lomustine and irradiation was started. However, this therapy was ineffective. At necropsy, neoplastic tissues were seen extending into the subarachnoid space of the spinal cord, liver, pancreas and kidneys as gross findings. A large mass was also identified occupying the caudal thorax. Histologic findings included infiltration in these organs and the mass by neoplastic lymphocytes. To date, involvement of peripheral nerves (neurolymphomatosis) is rarely reported in veterinary species.

Lipomatosis of nerve (LN), or fibrolipomatous hamartoma, is a rare condition of fibrofatty enlargement of the peripheral nerves. It is associated with bony and soft tissue overgrowth in approximately one-third to two-thirds of cases. It most commonly affects the median nerve at the carpal tunnel or digital nerves in the hands and feet. The authors describe a patient with previously diagnosed hemihypertrophy of the trunk who had a history of large thoracic lipomas resected during infancy, a thoracic hump due to adipose proliferation within the thoracic paraspinal musculature, and scoliotic deformity. She had fatty infiltration in the thoracic spinal nerves on MRI, identical to findings pathognomonic of LN at better-known sites. Enlargement of the transverse processes at those levels and thickened ribs were also found. This case appears to be directly analogous to other instances of LN with overgrowth, except that this case involved axial nerves rather than the typical appendicular nerves.

Intraneural bone was identified on pathologic examination of a neuroma-in-continuity resected for repair of the suprascapular nerve 4 months after a brachial plexus injury. The acute onset of the neurologic deficit, the location of the neuroma within the scapular notch, and the proximity of the neural pathology to a comminuted scapula fracture suggest traumatic penetration of the nerve by a bone fragment. To the authors' knowledge, the observation of bone within a neuroma has not been previously reported.

Introduction: Truncal sensory level (TSL) is a localizing sign for spinal cord pathology. However, in rare instances, lesions higher up in the spinothalamic tract can cause TSL., Case Report: A 26-year-old woman presented with numbness from waist down with a T7 TSL on examination with negative spine magnetic resonance imaging. Later, the patient developed the full picture of Guillain-Barré syndrome confirmed with electrophysiological testing., Conclusion: TSL can localize to the nerve roots and can be an early manifestation of Guillain-Barré syndrome.

Voltage-gated potassium (Kv) channels are critical in controlling neuronal excitability and are involved in the induction of neuropathic pain. Therefore, Kv channels might be potential targets for prevention and/or treatment of this disorder. We reported here that a majority of dorsal root ganglion (DRG) neurons were positive for Kv channel alpha subunit Kv1.2. Most of them were large and medium, although there was a variety of sizes. Peripheral nerve injury caused by lumbar (L)5 spinal nerve ligation (SNL) produced a time-dependent reduction in the number of Kv1.2-positive neurons in the ipsilateral L5 DRG, but not in the contralateral L5 DRG. Such reduction was also observed in the ipsilateral L5 DRG on day 7 after sciatic nerve axotomy. Rescuing nerve injury-induced reduction of Kv1.2 in the injured L5 DRG attenuated the development and maintenance of SNL-induced pain hypersensitivity without affecting acute pain and locomotor function. This effect might be attributed to the prevention of SNL-induced upregulation of endogenous Kv1.2 antisense RNA, in addition to the increase in Kv1.2 protein expression, in the injured DRG. Our findings suggest that Kv1.2 may be a novel potential target for preventing and/or treating neuropathic pain.

Objective: Peripheral nerve injury can induce immediate and long-standing remodelling of the brain cortex, which may affect outcomes of nerve repair. This study examined changes of corresponding cortical representations in patients with brachial plexus injuries., Methods: Resting-state fMRI was acquired for 13 adult patients with total brachial plexus root avulsion, three of whom underwent second scans 7 or 8 months later. The time of examination ranged from 1 to 16 months after injuries. Nine healthy adults were enrolled as control. Seed-based functional connectivity was performed for all subjects., Results: For nine patients whose first fMRI was performed from 1 to 4 months after brachial plexus injuries, images showed that their cortical maps of sensorimotor areas corresponding to the hand and arm in the hemisphere contralateral to the injured side had much weaker correlation with the supplementary motor area (SMA) than those ipsilateral to the injured side. Symmetrical maps of bilateral cortical sensorimotor areas corresponding to the hand and arm were observed in other four cases with fMRI tested from 7 to 16 months after injuries. For three of the nine patients with asymmetrical cortical representations, second scans indicated symmetric results or even stronger correlation with SMA in the cerebral cortex contralateral to the injured side., Conclusions: Total brachial plexus root avulsion causes cortical representations of the brachial plexus to undergo a change from an inactive to an active state. This implies that peripheral deafferentation after brachial plexus injuries will induce corresponding cortical representations to be occupied by adjacent non-deafferented cortical territories.

Context: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders., Objectives: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats., Materials and Methods: The screening study included the CCI and L5-L6 SNL models of neuropathic pain. Guggulipid (100 and 50 mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20)., Results: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50 mg/kg) significantly (p < 0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD50 of guggulipid was 1600 mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity., Discussion and Conclusion: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury.

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

Unlabelled: Early-life stress is associated with an increased risk of developing affective disorders and chronic pain conditions. This study examined the effect of maternal deprivation (MD) on nociceptive responding prior to and following peripheral nerve injury (L5-L6 spinal nerve ligation [SNL]). Because neuroimmune signaling plays an important role in pain and affective disorders, associated alterations in glial and cytokine expression were assessed in key brain regions associated with emotional and nociceptive responding, the hippocampus and prefrontal cortex. MD female, but not male, rats exhibited thermal hypoalgesia and mechanical allodynia compared with control (non-MD) counterparts. SNL resulted in mechanical and cold allodynia in MD and control rats of both sexes. However, MD females exhibited enhanced SNL-induced allodynic responding compared with non-MD counterparts. Interleukin 6 (IL-6) expression was reduced in the prefrontal cortex of MD-SNL males when compared with non-SNL counterparts. Glial fibrillary acidic protein and IL-1β expression in the hippocampus of MD-SNL males was increased compared with non-MD controls. MD-SNL females exhibited reduced tumor necrosis factor alpha in the prefrontal cortex with a concomitant increase in IL-6 and tumor necrosis factor alpha expression in the hippocampus, compared with either MD or SNL alone. In conclusion, MD female, but not male, rats exhibit enhanced nociceptive responding following peripheral nerve injury, effects that may relate to the distinct neuroinflammatory profile observed in female versus male rats., Perspective: This study demonstrates that females rats exposed to early-life stress exhibit enhanced neuropathic pain responding, effects that are associated with alterations in neuroinflammatory mediators. Increased understanding of the interactions among early-life stress, gender, and pain may lead to the identification of novel therapeutic targets for the treatment of chronic pain disorders., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Multiple Sclerosis (MS) is a disease that affects the Central Nervous System by destructing myelin shield and also can affects the peripheral nervous system. Demyelination is acquired characteristics disease and appears with the degeneration of myelin which protects the axons. Cuprizone (CPZ) model is a toxic demyelination model. The purpose of this study was to develop an MS model by cuprizone exposure to Wistar rats., Materials and Methods: Rats were separated into control and experimental groups and daily cuprizone was administered to experimental groups for 4, 5, 6 and 7 weeks. At the end of the experiments, spinal nerve conduction velocity was measured by EMG detected from the gastrocnemius muscle. After scarification, cerebrum and cerebellum of the animals were taken for histopathological investigation., Results: Spinal cord nerve conduction velocity (SNCV) of control animals was 76.54 m/s. Whereas SNCV of the rats that were feed with CPZ for 6 weeks was significantly reduced to 46.35 m/s in comparison with the control group. Demyelinated areas and vacuolization were seen on the brain sections of CPZ exposed rats., Conclusions: SNCV of the rats were feed with cuprizone began tendency of decrease after 4th weeks. These reductions were observed as maximum at 6th weeks. At 7th week increments were observed at SNCV. These results indicated that 6 weeks of cuprizone feedings could be suitable to bring into existence of MS model in Wistar rats.

Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated Aβ-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory Aβ-fiber inputs onto PKCγ+ neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents Aβ input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by Aβ-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.

NMNAT2 is an NAD(+)-synthesizing enzyme with an essential axon maintenance role in primary culture neurons. We have generated an Nmnat2 gene trap mouse to examine the role of NMNAT2 in vivo. Homozygotes die perinatally with a severe peripheral nerve/axon defect and truncated axons in the optic nerve and other CNS regions. The cause appears to be limited axon extension, rather than dying-back degeneration of existing axons, which was previously proposed for the NMNAT2-deficient Blad mutant mouse. Neurite outgrowth in both PNS and CNS neuronal cultures consistently stalls at 1-2 mm, similar to the length of truncated axons in the embryos. Crucially, this suggests an essential role for NMNAT2 during axon growth. In addition, we show that the Wallerian degeneration slow protein (Wld(S)), a more stable, aberrant NMNAT that can substitute the axon maintenance function of NMNAT2 in primary cultures, can also correct developmental defects associated with NMNAT2 deficiency. This is dose-dependent, with extension of life span to at least 3 months by homozygous levels of Wld(S) the most obvious manifestation. Finally, we propose that endogenous mechanisms also compensate for otherwise limiting levels of NMNAT2. This could explain our finding that conditional silencing of a single Nmnat2 allele triggers substantial degeneration of established neurites, whereas similar, or greater, reduction of NMNAT2 in constitutively depleted neurons is compatible with normal axon growth and survival. A requirement for NMNAT2 for both axon growth and maintenance suggests that reduced levels could impair axon regeneration as well as axon survival in aging and disease.

A 63-year-old Japanese man complained of lower back pain and numbness and was diagnosed as intradural tumors at the T11/12 and L1 level. The thoracic tumor originated from the posterior nerve root, and the lumbar tumor originated from the cauda equina. Five months after surgical resection, the patient developed recurrent tumor consisting of enlargement of multiple caudal nerves. Pathologically, the primary tumors showed a nodular and lobular pattern, including spindle cells in a fascicular, whorl and storiform pattern, with variable cellularity, nuclear palisading and frequent small onion bulb structures. Mild pleomorphism was present, and there were four mitoses per 10 high power fields. Many cells showed immunoreactivity for S-100 and Sox10. There were also claudin-1-positive spindle cells, but no epithelial membrane antigen (EMA)-positive cells. The cells in onion bulb structures were positive for claudin-1 and glucose transporter 1 (GLUT-1). These findings led to a diagnosis of hybrid schwannoma/perineurioma. The features of high cellularity, pleomorphism and a Ki-67 index over 10% suggested a low-malignant nature. The recurrent tumor also showed high proliferative activity, as reflected by mitotic figures and a Ki-67 index of 20%. This is the first case of spinal nerve hybrid schwannoma/perineurioma with low malignant potential and peculiar intraneural perineurioma component., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Protein translation controlled through activation of mammalian target of rapamycin (mTOR) participates in many physiological and pathological processes. However, whether such activation is required for chronic pain is still unknown. Here, we examined activation of the mTOR signaling pathway during complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and L5 spinal nerve ligation (SNL)-induced neuropathic pain in rats. Western blot analysis showed significantly increased levels of phosphorylated mTOR (p-mTOR) and phosphorylated p70S6 kinase 1 (p-S6K1, a downstream effector of mTOR) in the ipsilateral L4/5 spinal cord 2h, 1 day, 3 days, and 7 days after intraplantar CFA injection and in the ipsilateral L4/5 dorsal root ganglions (DRGs) 1 and 3 days after CFA injection. Immunohistochemistry also demonstrated increases in number of p-mTOR-labeled neurons in the ipsilateral L4/5 DRGs and in density of p-mTOR-labeled immunoreactivity in the ipsilateral L4/5 superficial dorsal horn 1 day after CFA injection. Moreover, intrathecal administration of rapamycin, a selective inhibitor of mTOR, significantly blocked CFA-induced mechanical allodynia and thermal hyperalgesia 1 day post-CFA injection. Interestingly, expression of neither p-mTOR nor p-S6K1 was markedly altered on days 3, 7, or 14 after L5 SNL in L5 spinal cord or DRG. These findings indicate that in DRG and spinal cord, mTOR and S6K1 are activated during chronic inflammatory pain, but not during neuropathic pain. Our results strongly suggest that mTOR and its downstream pathway contribute to the development of chronic inflammatory pain., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Neuropathic intermittent claudication (NIC) is a typical clinical symptom of lumbar spinal stenosis and the apoptosis of neurons caused by cauda equina compression (CEC) has been proposed as an important reason. Whereas, the factors and the mechanism involved in the process of apoptosis induced by CEC remain unclear., Methodology and Results: In our modified rat model of NIC, a trapezoid-shaped silicon rubber was inserted into the epidural space under the L5 and L6 vertebral plate. Obvious apoptosis was observed in spinal cord cells after compression by TUNEL assay. Simultaneously, qRT-PCR and immunohistochemistry showed that the expression levels of PUMA (p53 up-regulated modulator of apoptosis) and p53 were upregulated significantly in spinal cord under compression, while the expression of p53 inhibitor MDM2 and SirT2 decreased in the same region. Furthermore, CEC also resulted in the upregulation of Bcl-2 pro-apoptotic genes expression and caspase-3 activation. With the protection of Methylprednisolone, the upregulation of PUMA and p53 expression as well as the decrease of MDM2 and SirT2 in spinal cord were partially rescued in western bolt analysis., Conclusions: These results suggest that over-expression of PUMA correlates with CEC caused apoptosis of spinal cord cells, which is characterized by the increase of p53, Bax and Bad expression. PUMA upregulation might be crucial to induce apoptosis of spinal cord cells through p53-dependent pathway in CEC.

Aims: Hemangioblastomas may arise sporadically or in the setting of Von Hippel-Lindau (VHL) disease. In either instance, it rarely occurs outside the central nervous system. By analysis of a large case series, we sought to further characterize the clinical, radiologic and pathologic features of hemangioblastomas involving nerve root., Materials and Methods: The clinical resentations of 6 proximal nerve root hemangioblastomas (1 an aggressive tumor) were analyzed with emphasis on the neuroimaging, operative, and pathologic findings. The literature is fully reviewed and updated., Results: Nerve hemangioblastoma usually affects proximal spinal roots. Peripheral nerve is rarely involved. Both clinically and radiologically, the diagnosis is usually not suspected before surgery. Profuse bleeding at resection may be the first indication of the nature of the lesion. These tumors may arise both sporadically and in association with VHL disease., Conclusion: Given their rarity, nerve root hemangioblastomas are not generally considered in the preoperative differential diagnosis of proximal nerve root lesions. Given their propensity to bleed profusely at surgery and the potential association with VHL disease, knowledge of this entity is important.

The pathogenesis of low back pain is still elusive. Here, we proposed a new hypothesis that low pH is a possible cause of the development and progression of low back pain. We propose that low pH promotes the production of the inflammatory mediators and the depletion of proteoglycan in the damaged intervertebral disk. The inflammation response, evoked by the dorsal root ganglia, changes the delicate nutrient balance in the nucleus, resulting in a vicious cycle and leading to choronic back pain. Our hypothesis may explain many of the available clinical and experimental data on low back pain, thus it may help elucidate the pathogenesis of low back pain and improve clinical management., (© 2012 The Acta Anaesthesiologica Scandinavica Foundation.)

Evidence is emerging for a role of rough endoplasmic reticulum (RER) in the form of stress granules, the unfolded protein response and protein bodies in the response of neurons to injury and in neurodegenerative diseases. Here, we have studied the role of the peripheral target in regulating the RER and polyribosomes of Nissl bodies in axotomised adult cat dorsal root ganglion (DRG) neurons where axonal regeneration and peripheral target reinnervation was either allowed or denied. Retrograde labelling with horseradish peroxidise was used as an independent marker to enable selection of only those DRG neuronal cell bodies with axons in the injured intercostal nerves. Indications of polyribosomal dispersal were seen by 6h following axotomy, and by 24h the normal orderly arrangement of lamellae of RER in Nissl bodies had become disorganised. These ultrastructural changes preceded light microscopical chromatolysis by 1-3d. The retrograde response was maximal 8-32 d after axotomy. Clusters of debris-laden satellite cells/macrophages were present at this time but no ultrastructural evidence of neuronal apoptosis or necrosis was seen and there were no differences in the initial retrograde response according to the type of injury. By 64 d following axotomy with reinnervation, approximately half the labelled DRG neurons showed restoration of the orderly arrangement of RER and polyribosomes in their Nissl bodies. This was not seen after axotomy with reinnervation denied. We propose that the target-dependent changes in Nissl body ultrastructure described here are part of a continuum that can modify neuronal protein synthesis directed towards growth, maintenance or death of the neuron. This represents a possible structural basis for mediating the varied effects of neurotrophic interactions., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to examine the association of morphological changes in the-sensory ganglia of the spinal nerves (SGSN) with the cilinical symptomatology in rats with the experimentally induced ischemic myelopathy (IM), untreated or treated with repeated magnetic stimulation (RMS). The efficacy and mechanisms of RMS action on SGSN were studied by electron microscopy in 16 rats with IM. According to the results of treatment, in SGSN both at a distance from the damaged area (lumbar SGSN) and close to it (cervical SGSN) the morphological signs of regenerative-reparative processes were found in the cells and nerve fibers (restoration of the organelle structure in the cytoplasm o0f neurons and neurolemmocytes, the increase in the number of he latter and fiber remyelination). The expression of the structural changes correlated with the degree of functional recovery.

Endothelin-1 (ET-1) is an endogenously expressed potent peptide vasoconstrictor. There is growing evidence that ET-1 plays a role in the pain signaling system and triggers overt nociception in humans. The underlying neuronal pathways are still a matter of great debate. In the present study, we applied an intradermal ET-1 sensitization model to induce mechanical hyperalgesia in healthy subjects. Functional magnetic resonance imaging (fMRI) was used to tease out the cortical regions associated with the processing of ET-1-induced punctate hyperalgesia, as compared to a nonnoxious mechanical stimulation of the contralateral arm. Von Frey hair testing revealed the presence of increased responsiveness to punctate stimulation in all subjects. Activational patterns between nonpainful control stimulation and hyperalgesic stimulation were compared. Two major observations were made: (1) all cortical areas that showed activation during the control stimulation were also present during hyperalgesic stimulation, but in addition, some areas showed bilateral activation only during hyperalgesic stimulation, and (2) some brain areas showed significantly higher signal changes during hyperalgesic stimulation. Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions. This indicates that ET-1 activates an extended neuronal pathway.

Aim: This study evaluates the contribution of inhibitory pain pathways that descend to the spinal cord through the dorsolateral funiculus (DLF) on the effect of intrathecal gabapentin against spinal nerve ligation (SNL)-induced behavioral hypersensitivity to mechanical stimulation in rats., Main Method: Rats were submitted to a sham or complete ligation of the right L5 and L6 spinal nerves and a sham or complete DLF lesion. Next, the changes induced by intrathecal administration of gabapentin on the paw withdrawal threshold of rats to mechanical stimulation were evaluated electronically., Key Findings: Intrathecal gabapentin (200μg/5μl) that was injected 2 or 7days after surgery fully inhibited the SNL-induced behavioral hypersensitivity to mechanical stimulation in sham DLF-lesioned rats; gabapentin was effective against the SNL-induced behavioral hypersensitivity to mechanical stimulation also in DLF-lesioned rats., Significance: The effect of intrathecally administered gabapentin against SNL-induced behavioral hypersensitivity to mechanical stimulation in rats does not depend on the activation of nerve fibers that descend to the spinal cord via the DLF., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Study Design: Mechanical and biochemical analyses of cadaveric and surgically removed discs., Objective: To test the hypothesis that fissures in the annulus of degenerated human discs are mechanically and chemically conducive to the ingrowth of nerves and blood vessels., Summary of Background Data: Discogenic back pain is closely associated with fissures in the annulus fibrosus, and with the ingrowth of nerves and blood vessels., Methods: Three complementary studies were performed. First, 15 cadaveric discs that contained a major annulus fissure were subjected to 1 kN compression, while a miniature pressure transducer was pulled through the disc to obtain distributions of matrix compressive stress perpendicular to the fissure axis. Second, Safranin O staining was used to evaluate focal loss of proteoglycans from within annulus fissures in 25 surgically removed disc samples. Third, in 21 cadaveric discs, proteoglycans (sulfated glycosaminoglycans [sGAGs]) and water concentration were measured biochemically in disrupted regions of annulus containing 1 or more fissures, and in adjacent intact regions., Results: Reductions in compressive stress within annulus fissures averaged 36% to 46%, and could have been greater at the fissure axis. Stress reductions were greater in degenerated discs, and were inversely related to nucleus pressure (R(2) = 47%; P = 0.005). Safranin O stain intensity indicated that proteoglycan concentration was typically reduced by 40% at a distance of 600 μm from the fissure axis, and the width of the proteoglycan-depleted zone increased with age (P < 0.006; R(2) = 0.29) and with general proteoglycan loss (P < 0.001; R(2) = 0.32). Disrupted regions of annulus contained 36% to 54% less proteoglycans than adjacent intact regions from the same discs, although water content was reduced only slightly., Conclusion: Annulus fissures provide a low-pressure microenvironment that allows focal proteoglycan loss, leaving a matrix that is conducive to nerve and blood vessel ingrowth.

Background: In spite of its high clinical relevance, the relationship between disc degeneration and low back pain is still not well understood. Recent studies have shown that genome-wide gene expression studies utilizing ontology searches provide an efficient and valuable methodology for identification of clinically relevant genes. Here we use this approach in analysis of pain-, nerve-, and neurotrophin-related gene expression patterns in specimens of human disc tissue. Control, non-herniated clinical, and herniated clinical specimens of human annulus tissue were studied following Institutional Review Board approval., Results: Analyses were performed on more generated (Thompson grade IV and V) discs vs. less degenerated discs (grades I-III), on surgically operated discs vs. control discs, and on herniated vs. control discs. Analyses of more degenerated vs. less degenerated discs identified significant upregulation of well-recognized pain-related genes (bradykinin receptor B1, calcitonin gene-related peptide and catechol-0-methyltransferase). Nerve growth factor was significantly upregulated in surgical vs. control and in herniated vs. control discs. All three analyses also found significant changes in numerous proinflammatory cytokine- and chemokine-related genes. Nerve, neurotrophin and pain-ontology searches identified many matrix, signaling and functional genes which have known importance in the disc. Immunohistochemistry was utilized to confirm the presence of calcitonin gene-related peptide, catechol-0-methyltransferase and bradykinin receptor B1 at the protein level in the human annulus., Conclusions: Findings point to the utility of microarray analyses in identification of pain-, neurotrophin and nerve-related genes in the disc, and point to the importance of future work exploring functional interactions between nerve and disc cells in vitro and in vivo. Nerve, pain and neurotrophin ontology searches identified numerous changes in proinflammatory cytokines and chemokines which also have significant relevance to disc biology. Since the degenerating human disc is primarily an avascular tissue site into which disc cells have contributed high levels of proinflammatory cytokines, these substances are not cleared from the tissue and remain there over time. We hypothesize that as nerves grow into the human annulus, they encounter a proinflammatory cytokine-rich milieu which may sensitize nociceptors and exacerbate pain production.

Pain by definition is subjective. A variety of neural pathways are involved in the generation and propagation of pain. Pain is emotional. Pain pathways interact with the limbic system, and this interaction modulates pain. The experience of pain is related to the experience of past pain. Many potential pain generators are present in the low back. The most likely source of pain is the intervertebral disc. Treating pain requires a multifactorial approach, because pain is very complex., (Copyright © 2012 Elsevier Inc. All rights reserved.)