Intravenous Lidocaine in Chronic Neuropathic Pain: A Systematic Review.

OBJECTIVES: A systematic review of original research articles was conducted to evaluate the safety and efficacy of lidocaine infusion in the treatment of adult patients with chronic neuropathic pain. MATERIALS AND METHODS: Original research from 1970 to September 2021 describing adult patients with chronic neuropathic pain receiving at least 1 dose of intravenous lidocaine was included. Extracted data included study design, sample size, patient demographics and comorbidities, etiology and duration of pain, pain intensity scores, time to pain resolution, lidocaine dose and administration frequency, lidocaine serum concentration, and adverse events. Each study was evaluated for level of evidence using the 2017 American Association of Neurology classification system. RESULTS: Twenty-seven studies evaluating lidocaine infusion treatment in chronic neuropathic pain met inclusion criteria. One class I study was identified for patients with neuropathic pain due to spinal cord injury . Two Class II studies were identified, one describing neuropathic pain due to peripheral nerve injury and another due to diabetic neuropathy. Across all studies, study design, participants, and experimental interventions were heterogenous with wide variation. DISCUSSION: This qualitative review found insufficient, heterogenous evidence and therefore no recommendation can be made for lidocaine infusion treatment in patients with chronic neuropathic pain due to spinal cord injury, peripheral nerve injury, diabetic neuropathy, postherpetic neuralgia, or complex regional pain syndrome type II. Larger randomized, double-blind, placebo-controlled studies are required to further establish the efficacy of lidocaine infusion in patients with these etiologies of chronic neuropathic pain.

Differential methylation and expression of genes in the hypoxia-inducible factor 1 signaling pathway are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors and with preclinical models of chemotherapy-induced neuropathic pain.

BACKGROUND: Paclitaxel is an important chemotherapeutic agent for the treatment of breast cancer. Paclitaxel-induced peripheral neuropathy (PIPN) is a major dose-limiting toxicity that can persist into survivorship. While not all survivors develop PIPN, for those who do, it has a substantial negative impact on their functional status and quality of life. No interventions are available to treat PIPN. In our previous studies, we identified that the HIF-1 signaling pathway (H1SP) was perturbed between breast cancer survivors with and without PIPN. Preclinical studies suggest that the H1SP is involved in the development of bortezomib-induced and diabetic peripheral neuropathy, and sciatic nerve injury. The purpose of this study was to identify H1SP genes that have both differential methylation and differential gene expression between breast cancer survivors with and without PIPN. METHODS: A multi-staged integrated analysis was performed. In peripheral blood, methylation was assayed using microarray and gene expression was assayed using RNA-seq. Candidate genes in the H1SP having both differentially methylation and differential expression were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN. Then, candidate genes were evaluated for differential methylation and differential expression in public data sets of preclinical models of PIPN and sciatic nerve injury. RESULTS: Eight candidate genes were identified as both differential methylation and differential expression in survivors. Of the eight homologs identified, one was found to be differential expression in both PIPN and "normal" mice dorsal root ganglia; three were differential methylation in sciatic nerve injury versus sham rats in both pre-frontal cortex and T-cells; and two were differential methylation in sciatic nerve injury versus sham rats in the pre-frontal cortex. CONCLUSIONS: This study is the first to evaluate for methylation in cancer survivors with chronic PIPN. The findings provide evidence that the expression of H1SP genes associated with chronic PIPN in cancer survivors may be regulated by epigenetic mechanisms and suggests genes for validation as potential therapeutic targets.

Duloxetine Attenuates Paclitaxel-Induced Peripheral Nerve Injury by Inhibiting p53-Related Pathways.

Paclitaxel (PTX) is an antineoplastic drug extracted from the Taxus species, and peripheral neuropathy is a common side effect. Paclitaxel-induced peripheral neuropathy (PIPN) seriously affects patient quality of life. Currently, the mechanism of PIPN is still unknown, and few treatments are recognized clinically. Duloxetine is recommended as the only potential treatment of chemotherapy-induced peripheral neuropathy (CIPN) by the American Society of Clinical Oncology. However, this guidance lacks a theoretical basis and experimental evidence. Our study suggested that duloxetine could improve PIPN and provide neuroprotection. We explored the potential mechanisms of duloxetine on PIPN. As a result, duloxetine acts by inhibiting poly ADP-ribose polymerase cleavage (PARP) and tumor suppressor gene p53 activation and regulating apoptosis regulator the Bcl2 family to reverse PTX-induced oxidative stress and apoptosis. Taken together, the present study shows that using duloxetine to attenuate PTX-induced peripheral nerve injury and peripheral pain may provide new clinical therapeutic targets for CIPN. SIGNIFICANCE STATEMENT: This study reported that duloxetine significantly alleviates neuropathic pain induced by paclitaxel and is related to poly ADP-ribose polymerase (PARP), tumor suppressor gene p53, and apoptosis regulator the Bcl2 family. Our findings thus not only provide important guidance to support duloxetine to become the first standard chemotherapy-induced peripheral neuropathy (CIPN) drug but also will find potential new targets and positive control for new CIPN drug development.

SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair.

Platinum-based chemotherapy-induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA cross-links. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2's protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2's function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation-mediated neuroprotection during platinum-based cancer treatment.

[Study on the effect of diallyl sulfide on peripheral nerve injury in n-hexane intoxicated rats].

Objective: To investigate the antagonistic effect of diallyl sulfide (DAS) against peripheral nerve injury induced by n-hexane in rats. Methods: A total of 68 adult male Wistar rats were selected, among which 50 were randomly selected and divided into blank control group, DAS control group (100 mg/kg·bw) , n-hexane model group, low-dose DAS intervention group (50 mg/kg·bw) , and high-dose DAS intervention group (100 mg/kg·bw) . A rat model of peripheral nerve injury was established by n-hexane exposure, and the rats were treated with DAS at different doses. The changes in pyrrole adducts and behavior were observed, a metabolic analysis was performed for serum pyrrole adducts, and the intervention effect was evaluated. The remaining 18 rats were randomly assigned to the n-hexane model group, the low-dose DAS intervention group, and the high-dose DAS intervention group, with 6 rats in each group, as satellite groups used for the toxicokinetic analysis of serum pyrrole adducts. Results: Compared with the blank control group, the n-hexane model group and low-and high-dose DAS intervention groups had a significant reduction in body weight since week 2 (P<0.01) . Compared with the n-hexane model group at the end of the experiment at week 7, the high-dose DAS intervention group had a significantly higher body weight (P<0.05) , while there was no significant difference in body weight between the n-hexane model group and the low-dose DAS intervention group (P>0.05) . The n-hexane model group developed gait abnormality at week 2 of poisoning, while the low-and high-dose DAS intervention groups developed gait abnormality at weeks 3 and 5 of poisoning, respectively. At the end of the experiment, the n-hexane model group and the low-and high-dose DAS intervention groups had a significantly higher gait score than the blank control group (P<0.01) . At the end of the experiment, the n-hexane model group and the low-dose DAS intervention group had significantly shorter latency in rotarod test than the blank control group (P<0.01) , while there was no significant difference in latency between the DAS control group and the high-dose DAS intervention group (P>0.05) . Compared with the n-hexane model group, the low-and high-dose DAS intervention groups had a significant increase in latency in rotarod test (P<0.01) . Compared with blank control group, the n-hexane model group and the low-dose DAS intervention group had a significant increase in mean nerve conduction velocity (P<0.01) , while there was no significant difference between the blank control group and the DAS control group or high-dose DAS intervention group (P>0.05) , and compared with the n-hexane model group, the low-and high-dose DAS intervention groups had a significant increase in nerve conduction velocity (P<0.01) . Compared with the blank control group at the end of the experiment at week 7, the n-hexane model group and the low-and high-dose DAS intervention groups had significant increases in the concentration of pyrrole adducts in serum, urine, and hair (P<0.01) , while there was no significant difference between the blank control group and the DAS control group (P>0.05) , and the high-dose DAS intervention group had a significantly lower concentration of pyrrole adducts in serum, urine, and hair than the low-dose DAS intervention group (P<0.05) . Serum pyrrole adducts reached the peak level at 9-12 hours and then started to decrease. Compared with the n-hexane model group, the high-and low-dose DAS intervention groups had a significantly shorter half-life period of serum pyrrole adducts (P<0.01) . Compared with the n-hexane model group, the high-and low-dose DAS intervention groups had a significant reduction in the area under the curve of serum pyrrole adducts (P<0.05) . Conclusion: DAS can antagonize peripheral nerve injury induced by n-hexane.

Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors.

While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3ß-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3ß-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury.

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats.

BACKGROUND: Previous studies suggest that dexmedetomidine has a protective effect against local anaesthetic-induced nerve injury in regional nerve blocks. Whether this potentially protective effect exists in the context of diabetes mellitus is unknown. METHODS: A diabetic state was established in adult male Sprague-Dawley rats with intraperitoneal injection of streptozotocin. Injections of ropivacaine 0.5%, dexmedetomidine 20 µg kg-1 (alone and in combination), or normal saline (all in 0.2 ml) were made around the sciatic nerve in control and diabetic rats (n=8 per group). The duration of sensory and motor nerve block and the motor nerve conduction velocity (MNCV) were determined. Sciatic nerves were harvested at post-injection day 7 and assessed with light and electron microscopy or used for pro-inflammatory cytokine measurements. RESULTS: Ropivacaine and dexmedetomidine alone or in combination did not produce nerve fibre damage in control non-diabetic rats. In diabetic rats, ropivacaine induced significant nerve fibre damage, which was enhanced by dexmedetomidine. This manifested with slowed MNCV, decreased axon density, and decreased ratio of inner to outer diameter of the myelin sheath (G ratio). Demyelination, axon disappearance, and empty vacuoles were also found using electron microscopy. An associated increase in nerve interleukin-1ß and tumour necrosis factor-α was also seen. CONCLUSIONS: Ropivacaine 0.5% causes significant sciatic nerve injury in diabetic rats that is greatly potentiated by high-dose dexmedetomidine. Although the dose of dexmedetomidine used in this study is considerably higher than that used in clinical practice, our data suggest that further studies to assess ropivacaine (alone and in combination with dexmedetomidine) use for peripheral nerve blockade in diabetic patients are warranted.

Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.

Quantification of motor neuron loss and muscular atrophy in ricin-induced focal nerve injury.

BACKGROUND: Intrasciatic nerve injection of the Ricinus communis agglutinin (RCA or ricin) causes degeneration of motor neurons (MNs) with functional deficits, such as those that occur in amyotrophic lateral sclerosis (ALS). The objective of this study was to develop a new comprehensive platform for quantitative evaluation of MN loss, muscular atrophy and behavioral deficits using different ricin injection regimens. NEW METHOD: Fluorogold (FG)-guided stereological quantification of MNs, in vivo magnetic resonance imaging (MRI) of muscular atrophy, and CatWalk behavioral testing were used to evaluate the outcome of rats treated with different ricin regimens (RCA60 0.5 µg, RCA60 3 µg, and RCA120 6 µg) as animal models of MN degeneration. RESULTS: FG-guided stereological counting of MNs enabled identification, dissection and robust quantification of ricin-induced MN loss. The RCA60 0.5 µg and RCA120 6 µg regimens were found to be best suited as preclinical MN depletion models, with a low mortality and a reproducible MN loss, accompanied by muscle atrophy and functional deficits evaluated by MRI and the CatWalk method, respectively. COMPARISON WITH EXISTING METHODS: 1) Fluorogold neuronal tracing provides a robust and straightforward means for quantifying MN loss in the spinal cord; 2) MRI is well-suited to non-invasively assess muscle atrophy; and 3) The CatWalk method is more flexible than rotarod test for studying motor deficits. CONCLUSION: Intrasciatic injection of RCA60 or RCA120 induces nerve injury and muscle atrophy, which can be properly evaluated by a comprehensive platform using FG-guided quantitative 3D topographic histological analysis, MRI and the CatWalk behavioral test.

Temporal changes in macrophage phenotype after peripheral nerve injury.

BACKGROUND: Macrophages play a key role in peripheral nerve repair and demonstrate complex phenotypes that are highly dependent on microenvironmental cues. METHODS: We determined temporal changes in macrophage gene expression over time using RNA sequencing after fluorescence-activated cell sorting (FACS) macrophage populations from injured peripheral nerve. We identified key upstream regulators and dominant pathways using ingenuity pathway analysis and confirmed these changes with NanoString technology. We then investigate the effects of extreme polarizers of macrophage phenotype (IL4 and IFNγ) on nerve regeneration. We determined macrophage gene expression in vivo at the site of peripheral nerve injury with NanoString technology, and assessed recovery from sciatic nerve injury by cranial tibial muscle weights and retrograde labeling motor neurons in mice with deletion of IL4 or IFNγ receptors. RESULTS: We demonstrate that IL4R and IFNγR deletions provide complementary responses to polarization, and alter expression of genes associated with angiogenesis and axonal extension, but do not influence recovery from peripheral nerve transection at 8 weeks after repair. CONCLUSIONS: Overall, this study provides a framework to evaluate the phenotype of macrophages over time, and provides a broader and more precise assessment of gene expression changes than has previously been commonly used. This data suggests ways in which polarization may be modulated to improve repair.

Diphenyleneiodonium Mitigates Bupivacaine-Induced Sciatic Nerve Damage in a Diabetic Neuropathy Rat Model by Attenuating Oxidative Stress.

BACKGROUND: Increased oxidative stress has been linked to local anesthetic-induced nerve injury in a diabetic neuropathy (DN) rat model. The current study explores the effects of diphenyleneiodonium (DPI) chloride, an NADPH oxidase (NOX) inhibitor, on bupivacaine-induced sciatic nerve injury in DN rats. METHODS: A rat DN model was established through high-fat diet feeding and streptozotocin injection. The model was confirmed via testing (i) blood glucose, (ii) hindpaw allodynia responses to von Frey (VF) monofilaments, (iii) paw withdrawal thermal latency (PWTL), and (iv) nerve conduction velocity (NCV). Bupivacaine (Bup, 0.2 mL, 5 mg/mL) was used to block the right sciatic nerve. DPI (1 mg/kg) was injected subcutaneously 24 hours and 30 minutes before the sciatic block. At 24 hours after the block, NCV, various reactive oxygen species, and Caspase-3 were evaluated to determine the extent of sciatic nerve injury. RESULTS: The DN rat model was successfully established. Compared with the DN control group, the postblock values of VF responses (DN-Con, 16.5 ± 1.3 g; DN + Bup, 19.1 ± 1.5 g, P < .001) and PWTL significantly increased (DN-Con, 13.3 ± 1.1 seconds; DN + Bup, 14.6 ± 1.1 seconds, P = .028); the NCV of sciatic nerve was significantly reduced (DN-Con, 38.8 ± 2.4 m/s, DN + Bup, 30.5 ± 2.0 m/s, P = .003), and sciatic nerve injury (as indicated by axonal area) was more severe in the bupivacaine-treated DN group (DN-Con, 11.6 ± 0.3 µm, DN + Bup, 7.5 ± 0.3 µm, P < .001). In addition, DPI treatment significantly improved nerve function (VF responses, 17.3 ± 1.3 g; PWTL, 13.4 ± 1.1 seconds; NCV, 35.6 ± 3.1 m/s) and mitigated loss of axonal area (9.6 ± 0.3 µm). Compared to the DN + Bup group (without DPI), the levels of lipid peroxides and hydroperoxides, as well as the protein expression of NOX2, NOX4, and Caspase-3, were significantly reduced in the DN + Bup + DPI group (P < .05). CONCLUSIONS: Subcutaneous injection of DPI appears to protect against the functional and neurohistological damage of bupivacaine-blocked sciatic nerves in a high-fat diet/streptozotocin-induced DN model.

Obstetric Anesthesia Liability Concerns.

Obstetric practice carries a high risk of medical liability and involves both obstetricians and anesthesiologists. Analysis of data from the Anesthesia Closed Claims Project database shows an increase in the proportion of anesthesia claims for maternal death and brain damage between the 1990s and 2000 and later, primarily due to hemorrhage. The proportion of claims for newborn brain damage remained unchanged while those for maternal nerve injury and minor injuries decreased. Use of massive transfusion protocols and clinical drills have been shown to improve outcomes from hemorrhage. Good communication and teamwork are critical for reducing obstetric liability.

Evaluation of sciatic nerve damage following intraneural injection of bupivacaine, levobupivacaine and lidocaine in rats / Avaliação da lesão do nervo ciático após injeção intraneural de bupivacaína, levobupivacaína e lidocaína em ratos

ABSTRACT OBJECTIVE: The local anesthetics may cause neurotoxicity. We aimed to compare the neurotoxic potential of different local anesthetics, local anesthetic induced nerve damage and pathological changes of a peripheral nerve. METHODS: Sixty Wistar rats weighing 200-350 g were studied. Rats were assigned into 3 groups and 26-gauge needle was inserted under magnification into the left sciatic nerve and 0.2 mL of 0.5% bupivacaine, 5% levobupivacaine, and 2% lidocaine were injected intraneurally. An individual who was blind to the specifics of the injection monitored the neurologic function on postoperative 1st day, and daily thereafter. Neurologic examination included assessment for the presence and severity of nociception and grasping reflexes. At the 7th day sciatic nerve specimen was taken for evaluation of histopathologic changes. RESULTS: There was no statistical difference detected among groups regarding grasping reflex and histopathologic evaluation. Two cases in bupivacaine group, 1 case in levobupivacaine group and 2 cases in lidocaine group had slight grasping, while 1 case in lidocaine group had no grasping reflex on the seventh day. Severe axonal degeneration was observed in all groups, respectively in bupivacaine group 4 (20%), levobupivacaine group 3 (15%), and lidocaine group 6 (30%). CONCLUSION: In all groups, histopathological damage frequency and severity were more than the motor deficiency.

RESUMO OBJETIVO: Os anestésicos locais podem causar neurotoxicidade. Nosso objetivo foi comparar o potencial neurotóxico de diferentes anestésicos locais, os danos induzidos aos nervos e as alterações patológicas de um nervo periférico. MÉTODOS: Foram estudados 60 ratos Whistler com 200-350 g. Os ratos foram divididos em três grupos, uma agulha de calibre 26 foi inserida no nervo ciático esquerdo, com o uso de ampliação, e 0,2 mL de bupivacaína a 0,5%, levobupivacaína a 5% e lidocaína a 2% foram injetados por via intraneural. Um colaborador, cego para os conteúdos das injeções, monitorou a função neurológica no primeiro dia de pós-operatório e depois diariamente. O exame neurológico incluiu a avaliação da presença e da gravidade da nocicepção e dos reflexos de agarrar. No sétimo dia, uma amostra do nervo ciático foi colhida para avaliar as alterações histopatológicas. RESULTADOS: Não houve diferença estatística entre os grupos em relação ao reflexo de agarrar e à avaliação histopatológica. Dois casos no grupo bupivacaína, um no grupo levobupivacaína e dois no grupo lidocaína apresentaram um leve reflexo de agarrar; também no grupo lidocaína, um caso não apresentou reflexo de agarrar no sétimo dia. Degeneração axonal grave foi observada em todos os grupos: quatro casos no grupo bupivacaína (20%), três no grupo levobupivacaína 3 (15%) e seis no grupo lidocaína (30%). CONCLUSÃO: Em todos os grupos, a frequência de dano histopatológico e de gravidade foi maior do que a deficiência motora.

Evaluation of sciatic nerve damage following intraneural injection of bupivacaine, levobupivacaine and lidocaine in rats.

OBJECTIVE: The local anesthetics may cause neurotoxicity. We aimed to compare the neurotoxic potential of different local anesthetics, local anesthetic induced nerve damage and pathological changes of a peripheral nerve. METHODS: Sixty Wistar rats weighing 200-350g were studied. Rats were assigned into 3 groups and 26-gauge needle was inserted under magnification into the left sciatic nerve and 0.2mL of 0.5% bupivacaine, 5% levobupivacaine, and 2% lidocaine were injected intraneurally. An individual who was blind to the specifics of the injection monitored the neurologic function on postoperative 1st day, and daily thereafter. Neurologic examination included assessment for the presence and severity of nociception and grasping reflexes. At the 7th day sciatic nerve specimen was taken for evaluation of histopathologic changes. RESULTS: There was no statistical difference detected among groups regarding grasping reflex and histopathologic evaluation. Two cases in bupivacaine group, 1 case in levobupivacaine group and 2 cases in lidocaine group had slight grasping, while 1 case in lidocaine group had no grasping reflex on the seventh day. Severe axonal degeneration was observed in all groups, respectively in bupivacaine group 4 (20%), levobupivacaine group 3 (15%), and lidocaine group 6 (30%). CONCLUSION: In all groups, histopathological damage frequency and severity were more than the motor deficiency.

Effects on Spatial Cognition and Nociceptive Behavior Following Peripheral Nerve Injury in Rats with Lesion of the Striatal Marginal Division Induced by Kainic Acid.

Neuropathic pain and cognitive deficit are frequently comorbidity in clinical, but their underlying correlation and mechanisms remain unclear. Here, we utilized a combined rat model including kainic acid (KA) injection into bilateral striatal marginal division and chronic constriction nerve injury (CCI). PET/CT scans revealed that the SUVmax of KA rats was significantly decreased when compared to naive and saline rats. In contrast to the naive and saline rats, KA rats had longer latencies in locating the hidden platform on day 4, 5 in Morris water maze task. Thermal hyperalgesia and mechanical allodynia of KA rats were alleviated following CCI. Immunostaining results showed that substance P was markedly increased within ipsilateral spinal cord dorsal horn of KA rats after CCI, especially on the post-operative day 14. By means of real-time PCR, the up-regulation of GluR within ipsilateral spinal cord dorsal horn was observed in all KA and CCI rats. PKCγ, IL-6 and NF-κB were up-regulated in both CCI rats when compared to naive and their respective sham rats. These results suggest that cognitive impairment of rats altered the pain behaviors, and these intracellular regulators play crucial roles in the process of neuropathic pain.

Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury.

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function.

Possible involvement of convergent nociceptive input to medullary dorsal horn neurons in intraoral hyperalgesia following peripheral nerve injury.

Previous studies demonstrated that the number of c-Fos protein-like immunoreactive (c-Fos-IR) neurons in the medullary dorsal horn (MDH) evoked by noxious stimulation was increased after peripheral nerve injury, and such increase has been proposed to reflect the development of neuropathic pain state. The aim of this study was to examine the MDH for convergent collateral primary afferent input to second order neurons deafferented by peripheral nerve injury, and to explore a possibility of its contribution to the c-Fos hyperinducibility. Double immunofluorescence labeling for c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) was performed to detect convergent synaptic input. c-Fos expression and the phosphorylation of ERK were induced by the intraoral application of capsaicin and by electrical stimulation of the inferior alveolar nerve (IAN), respectively. The number of c-Fos-IR neurons in the MDH induced by the intraoral application of capsaicin was increased after IAN injury, whereas the number of p-ERK immunoreactive neurons remained unchanged. The number of double-labeled neurons, that presumably received convergent primary afferent input from the lingual nerve and the IAN, was significantly increased after IAN injury. These results indicated that convergent primary nociceptive input through neighboring intact nerves may contribute to the c-Fos hyperinducibility in the MDH and the pathogenesis of neuropathic pain following trigeminal nerve injury.

Systemic toxicity related to metal hip prostheses.

INTRODUCTION: One in eight of all total hip replacements requires revision within 10 years, 60% because of wear-related complications. The bearing surfaces may be made of cobalt/chromium, stainless steel, ceramic, or polyethylene. Friction between bearing surfaces and corrosion of non-moving parts can result in increased local and systemic metal concentrations. OBJECTIVES: To identify and systematically review published reports of systemic toxicity attributed to metal released from hip implants and to propose criteria for the assessment of these patients. METHODS: Medline (from 1950) and Embase (from 1980) were searched to 28 February 2014 using the search terms (text/abstract) chrom* or cobalt* and [toxic* or intox* or poison* or adverse effect or complication] and [prosthes* or 'joint replacement' or hip or arthroplast*] and PubMed (all available years) was searched using the search term (("Chromium/adverse effects"[Mesh] OR "Chromium/poisoning"[Mesh] OR "Chromium/toxicity"[Mesh]) OR ("Cobalt/adverse effects"[Mesh] OR "Cobalt/poisoning"[Mesh] OR "Cobalt/toxicity"[Mesh])) AND ("Arthroplasty, Replacement, Hip"[Mesh] OR "Hip Prosthesis"[Mesh]). These searches identified 281 unique references, of which 23 contained original case data. Three further reports were identified from the bibliographies of these papers. As some cases were reported repeatedly the 26 papers described only 18 individual cases. Systemic toxicity. Ten of these eighteen patients had undergone revision from a ceramic-containing bearing to one containing a metal component. The other eight had metal-on-metal prostheses. Systemic toxicity was first manifest months and often several years after placement of the metal-containing joint. The reported systemic features fell into three main categories: neuro-ocular toxicity (14 patients), cardiotoxicity (11 patients) and thyroid toxicity (9 patients). Neurotoxicity was manifest as peripheral neuropathy (8 cases), sensorineural hearing loss (7) and cognitive decline (5); ocular toxicity presented as visual impairment (6). All these neurological features, except cognitive decline, have been associated with cobalt poisoning previously. Type of prosthesis and blood metal concentrations. Where blood or serum metal concentrations were reported (n = 17 for cobalt and n = 14 for chromium), the median cobalt concentration was 398 (range, 13.6-6521) µg/L and the median chromium concentration was 48 µg/L (in whole blood) (range, 4.1-221 µg/L including serum and blood values). Those patients reported to have systemic features who had received a metal-on-metal prosthesis (n = 8) had a median peak blood cobalt concentration of 34.5 (range, 13.6-398.6) µg/L; those with a metal-containing revision of a failed ceramic prosthesis (n = 10) had a median blood cobalt concentration of 506 (range, 353-6521) µg/L. Management. The most common treatment was removal of the metal-containing prosthesis, undertaken in all but 2 patients. This was usually associated with a fall in circulating cobalt concentration and improvement in some or all features. Clinical and toxicological assessment of systemic features. We propose the following criteria for assessing the likelihood that clinical features are related to cobalt toxicity: clinical effects consistent with the known neurological, cardiac, or thyroidal effects of cobalt, and for which any other explanation is less likely; increased blood cobalt concentrations (substantially higher than those in patients with well-functioning prostheses) several months after hip replacement; a fall in the blood cobalt concentration, usually accompanied by signs of improvement in features. When judged by these criteria, the systemic features in 10 of the reported cases are likely to be related to cobalt exposure from a metal-containing hip prosthesis. CONCLUSIONS: Rarely, patients exposed to high circulating concentrations of cobalt from failed hip replacements develop neurological damage, hypothyroidism and/or cardiomyopathy, which may not resolve completely even after removal of the prosthesis. The greatest risk of systemic cobalt toxicity seems to result from accelerated wear of a cobalt-containing revision of a failed ceramic prosthesis, rather than from primary failure of a metal-on-metal prosthesis.