Improved antiallodynic, antihyperalgesic and anti-inflammatory response achieved through potential prodrug of curcumin, curcumin diethyl diglutarate in a mouse model of neuropathic pain.

Neuropathic pain is a debilitating chronic pain condition, and its treatment remains a clinical challenge. Curcumin, a naturally occurring phenolic compound, possesses diverse biological and pharmacological effects but has not yet been approved as a drug due to its low bioavailability. In order to overcome this limitation, we synthesized a potential ester prodrug of curcumin, curcumin diethyl diglutarate (CurDDG). In this study, we evaluated the pharmacological advantages of CurDDG over curcumin in a mouse model of chronic constriction injury (CCI), and the anti-inflammatory effect of CurDDG in LPS-induced RAW 264.7 macrophage cells was accessed to clarify the underline mechanism. Mice were treated with various oral doses of curcumin (25, 50, 100 and 200 mg/kg/day, daily for 14 days) or equimolar doses of CurDDG. CurDDG at all doses tested significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia compared with the CCI-control group. CurDDG at 25, 50 and 100 mg/kg demonstrated significantly greater efficacy on both mechanical and thermal hypersensitivities compared to that of curcumin. The effect of CurDDG correlated well with the inhibition of TNF-α and IL-6 levels in both the sciatic nerve and the spinal cord, as compared to its respective control groups. Similarly, in the in vitro study, CurDDG significantly reduced the LPS-induced expression of TNF-α and IL-6. Moreover, CurDDG significantly decreased COX-2 and iNOS levels and attenuated p38, JNK, and ERK1/2 phosphorylation as compared to the curcumin-treated cells. Altogether, this study demonstrated the improved pharmacological effects of curcumin by its diglutarate conjugate, CurDDG.

Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve.

ETHNOPHARMACOLOGY RELEVANCE: Escin is a natural mixture of triterpene saponins extracted from the seeds of Aesculus wilsonii Rehd. And has been reported to possess the therapeutic effects against neuropathic pain (NP). However, the underlying mechanisms remain unclear. AIM OF THE STUDY: The present study aimed to investigate the therapeutic effects and explore the underlying mechanisms of escin on rats of NP induced by chronic constriction injury (CCI) of sciatic nerve. MATERIALS AND METHODS: Rats were treated with escin (7, 14, and 28 mg/kg, i. g.) daily from the third day after the surgery (day 0) for consecutive 14 days. Regular behavior and thermal threshold were measured on days 0, 3, 5, 7, 10 and 14. Investigations into mechanisms involved measurement of inflammatory factors and biochemical factors in dorsal root ganglion (DRG). Inflammatory pain responses and nerve injuries were induced by the CCI model. Tonic pain model and acute inflammatory model induced by formalin or carrageenan were established to evaluated the pharmacological effects of escin on acute inflammatory pain. Corresponding behaviors were monitored and relevant gene expression such as c-fos, mu opioid receptor (MOR) and KCNK1 were detected by qRT-PCR. Investigate the neuroprotective effects of escin on PC12 cell injury induced by lipopolysaccharide (LPS). Cell morphology was observed under inverted microscope and neuroprotective effect of escin on cell activity was assessed by MTT assay. RESULTS: Escin could widen thermal threshold, downregulate the concentration of inflammatory factors like tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, suppress the gene expression of toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), decrease the level of glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) remarkably. In addition, escin significantly lowered the duration of licking, numbers of flinches and increase in paw edema, showing great therapeutic effects on inflammatory pain responses. Moreover, the activity of injured PC12 cells was significantly improved after escin administrated. CONCLUSION: Escin exerted the ameliorative effects on NP induced by CCI which may be related to downregulating the release of pro-inflammatory cytokines, suppressing TLR-4/NF-κB signal pathway, thereafter decreasing the level of GFAP and NGF.

Synergistic interaction between haloperidol and gabapentin in a model of neuropathic nociception in rat.

Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.

TRPV1, Targeted by miR-338-3p, Induces Neuropathic Pain by Interacting with NECAB2.

A variety of studies have proposed that transient receptor potential vanilloid 1 (TRPV1) is involved in the progression of multiple diseases, including neuropathic pain. Although increased expression of TRPV1 in chronic constriction injury was described earlier, the underlying regulatory mechanisms of TRPV1 in neuropathic pain remain largely unknown. In our study, we constructed a chronic constriction injury (CCI) rat model to deeply analyze the mechanisms underlying TRPV1. RT-qPCR-indicated TRPV1 mRNA and protein expression were extremely upregulated in CCI rat dorsal spinal cord tissues. Then, TRPV1 was corroborated to interact with N-terminal EF-hand Ca2+-binding protein 2 (NECAB2). The mRNA and protein levels of NECAB2 were increased in CCI tissues. Moreover, TRPV1 and NECAB2 together regulated nociceptive procession-associated protein metabotropic glutamate receptor 5 (mGluR5), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and Ca2+ in isolated microglia of CCI rats. Moreover, TRPV1 upregulation apparently increased mechanical allodynia and thermal hyperalgesia as well as the expression of inflammation-associated genes (COX-2, TNF-α, and IL-6). In addition, downregulation of NECAB2 significantly decreased mechanical allodynia and thermal hyperalgesia as well as the expression of COX-2, TNF-α, and IL-6. Furthermore, TRPV1 was confirmed to be a downstream target of miR-338-3p. TRPV1 overexpression abolished the inhibitory effect by miR-338-3p elevation on neuropathic pain development. In summary, this study proved TRPV1, targeted by miR-338-3p, induced neuropathic pain by interacting with NECAB2, which provides a potential therapeutic target for neuropathic pain treatment.

Shear Wave Elastographic Investigation of the Immediate Effects of Slump Neurodynamics in People With Sciatica.

OBJECTIVES: Neurodynamic techniques are often used to treat people with sciatica pain, but their mechanical effects on the sciatic nerve are unknown. Shear wave elastography (SWE) has been shown to effectively estimate the stiffness of peripheral nerves in real time. The aim of this study was to use SWE to assess the effects of slump neurodynamics in the sciatic stiffness of people with sciatica. METHODS: Sixteen participants volunteered for this study. The sciatic stiffness of 8 patients with unilateral chronic sciatica and 8 healthy control participants was measured by SWE, with the participants in a prone position and during a dynamic condition (ie, ankle dorsiflexion). These measurements were performed before and immediately after the neurodynamic intervention, which consisted of a static slump position applied to the symptomatic limb of the patients with sciatica and in a randomly chosen limb of the healthy participants. RESULTS: The 8 patients with sciatica included 6 male and 2 female patients, and the 8 healthy control participants included 5 male and 3 female volunteers. Slump neurodynamics resulted in an immediate decrease in the sciatic nerve stiffness of the symptomatic limb in people with sciatica by 16.1% (effect size = 0.65; P = .019). The intervention showed no significant changes in the sciatic nerve stiffness of the healthy participants (effect size = 0.05; P = .754). CONCLUSIONS: Slump neurodynamics have the potential of decreasing the sciatic nerve stiffness in people with sciatica, and this effect can be quantified by SWE, which may provide valuable information for health professionals.

The pivotal role for the multidisciplinary approach at all phases and at all levels in the national pathway for the management of low back pain and radicular pain in Belgium.

INTRODUCTION: High level evidence on management of spinal disorders is scarce, which results in guidelines being of limited practical use for practitioners. Care pathways are complex interventions intended for the mutual decision making of organization of care processes for a well-defined group of patients. The goal of this project was to design a pathway for the management of low back pain and radicular pain for national implementation in Belgium. EVIDENCE ACQUISITION: An international and Belgian study on characteristics of low back pain care pathways was performed along with a literature study and focus group interrogation. Based on essential building elements identified and a consensus approach among all relevant stakeholders in primary, hospital and reintegration care, a national pathway was constructed. The process was endorsed by the Belgian Health Care Knowledge Center, Belgian National Institute of Health and Disability Insurance and the Spine Society of Belgium. EVIDENCE SYNTHESIS: Eleven international pathways were identified, varying in implementation width from hospital-based to region/province-based. Seven Belgian pathway initiatives were detected. Notwithstanding differences, consistent building elements were identified. Three groups of caregivers, divided in primary care, hospital care and reintegration and including all relevant medical/paramedical disciplines, worked on integrating the essential building elements into a single concrete patient pathway of direct use to any caregiver and patient and based on a consensus model including reference to the 2017 Belgian adaptation of the 2016 NICE guidelines. The resulting pathways on management of low back pain and radicular pain underpin the importance of multidisciplinary teamwork. CONCLUSIONS: Essential building elements were identified from literature and established pathways and were successfully integrated in a Belgian national low back pain and radicular pain pathway using an integrative consensus approach. The pathways are consultable at www.lowbackpain.kce.be.

Parallels between lumbosacral radiculopathy and complex regional pain syndrome: α1-adrenoceptor upregulation, reduced dermal nerve fibre density, and hemisensory disturbances in postsurgical sciatica.

Residual lower-limb pain after low back surgery (postsurgical sciatica) and complex regional pain syndrome (CRPS) involving a lower limb are separate conditions but may share some mechanisms (eg, tissue inflammation, neuroimmune disturbances, and central neuroplasticity). As adrenergically evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to postsurgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with postsurgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all 4 limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in postsurgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick, and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuroplastic changes are involved not only in the pathophysiology of CRPS but also in postsurgical sciatica. This may have treatment implications for patients with postsurgical sciatica.

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain.

OBJECTIVE: Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS: Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS: MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS: These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.

Risk Factors for Low Back Pain: A Population-Based Longitudinal Study.

OBJECTIVE: To identify risk factors for low back pain (LBP) and lumbar radicular pain and to assess whether obesity and exposure to workload factors modify the effect of leisure-time physical activity on LBP and lumbar radicular pain. METHODS: The population of this 11-year longitudinal study consists of a nationally representative sample of Finns ages ≥30 years (n = 3,505). The outcomes of the study were LBP and lumbar radicular pain for >7 days or for >30 days in the past 12 months at follow-up. RESULTS: LBP and lumbar radicular pain were more common in women than in men. LBP slightly declined with increasing age, while lumbar radicular pain increased with age. Abdominal obesity (defined by waist circumference) increased the risk of LBP (adjusted odds ratio [OR] 1.40 [95% confidence interval (95% CI) 1.16-1.68] for LBP >7 days and adjusted OR 1.41 [95% CI 1.13-1.76] for LBP >30 days) and general obesity (defined by body mass index) increased the risk of lumbar radicular pain (adjusted OR 1.44 [95% CI 1.12-1.85] for pain >7 days and adjusted OR 1.62 [95% CI 1.16-2.26] for pain >30 days). Smoking and strenuous physical work increased the risk of both LBP and lumbar radicular pain. Walking or cycling to work reduced the risk of LBP, particularly LBP for >30 days (adjusted OR 0.75 [95% CI 0.59-0.95]), with the largest reductions among nonabdominally obese individuals and among those not exposed to physical workload factors. Using vibrating tools increased the risk of lumbar radicular pain. CONCLUSION: Lifestyle and physical workload factors increase the risk of LBP and lumbar radicular pain. Walking and cycling may have preventive potential for LBP.

Nerve root block versus surgery (NERVES) for the treatment of radicular pain secondary to a prolapsed intervertebral disc herniation: study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Sciatica is a common condition reported to affect over 3% of the UK population at any time and is often caused by a prolapsed intervertebral disc (PID). Although the duration and severity of symptoms can vary, pain persisting beyond 6 weeks is unlikely to recover spontaneously and may require investigation and treatment. Currently, there is no specific care pathway for sciatica in the National Health Service (NHS), and no direct comparison exists between surgical microdiscectomy and transforaminal epidural steroid injection (TFESI). The NERVES (NErve Root block VErsus Surgery) trial aims to address this by comparing clinical and cost-effectiveness of surgical microdiscectomy and TFESI to treat sciatica secondary to a PID. METHODS/DESIGN: A total of 163 patients were recruited from NHS out-patient clinics across the UK and randomised to either microdiscectomy or TFESI. Adult patients (aged 16-65 years) with sciatic pain endured for between 6 weeks and 12 months are eligible if their symptoms have not been improved by at least one form of conservative (non-operative) treatment and they are willing to provide consent. Patients will be excluded if they present with neurological deficit or have had previous surgery at the same level. The primary outcome is patient-reported disability measured using the Oswestry Disability Questionnaire (ODQ) score at 18 weeks post randomisation and secondary outcomes include disability and pain scales using numerical pain ratings, modified Roland-Morris and Core Outcome Measures Index at 12-weekly intervals, and patient satisfaction at 54 weeks. Cost-effectiveness and quality of life (QOL) will be assessed using the EQ-5D-5 L and self-report cost data at 12-weekly intervals and Hospital Episode Statistics (HES) data. Adverse event data will be collected. Analysis will follow the principle of intention-to-treat. DISCUSSION: NERVES is the first trial to evaluate the comparative clinical and cost-effectiveness of microdiscectomy to local anaesthetic and steroid administered via TFESI. The results of this research may facilitate the development of an evidence-based treatment strategy for patients with sciatica. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN04820368 . Registered on 5 June 2014. EudraCT EudraCT2014-002751-25. Registered on 8 October 2014.

Lessons learnt from a discontinued randomised controlled trial: adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica (Subcutaneous Injection of Adalimumab Trial compared with Control: SCIATiC).

BACKGROUND: Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. METHODS: A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months' duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. RESULTS: The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. CONCLUSIONS: Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN14569274 . Registered on 15 December 2014.

Chronic constriction injury-induced microRNA-146a-5p alleviates neuropathic pain through suppression of IRAK1/TRAF6 signaling pathway.

BACKGROUND: microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain. METHODS: The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. RESULTS: We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further. CONCLUSIONS: miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

Radicular pain caused by Schmorl's node: a case report / Dor radicular causada por nódulo de Schmorl: relato de caso

Abstract Schmorl's node a focal herniation of intervertebral disc through the end plate into the vertebral body. Most of the established Schmorl's nodes are quiescent. However, disc herniation into the vertebral marrow can cause low back pain by irritating a nociceptive system. Schmorl's node induced radicular pain is a very rare condition. Some cases of Schmorl's node which generated low back pain or radicular pain were treated by surgical methods. In this article, authors reported a rare case of a patient with radicular pain cause by Schmorl's node located at the inferior surface of the 5th lumbar spine. The radicular pain was alleviated by serial 5th lumbar transforaminal epidural blocks. Transforaminal epidural block is suggested as first conservative option to treat radicular pain due to herniation of intervertebral disc. Therefore, non-surgical treatment such as transforaminal epidural block can be considered a first treatment option for radicular pain caused by Schmorl's node.

Resumo O nódulo de Schmörl (NS) é a herniação focal do disco intervertebral através da placa terminal para dentro do corpo vertebral. A maioria dos nódulos de Schmörl já estabelecidos é quiescente. Porém, a hérnia de disco na medula vertebral pode causar dor lombar quando afeta um sistema nociceptivo. A dor radicular induzida por NS é uma condição muito rara. Alguns casos de NS que causaram dor lombar ou radicular foram tratados com procedimentos cirúrgicos. Neste artigo, relatamos o caso raro de um paciente com dor radicular causada por NS localizado na superfície inferior da quinta vértebra lombar (L5). A dor radicular foi atenuada mediante uma série de bloqueios peridurais transforaminais no nível L5. O bloqueio epidural transforaminal (BET) foi sugerido como primeira opção conservadora para tratar a dor radicular devido à herniação do disco intervertebral. Portanto, um tratamento não cirúrgico como o BET pode ser considerado como uma primeira opção de tratamento da dor radicular causada por NS.

Wallet Neuritis - An Example of Peripheral Sensitization.

BACKGROUND: Wallet neuritis is an example of extra-spinal tunnel neuropathy concerning sciatic nerve. Its clinical appearance often gets confused with sciatica of lumbar spine origin. Wallet- induced chronic sciatic nerve constriction produces gluteal and ipsilateral lower extremity pain, tingling, and burning sensation. It was Lutz, first describing credit-card wallet sciatica in an Attorney, surfaced on Journal of American Medical Association (JAMA), 1978; however, the condition has not been well-studied in various other occupations. CASE SUMMARY: In this write-up, we take the privilege of demonstrating wallet neuritis as an example of peripheral sensitization in three different professionals' namely specialist doctor, driver, and banker first time in Bangladesh. All the three patients' demonstrated aggravated gluteal pain with radiation on the homo-lateral lower extremity while remained seated on heavy wallet for a while, fortunately improved discontinuing such stuff with. Alongside radical wallectomy, piriformis stretching exercise on the affected side had also been recommended and found worthy in terms of pain relief. CONCLUSION: long-standing use of rear pocket wallet may compress and sensitize ipsilateral sciatic nerve, generating features resembling lumbago sciatica; thereby, remains a source of patients' misery and diagnostic illusion for pain physicians as well.

The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury-induced pain.

Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm2 were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide, a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X3 receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X3 epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia.

Exercise Combined With Ultrasound Attenuates Neuropathic Pain in Rats Associated With Downregulation of IL-6 and TNF-α, but With Upregulation of IL-10.

BACKGROUND: Although there are several evidences that suggest efficacies of therapeutic ultrasound (TU) or treadmill exercise (TE) to alleviate nerve injury-associated pain, molecular mechanisms are less clear. We aimed to investigate the impact of TU and/or TE on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve and their roles of proinflammatory and anti-inflammatory cytokines. METHODS: Rats were randomly divided into (n = 10 per group) sham operation (sham), CCI procedure followed by false application of TU (CCI + TU0), CCI procedure followed by false application of TU and TE (CCI + TU0 + TE), CCI, and CCI procedure followed by TU alone (CCI + TU), TE alone (CCI + TE), or both TU and TE (CCI + TU + TE) groups. TU and TE were administered daily, starting on postoperative day 8 (POD 8) for 3 weeks. Mechanical and thermal hypersensitivity, tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and IL-6 in the sciatic nerve were assessed on PODs 14 and 28. Data were analyzed by 1-way, 2-way, or 3-way analysis of variance of repeated measures or 1-way analysis of variance. RESULTS: After the interventions, there was statistical significance (all P ≤ .0001) between the groups for all outcome parameters, all in favor of the experimental group: 4.2 for mean mechanical withdrawal thresholds (95% confidence interval, 1.8-7.6) and 4.8 for mean thermal withdrawal latencies (95% confidence interval, 2.2-8.1). TU and/or TE provoked an increase in mechanical withdrawal thresholds and thermal withdrawal latencies in CCI rats. TU + TE was more effective to reverse pain hypersensitivity than having each treatment alone. On PODs 14 and 28, the CCI rats exhibited an upregulation of sciatic TNF-α and IL-6 expression, whereas TU or TE alone or TU + TE combination prevented the upregulation. TU and/or TE also showed the upregulation of less IL-10 expression in the sciatic nerve. CONCLUSIONS: We found that TU + TE is better than TU or TE alone for treating neuropathic pain. TU and/or TE for pain management may be straightly associated with less TNF-α and IL-6 expression and more IL-10 expression.

Neuron-astrocyte interactions in spinal cord dorsal horn in neuropathic pain development and docosahexaenoic acid therapy.

The analgesic activity of docosahexaenoic acid (DHA, 22:6 n-3) was studied using a chronic constriction injury (CCI) rat model. Animals were subcutaneously injected with DHA emulsion at a dose of 4.5mg/kg (125mМ/kg) daily during 2weeks after surgery. We characterized the dynamics of GFAP-positive astrocyte, substance P (SP) and nNOS-positive neurons activity in the spinal cord dorsal horn (SCDH) superficial lamina. We found that DHA treatment decrease the intensity and duration of neurogenic pain syndrome, results in earlier stabilization of weight distribution, prevents the cold allodynia and dystrophic changings in denervated limb tissue. DHA treatment reduced the reactive astrocyte number, decrease SP-immunopositive fibers and nNOS-positive neurons number in the SCDH in neuropathic pain.

Prognostic value of magnetic resonance imaging findings in patients with sciatica.

OBJECTIVE This study aimed to determine the prognostic value of MRI variables to predict outcome in patients with herniated disc-related sciatica, and whether MRI could facilitate the decision making between early surgery and prolonged conservative care in these patients. METHODS A prospective observational evaluation of patients enrolled in a randomized trial with 1-year follow-up was completed. A total of 283 patients with sciatica who had a radiologically confirmed disc herniation were randomized either to surgery or to prolonged conservative care with surgery if needed. Outcome measures were recovery and leg pain severity. Recovery was registered on a 7-point Likert scale. Complete/near complete recovery was considered a satisfactory outcome. Leg pain severity was measured on a 0- to 100-mm visual analog scale. Multiple MRI characteristics of the degenerated disc herniation were independently scored by 3 spine experts. Cox models were used to study the influence of MRI variables on rate of recovery, and linear mixed models were used to determine the predictive value of MRI variables for leg pain severity during follow-up. The interaction of each MRI predictor with treatment allocation was tested. There were no study-specific conflicts of interest. RESULTS Baseline MRI variables associated with less leg pain severity were the reader's assessment of presence of nerve root compression (p < 0.001), and assessment of extrusion compared with protrusion of the disc herniation (p = 0.006). Both variables tended to be associated, but not significantly, with satisfactory outcome during follow-up (HR 1.45, 95% CI 0.93-2.24, and HR 1.24, 95% CI 0.96-1.61, respectively). The size of disc herniation at baseline was not associated with outcome. There was no significant change in the effects between treatment groups. CONCLUSIONS MRI assessment of the presence of nerve root compression and extrusion of a herniated disc at baseline was associated with less leg pain during 1-year follow-up, irrespective of a surgical or conservative treatment. MRI findings seem not to be helpful in determining which patients might fare better with early surgery compared with a strategy of prolonged conservative care. Clinical trial registration no.: ISRCTN26872154 ( controlled-trials.com ).

Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats.

BACKGROUND: Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state. METHODS: Neuropathic pain was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. Mechanical threshold was tested using von Frey filaments. The mechanical threshold response was assessed over time using the area under curves. Intrathecal administration of antisense oligodeoxynucleotide (ODN) against Drp1, mitochondrial division inhibitor-1 (mdivi-1), or phenyl-N-tert-butylnitrone (a reactive oxygen species scavenger) was given. The expression of spinal Drp1 was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. RESULTS: Intrathecal administration of either antisense ODN against Drp1 or mdivi-1 decreased mechanical allodynia (a sensation of pain evoked by nonpainful stimuli) in the gp120 model. Intrathecal ODN or mdivi-1 did not change basic mechanical threshold in sham surgery rats. Intrathecal Drp1 antisense ODN decreased the spinal expression of increased Drp1 protein induced by peripheral gp120 application. Intrathecal phenyl-N-tert-butylnitrone reduced mechanical allodynia. Furthermore, both intrathecal Drp1 antisense ODN and mdivi-1 reversed the upregulation of mitochondrial superoxide in the spinal dorsal horn in the gp120 neuropathic pain state. CONCLUSIONS: These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV.