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.

Role of calcitonin gene-related peptide in pain regulation in the parabrachial nucleus of naive rats and rats with neuropathic pain.

Researches have shown that calcitonin gene-related peptide (CGRP) plays a pivotal role in pain modulation. Nociceptive information from the periphery is relayed from parabrachial nucleus (PBN) to brain regions implicated involved in pain. This study investigated the effects and mechanisms of CGRP and CGRP receptors in pain regulation in the PBN of naive and neuropathic pain rats. Chronic sciatic nerve ligation was used to model neuropathic pain, CGRP and CGRP 8-37 were injected into the PBN of the rats, and calcitonin receptor-like receptor (CLR), a main structure of CGRP receptor, was knocked down by lentivirus-coated CLR siRNA. The hot plate test (HPT) and the Randall Selitto Test (RST) was used to determine the latency of the rat hindpaw response. The expression of CLR was detected with RT-PCR and western blotting. We found that intra-PBN injecting of CGRP induced an obvious anti-nociceptive effect in naive and neuropathic pain rats in a dose-dependent manner, the CGRP-induced antinociception was significantly reduced after injection of CGRP 8-37, Moreover, the mRNA and protein levels of CLR, in PBN decreased significantly and the antinociception CGRP-induced was also significantly lower in neuropathic pain rats than that in naive rats. Knockdown CLR in PBN decreased the expression of CLR and the antinociception induced by CGRP was observably decreased. Our results demonstrate that CGRP induced antinociception in PBN of naive or neuropathic pain rats, CGRP receptor mediates this effect. Neuropathic pain induced decreases in the expression of CGRP receptor, as well as in CGRP-induced antinociception in PBN.

The synergistic effects of opioid and neuropeptide B/W in rat acute inflammatory and neuropathic pain models.

The use of morphine is controversial due to the incidence of rewarding behavior, respiratory depression, and tolerance, leading to increased drug dose requirements, advancing to morphine addiction. To overcome these barriers, strategies have been taken to combine morphine with other analgesics. Neuropeptide B23 and neuropeptide W23 (NPB23 and NPW23) are commonly used to relieve inflammatory pain and neuropathic pain. As NPB23 and NPW23 system shares similar anatomical basis with opioid system at least in the spinal cord we hypothesized that NPB23 or NPW23 and morphine may synergistically relieve inflammatory pain and neuropathic pain. To test this hypothesis, we demonstrated that µ opioid receptor and NPBW1 receptor (receptor of NPB23 and NPW23) are colocalized in the superficial dorsal horn of the spinal cord. Secondly, co-administration of morphine witheitherNPB23 or NPW23 synergistically attenuated inflammatory and neuropathic pain. Furthermore, either NPB23 or NPW23 significantly reduced morphine-induced conditioned place preference (CPP) and constipation. We also found that phosphorylation of extracellular-regulated protein kinase (ERK1/2) following morphine was profoundly potentiated by the application of NPB23 or NPW23. Hence, combination of morphine with either NPB23 or NPW23 reduced dose of morphine required for pain relief in inflammatory and neuropathic pain, while effectively prevented some side-effects of morphine.

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.

Low back pain and sciatica in over 16s: assessment and management: Last updated 11 December 2020

This guideline covers assessing and managing low back pain and sciatica in people aged 16 and over. It outlines physical, psychological, pharmacological and surgical treatments to help people manage their low back pain and sciatica in their daily life. The guideline aims to improve people's quality of life by promoting the most effective forms of care for low back pain and sciatica. The recommendations in this guideline were developed before the COVID-19 pandemic. For advice on neuropathic pain not related to sciatica, see the NICE guideline on neuropathic pain in adults.

Ultrasound detection of sciatic nerve movements with ankle dorsiflexion/plantar flexion: Prospective comparative study of a novel method to locate the sciatic nerve.

OBJECTIVES: It is possible to observe the in-vivo movements of nerves using real-time ultrasound. In this study, we aimed to visualize the movements of the sciatic nerve as a guide to identify the sciatic nerve to distinguish from surrounding tissue. METHODS: This trial was a prospective, cross-over comparative study. We included 25 healthy volunteers in this study. The movements of the sciatic nerve were visualized in the transverse view at popliteal and midthigh levels using ultrasonography. Anterior-posterior movements were assessed by measuring skin-to-nerve distance. The distances were measured during maximum ankle dorsiflexion, maximum plantar flexion and neutral position and compared with each other. We also evaluated the quality of dynamic (real-time) rotation/lateral movements of the sciatic nerve by assigning a subjective observer score. RESULTS: The movement of sciatic nerve was significant at popliteal region with active and passive ankle dorsiflexion which was 0.32 cm and 0.23 cm respectively (p=0.003). The movement of sciatic nerve was significant at midthigh region with active and passive ankle plantar flexion which was 0.11 cm and 0.01 cm respectively (p<0.001). Excellent rotation/lateral movement was observed in subjects at popliteal region and good rotation/lateral movement was observed at midthigh level. CONCLUSION: Sciatic nerve movement can be observed with ankle dorsiflexion and plantar flexion in the transverse plane at popliteal and midthigh locations under real time ultrasound. This preliminary study suggest that observing the movements of sciatic nerve is potentially valuable in clinical sciatic nerve blocks for facilitating the localization of the sciatic nerve.

Covering the proximal nerve stump with chondroitin sulfate proteoglycans prevents traumatic painful neuroma formation by blocking axon regeneration after neurotomy in Sprague Dawley rats.

OBJECTIVE: Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs' spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation. METHODS: Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30). RESULTS: Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p < 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p < 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α-smooth muscle actin were significantly lower in the CSPG group than in the positive group (p < 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)-17, and IL-1ß levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p < 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p < 0.05). CONCLUSIONS: The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.

DGCR5 attenuates neuropathic pain through sponging miR-330-3p and regulating PDCD4 in CCI rat models.

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1ß in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors.

CONTEXT: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception. OBJECTIVE: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed. MATERIALS AND METHODS: Behavioural (von Frey's/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 µG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7. RESULTS: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy. CONCLUSIONS: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.

Inhibition of miR-200b/miR-429 contributes to neuropathic pain development through targeting zinc finger E box binding protein-1.

Many studies have reported that microRNAs participate in neuropathic pain development. Previously, miR-200b and miR-429 are reported to be involved in various diseases. In our current study, we focused on their roles in neuropathic pain and we found that miR-200b and miR-429 were significantly decreased in chronic constriction injury (CCI) rat spinal cords and isolated microglials. miR-200b and miR-429 overexpression were able to relieve neuropathic pain through modulating PWT and PWL in CCI rats. Meanwhile, we observed that both miR-200b and miR-429 upregulation could repress neuroinflammation via inhibiting inflammatory cytokines such as IL-6, IL-1ß, and TNF-α in CCI rats. By carry out bioinformatics technology, Zinc finger E box binding protein-1 (ZEB1) was predicted as target of miR-200b, and miR-429 and dual-luciferase reporter assays confirmed the correlation between them. ZEB1 has been reported to regulate a lot of diseases. Here, we found that ZEB1 was greatly increased in CCI rats and miR-200b and miR-429 overexpression markedly suppressed ZEB1 mRNA expression in rat microglial cells. In addition, knockdown of ZEB1 can reduce neuropathic pain development and co-transfection of LV-anti-miR-200b/miR-429 reversed this phenomenon in vivo. Taken these together, our results suggested that miR-200b/miR-429 can serve as an important regulator of neuropathic pain development by targeting ZEB1.

Percutaneous laser disc decompression versus microdiscectomy for sciatica: Cost utility analysis alongside a randomized controlled trial.

Background Percutaneous laser disc decompression (PLDD) for patients with lumbar disc herniation is believed to be cheaper than surgery. However, cost-effectiveness has never been studied. Materials and Methods A cost utility analysis was performed alongside a randomized controlled trial comparing PLDD and conventional surgery. Patients reported their quality of life using the EuroQol five dimensions questionnaire (EQ-5D), 36-item short form health survey (SF-36 and derived SF-6D) and a visual analogue scale (VAS). Using cost diaries patients reported health care use, non-health care use and hours of absenteeism from work. The 1-year societal costs were compared with 1-year quality adjusted life years (QALYs) based on the United States (US) EQ-5D. Sensitivity analyses were carried out on the use of different utility measures (Netherland (NL) EQ-5D, SF-6D, or VAS) and on the perspective (societal or healthcare). Results On the US EQ-5D, conventional surgery provided a non-significant gain in QALYs of 0.033 (95% confidence interval (CI) -0.026 to 0.093) in the first year. PLDD resulted in significantly lower healthcare costs (difference €1771, 95% CI €303 to €3238) and non-significantly lower societal costs (difference €2379, 95% CI -€2860 to €7618). For low values of the willingness to pay for a QALY, the probability of being cost-effective is in favor of PLDD. For higher values of the willingness to pay, between €30,000 and €70,000, conventional microdiscectomy becomes favorable. Conclusions From a healthcare perspective PLDD, followed by surgery when needed, results in significantly lower 1-year costs than conventional surgery. From a societal perspective PLDD appears to be an economically neutral innovation.

Cyclic Sciatica and Back Pain Responds to Treatment of Underlying Endometriosis: Case Illustration.

BACKGROUND: Multiple causes outside the spine can mimic spinal back pain. Endometriosis is an important gynecologic disorder, which commonly affects the lower region of the female pelvis and less frequently the spine and soft tissues. The lumbosacral trunk is vulnerable to pressure from any abdominal mass originating from the uterus and the ovaries. Therefore symptoms of endometriosis include severe reoccurring pain in the pelvic area as well as lower back and abdominal pain. CASE DESCRIPTION: We report on a 39-year-old gymnast with cyclic sciatica and back pain, whose initial presentation initially led to a spinal fusion at L4/5 and L5/S1, but that procedure did not change her symptoms. Her diagnosis of endometriosis was not made until 2 years after her spinal fusion. Ultimately, once diagnosed with endometriosis of the retroperitoneal spinal and neural elements, her back and leg pain responded completely to hormonal therapy and then to a hysterectomy and a bilateral salpingo-oophorectomy. Because her true diagnosis of endometriosis was unknown and she had some degenerative changes in her spine, she underwent a spinal fusion that would probably not have been done if the diagnosis of endometriosis had been suggested. CONCLUSIONS: It is critical for any clinician who deals with back pain to at least consider the diagnosis of endometriosis in female patients who have a history of pelvic pain. The diagnosis of endometriosis should be considered in candidate patients by asking whether there is a significant hormonal cyclic nature to the symptoms, to prevent such unnecessary surgical adventures.

Low back pain and sciatica in over 16s: assessment and management

This guideline covers assessing and managing low back pain and sciatica in people aged 16 and over. It outlines physical, psychological, pharmacological and surgical treatments to help people manage their low back pain and sciatica in their daily life. The guideline aims to improve people's quality of life by promoting the most effective forms of care for low back pain and sciatica.

Leisure-time physical activity and sciatica: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The role of leisure-time physical activity in sciatica is uncertain. This study aimed to assess the association of leisure-time physical activity with lumbar radicular pain and sciatica. DATABASES AND DATA TREATMENT: Literature searches were conducted in PubMed, Embase, Web of Science, Scopus, Google Scholar and ResearchGate databases from 1964 through August 2015. A random-effects meta-analysis was performed, and heterogeneity and small-study bias were assessed. RESULTS: Ten cohort (N = 82,024 participants), four case-control (N = 9350) and four cross-sectional (N = 10,046) studies qualified for meta-analysis. In comparison with no regular physical activity, high level of physical activity (≥4 times/week) was inversely associated with new onset of lumbar radicular pain or sciatica in a meta-analysis of prospective cohort studies [risk ratio (RR) = 0.88, 95% CI 0.78-0.99, I2  = 0%, 7 studies, N = 78,065]. The association for moderate level of physical activity (1-3 times/week) was weaker (RR = 0.93, CI 0.82-1.05, I2  = 0%, 6 studies, N = 69,049), and there was no association with physical activity for at least once/week (RR = 0.99, CI 0.86-1.13, 9 studies, N = 73,008). In contrast, a meta-analysis of cross-sectional studies showed a higher prevalence of lumbar radicular pain or sciatica in participants who exercised at least once/week [prevalence ratio (PR) = 1.29, CI 1.09-1.53, I2  = 0%, 4 studies, N = 10,046], or 1-3 times/week (PR = 1.34, CI 1.02-1.77, I2  = 0%, N = 7631) than among inactive participants. There was no evidence of small-study bias. CONCLUSIONS: This meta-analysis suggests that moderate to high level of leisure physical activity may have a moderate protective effect against development of lumbar radicular pain. However, a large reduction in risk (>30%) seems unlikely. WHAT DOES THIS REVIEW ADD: Leisure-time physical activity may reduce the risk of developing lumbar radicular pain.

Does the duration of symptoms influence outcome in patients with sciatica undergoing micro-discectomy and decompressions?

BACKGROUND: Early surgical treatment for back and leg pain secondary to disc herniation has been associated with very good outcomes. However, there are conflicting data on the role of surgical treatment in case of prolonged radicular symptomatology. PURPOSE: We aimed to evaluate whether the duration of symptoms at presentation affects the subjective outcome. STUDY DESIGN/SETTING: This is a retrospective review of prospectively collected data from a single surgeon including micro-discectomies and lateral recess decompressions in patients younger than 60 years old using patient medical notes, radiology imaging, operation notes, and Patient Reported Outcome Measures (PROMS) including Oswestry Disability Index (ODI), visual analogue scale for back pain and leg pain (VAS-BP and VAS-LP). The final follow-up was carried out through postal questionnaire or telephone consultation. METHODS: Demographic information, duration of symptoms, type and incidence of complications, length of hospital stay, and follow-up were analyzed. Data were categorized into four subgroups: symptoms 0≥6 months, 6 months≥1 year, 1 year≥2 years, and >2 years. A clinically significant result was an average improvement of 2 or more points in the VAS and of 20% and over in the ODI. The level of statistical significance was <0.05%. RESULTS: A total number of 107 patients who underwent 109 operations were included. The level of surgery was L5/S1 (50), L4/L5 (43), L3/L4 (3), L2/L3 (2), and two levels (11). The mean improvement was from 0 to ≤6 months (VAS-LP 5.21±2.81, VAS-BP 3.04±3.15, ODI 35.26±19.25), 6 months to ≤1 year (VAS-LP 4.73±2.61, VAS-BP 3.30±3.05, ODI 26.92±19.49), 1 year to ≤2 years (VAS-LP 3.78±3.68, VAS-BP 3.00±2.78, ODI 19.03±20.24), and >2 years (VAS-LP 4.77±3.61, VAS-BP 3.54±3.43, ODI 28.36±20.93). The length of hospital stay and complication rate was comparable between groups. Average follow-up was 15.69 months. CONCLUSIONS: Our study showed significant improvement in patients with symptoms beyond 1 as well as 2 years since onset, and surgery is a viable option in selected patients.

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.

Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.

BACKGROUND: Insulin therapy plays a critical role in managing type 1 diabetes mellitus, and exercise produces alterations in pain sensation. This experiment explored the effects of insulin therapy combined with treadmill training on diabetic neuropathic pain and on the expression of malondialdehyde (MDA) and cytokines. METHODS: Rats were given 4 weeks of insulin (100 IU/kg) therapy and treadmill training (30-60 min/d of training at 20-25 m/min) each day beginning on day 3 after streptozotocin (65 mg/kg, IV) injection and continuing until day 27. Sensitivity to heat and mechanical stimuli and the expression of interleukin (IL)-10, IL-6, tumor necrosis factor-α, and MDA in the sciatic nerve were estimated. RESULTS: We showed that 2 to 4 weeks of treadmill training, insulin treatment, or their combination increased both paw withdrawal thresholds and latencies compared with the same regimen in sedentary diabetic rats (all P < 0.0022). Treatment with insulin, but without treadmill training, had significant effects on glycemic control (P < 0.0001) and restored body weight (P < 0.0001) in the diabetic rats. The diabetic rats demonstrated the upregulation (all P < 0.009) of IL-6, MDA, and tumor necrosis factor-α in the sciatic nerve on days 14 and 28 after streptozotocin treatment, whereas in diabetic rats receiving insulin, treadmill training, or a combination (all P < 0.01), this upregulation was decreased. Insulin, treadmill training, or the combination increased IL-10 expression (all P < 0.0051) in all diabetic rats. CONCLUSIONS: Treadmill training combined with insulin therapy showed the best improvements in tactile allodynia and thermal hyperalgesia among our 3 treatment groups. The benefits of insulin intervention and treadmill training could be related to chronic inflammation (proinflammatory cytokines) and oxidative stress (MDA).

Psychological defensive profile of sciatica patients with neuropathic pain and its relationship to quality of life.

AIM: To identify differences between defense styles and mechanisms in sciatica patients with or without neuropathic pain and their relationship to quality of life. STUDY DESIGN: The study included 37 sciatica patients with neuropathic pain (SNP), 36 sciatica patients without neuropathic pain and 38 healthy subjects. Pain severity was measured using the Visual Analogue Scale (VAS). Psychological condition was assessed using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). Defense mechanisms were assessed using a 40-item Defense Style Questionnaire (DSQ-40) and quality of life was assessed using Short Form-36 (SF-36). RESULTS: BDI and BAI scores were significantly higher in the SNP group (p < 0.001). Idealization and immature defense styles, as well as isolation, displacement and somatization were significantly higher in the SNP group (p < 0.05). SF-36 parameters also differed significantly between the groups, with controls having the best scores and the SNP group the worst. In linear regression analysis, acting out and BDI were found to affect the pain domain of the SF-36 (p < 0.001). CONCLUSION: The acting out defensive style and BDI were independently associated with pain-related quality of life. In the SNP group, significant differences were found in the immature and neurotic styles of the defense mechanisms.

The origin variability of the iliolumbar artery and iatrogenic sciatica.

The iliolumbar artery (ILA) is a standard branch from the posterior trunk of the internal iliac artery. It is the only pelvic artery ascending from pelvic cavity. Current study comprises 171 cadavers dissection to assess the origin variability of ILA. The present study identified the incidence of the ILA origin variability in Caucasian population which also clarified the iliolumbar variability in males and females. The current study shows that the ILA arises from the common iliac artery in 2%, from the external iliac artery in 0.3% and from the internal iliac artery in 13.8% either from its dorsal or dorsomedial aspects in 1 and 12.8%, respectively. The common, external and internal iliac arteries are defined as a high (early) origin and occurred in 16.1%. The posterior trunk of the internal iliac artery is the most common origin of the ILA found to be in 77.9%. Occasionally, it also arose from the superior gluteal artery (0.7%) and the sciatic artery (0.3%). Furthermore, the ILA arises from the anterior trunk indirectly as from the inferior gluteal artery in 0.3%. The ILA arising from the superior or inferior gluteal artery or from the sciatic artery is defined as a low (delayed) origin and occurred in 1.3%. In contrast, the ILA was 4.7%. Consequently, variability of the ILA leads to vascular variability of the lumbosacral trunk of the sciatic nerve. Clinicians have to be aware of these variations to avoid unnecessary ligation to prevent sciatic neuropathy.

Osteopathy: helping pregnant women in pain.

Various therapies are accessed by women who are looking to enhance the experience of pregnancy or to relieve pain from pregnancy-related ailments. This article gives an introduction to how osteopathy may help women presenting with pain. It includes an overview of a case study, in order that midwives can gain insight into how osteopathic medicine approaches and applies knowledge of anatomy and physiology to improve biomechanics that may have become sub optimal giving the symptom of pain. An underlying philosophy of structure governs function.