Neuropathic Group Research Articles

Effect of amitriptyline on phosphorylation of HDAC5 in basolateral amygdale of rats with neuropathic pain

Objective To evaluate the effect of amitriptyline on the phosphorylation of histone deacetylase 5 (HDAC5) in the basolateral amygdala (BLA) of rats with neuropathic pain. Methods Thirty healthy male Wistar rats, weighing 250-300 g, were divided into 3 groups (n=10 each) using a random number table method: sham operation group (S group), neuropathic pain group (NP group) and amitriptyline group (A group). Spared nerve injury was produced by exposing the sciatic nerve and its branches and ligation and transection of tibial nerve and common fibular nerve in anesthetized rats.Amitriptyline 10 mg/kg was intraperitoneally injected every day on 14-35 days after establishing the model in group A, while the equal volume of normal saline was given instead of amitriptyline in S and NP groups.The mechanical paw withdrawal threshold (MWT) was measured on 3, 7, 14, 21, 28 and 35 days after establishing the model in each group.The forced swimming test was performed on day 36 after establishing the model, and immobility time, climbing time and swimming time were recorded.The rats were then sacrificed, and brain tissues in BLA were obtained for determination of the expression of HDAC5 and phosphorylated HDAC5 (p-HDAC5) (by Western blot) and expression of HDAC5 mRNA (by real-time quantitative polymerase chain reaction). Results Compared with group S, the MWT was significantly decreased at each time point, the immobility time was prolonged, and the swimming time and climbing time were shortened in group NP, and the MWT was significantly decreased on days 14, 21 and 28 after establishing the model, the expression of p-HDAC5 was down-regulated, and the expression of HDAC5 mRNA was up-regulated in group A (P<0.05). Compared with group NP, the MWT was significantly increased on days 21, 28 and 35 after establishing the model, the immobility time was shortened, the climbing time was prolonged, the expression of p-HDAC5 was up-regulated, and the expression of HDAC5 mRNA was down-regulated in group A (P<0.05 or 0.01). Conclusion The mechanism by which amitriptyline improves depression is associated with promoting the phosphorylation of HDAC5 in BLA of rats with NP. Key words: Amitriptyline; Neuralgia; Depression; Basolateral nuclear complex; Histone deacetylases

Plantar pressure distribution in diverse stages of diabetic neuropathy.

Diabetic Foot Ulceration in patients with diabetes could be associated with high plantar pressure caused by diabetes neuropathy. Therefore, it seems that one of the ways of identifying high-risk legs in diabetic patients with neuropathy would be characterization of elevated plantar pressure distributions. Comparing the plantar pressure distribution in diabetic patients who suffered neuropathy with those without neuropathy. Plantar pressure distribution was recorded in the following categories: 38 diabetic patients without neuropathy, 30, 40 and 34 patients with mild neuropathy, moderate and severe neuropathy respectively. Patients suffered from severe neuropathy suggested higher maximum peak plantar pressure at midfoot, heel, and medial forefoot. The peak pressure of midfoot was significantly different in the following categories as well: patient without neuropathy (32.3 ± 17.9kPa), mild neuropathic (24.0 ± 17.9kPa), moderate neuropathic (21.5 ± 12.6kPa), and severe neuropathic (22.9 ± 10.7kPa) groups (p = 0.02). The progression of diabetic neuropathy would have been increased followed by the peak plantar pressure.

Investigation of prevalence and risk predictors of depressive tendency in type 2 diabetic patients with peripheral neuropathy

Objective To investigate the prevalence and risk predictors of depressive tendency in type 2 diabetic patients with peripheral neuropathy. Methods From May 2017 to December 2017, 150 diabetic patients with peripheral neuropathy and 150 diabetic patients without peripheral neuropathy in the First Affiliated Hospital of Harbin Medical University were collected.The general clinical data, including age, sex, diabetic duration, height, weight, body mass index(BMI), fasting blood glucose(FBG), fasting insulin(FINS), homeostasis model assessment-insulin resistance index(HOMA-IR), glycated hemoglobin(HbA1c), blood lipid and blood pressure were collected.The motor nerve and sensory nerve conduction velocity of lower limbs were measured by electromyograph.Zung depression self-rating scale(SDS) was used for self-rating of depression syndrome. Results There were 46 cases(30.67%) suffered from depression(SDS>50) in the neuropathic group, and 25 cases(16.67%) suffered from depression in the non-neuropathic group.The incidence rate of depression in the neuropathic group was significantly higher than that in the non-neuropathic group and tended to be severe(χ2=12.732, P=0.005). Non-conditional Logistic multivariate stepwise regression analysis showed that sex, the course of diabetes and low density lipoprotein(LDL) were associated with depressive tendency(χ2=3.994, P=0.049; χ2=5.334, P=0.032; χ2=6.172, P=0.020). Conclusion The prevalence of depression in diabetic patients with peripheral neuropathy is higher and tends to be severe.Sex, the course of diabetes and LDL are risk factors of depressive tendency. Key words: Type 2 diabetes mellitus; Peripheral neuropathy; Depression; Dody mass index; Insulin resistance; Depression self-rating scale; Morbidity; Risk factor

Quantitative sensory profiles of upper extremity chemotherapy induced peripheral neuropathy: Are there differences in sensory profiles for neuropathic versus nociceptive pain?

ABSTRACT Aims The aim of this study was to define the sensory phenotypes of taxane-induced peripheral neuropathy (TIPN) between neuropathic and nonneuropathic symptoms in a breast cancer population to identify future targets for mechanism-based pain management. Methods Participants (n = 48) with stage I–III breast cancer. Self-report questionnaires and quantitative sensory testing were used to assess sensory symptoms. The self-report version of the Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS) divided the groups into neuropathic and nonneuropathic sensory phenotypes. In total, five visits over approximately 8 months assessed each participant from pre-chemotherapy to 6 months post-chemotherapy. Results Out of 191 nerve assessments, 150 had an S-LANSS <12 defined as “nonneuropathic” and 41 scored >12, which was defined as “neuropathic.” Numeric Pain Rating Scale (NPRS) was analyzed based on percentages of those experiencing 1+ pain (graded 1/10 or higher) versus no pain. The neuropathic group had 82.9% of 1+ pain vs. 28.7% in the nonneuropathic group (odds ratio = 7.49; 95% confidence interval, 2.76–20.3; P = 0.001). The neuropathic group reported impaired function on the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire (P = 0.002). Heat pain threshold resulted in statistical differences for the left hand but not the right hand in the neuropathic group (P = 0.05). No other quantitative data on warm/cool or cold or vibration demonstrated sensory differences between the groups. Conclusions Few differences in sensory profiles measured using quantitative sensory testing (QST) were found. Heat pain thresholds were normalized, possibly suggesting that the neuropathic group retained C-fiber and transient potential vanilloid 1 (TRPV1) function. Participants with neuropathic pain demonstrated significant differences with increased pain and decreased function.

Effect of intrathecal oxytocin on neuropathic pain in rats

Objective To evaluate the effect of intrathecal oxytocin on neuropathic pain in rats. Methods Thirty-six SPF male Sprague-Dawley rats, aged 4-6 weeks , weighing 100-150 g, were divided into 4 groups(n=9 each)using a random number table: control group(group C), neuropathic pain group(group NP), neuropathic pain plus normal saline group(group NPN)and neuropathic pain plus oxytocin group(group NPO). The neuropathic pain model was made by partial sciatic nerve injury in NP, NPN and NPO groups.In group NPO, oxytocin 10 μl(0.1 μg)was intrathecally injected on the day of establishing the model and 1 and 2 days after establishing the model, and then normal saline 10 μl was given for tube sealing at 9 a. m.and 4 p. m.every day.In group NPN, normal saline 20 μl was given for tube sealing at the corresponding time points.The mechanical paw withdrawal threshold(MWT)and thermal paw withdrawal latency(TWL)were measured at 1 day before establishing the model and 1, 2, 3, 4, 5, 6 and 7 days after establishing the model.The expression of the astrocyte marker glial fibrillary acidic protein(GFAP)and a specific marker of microglia ionized calcium-binding adaptor molecule 1(IBa-1)was detected by Western blot at 1 day before establishing the model and 3 and 7 days after establishing the model. Results Compared with group C, the MWT was significantly decreased, TWL was shortened and the expression of GFAP and IBa-1 was up-regulated at each time point in NP and NPN groups(P 0.05). Compared with NP group, MWT was significantly increased at 2-4 days after establishing the model, TWL was prolonged at 1-4 days after establishing the model, the expression of IBa-1 was down-regulated on 3 days after establishing the model, and the expression of GFAP was down-regulated on 3 and 7 days after establishing the model in group NPO(P<0.05). Conclusion Oxytocin can reduce neuropathic pain, and the mechanism may be related to inhibiting activation of glial cells in the spinal cord of rats. Key words: Oxytocin; Injections, spinal; Neuralgia

Role of c-Jun N-terminal kinase in activation of astrocytes in midbrain periaqueductal gray of rats with neuropathic pain

Objective To evaluate the role of c-Jun N-terminal kinase(JNK)in activation of astrocytes in midbrain periaqueductal gray(PAG)of rats with neuropathic pain. Methods A total of 72 pathogen-free male Sprague-Dawley rats, aged 9 weeks, weighing 160-200 g, were divided into 4 groups using a random number table: control group(group C, n=8), neuropathic pain group(group NP, n=40), dimethyl sulfoxide control group(group DS, n=12)and JNK inhibitor SP600125 group(group SP, n=12). Neuropathic pain was produced by chronic constriction injury(CCI). At 14 days after CCI, 10 nmol JNK inhibitor SP600125 0.5 μl was intraperitoneally injected into the PAG in group SP, and 10% dimethyl sulfoxide 0.5 μl was given instead in group DS.Eight rats were selected in group C, before CCI and at 3, 7, 14 and 21 days after CCI in group NP, and in DS and SP groups, and the mechanical pain threshold was measured before CCI, before administration on 14 days after CCI and at 30, 45, 60, 75 and 90 min after administration.The rats in group C were sacrificed after the end of measurement of the mechanical pain threshold, and brains were removed for determination of phosphorylated JNK(p-JNK)and glial fibrillary acidic protein expression(by Western blot)in PAG region.The rats in group NP were sacrificed after the end of measurement of the mechanical pain threshold at each time point, and brains were removed for detection of p-JNK expression in PAG region.Four rats in DS and SP groups were sacrificed after the last measurement of the mechanical pain threshold at 45 min after administration, and brains were removed for determination of glial fibrillary acidic protein expression in PAG region. Results Compared with group C, the mechanical pain threshold was significantly decreased at each time point after CCI, and the expression of p-JNK was up-regulated at 7-21 days after CCI in group NP(P<0.01). Compared with group DS, the mechanical pain threshold was significantly increased at 30 min after administration, and GFAP expression was down-regulated at 45 min after administration in group SP(P<0.01). The mechanical pain threshold was significantly higher at 30-75 min after administration than before administration in group SP(P<0.01). Conclusion The mechanism underlying activation of astrocytes in PAG is related to activating JNK in the rats with neuropathic pain. Key words: Astrocytes; JNK mitogen-activated protein kinases; Cerebral aqueduct; Periaqueductal gray; Neuralgia

Relationship between neuropeptide S in amygdala and 5-hydroxytryptamine and GABA in spinal dorsal horns of rats with neuropathic pain

Objective To evaluate the relationship between neuropeptide S (NPS) in the amygdala and 5-hydroxytryptamine (5-HT) and GABA in spinal dorsal horns of rats with neuropathic pain. Methods Eighty pathogen-free healthy male Sprague-Dawley rats, weighing 200-260 g, aged 2 months, were divided into 4 groups (n=20 each) using a random number table: sham operation group (group Sham), neuropathic pain group (group NP), low dose NPS group (group L-NPS) and high dose NPS group (group H-NPS). The neuropathic pain model was established by left L5, 6 spinal nerve ligation (SNL) in anesthetized rats.NPS was injected into the bilateral amygdala at 3, 6, 9, 12, 15 and 18 days after SNL in L-NPS group (10 pmol per side) and H-NPS group (100 pmol per side). The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 2 days before SNL and 1, 4, 7, 11, 14, 17 and 21 days after SNL.Five rats were selected at 7, 14 and 21 days after SNL and sacrificed, and the lumbar segment (L5) of the spinal cord was removed for detection of the expression of 5-HT and GABA in spinal dorsal horns by immunofluorescence histochemistry. Results Compared with group Sham, the MWT was significantly decreased, the TWL was shortened, and the expression of 5-HT and GABA in spinal dorsal horns was down-regulated in NP, L-NPS and H-NPS groups (P<0.05). Compared with group NP, the MWT was significantly increased, the TWL was prolonged, and the expression of 5-HT and GABA in spinal dorsal horns was up-regulated in L-NPS and H-NPS groups (P<0.05). Compared with group L-NPS, the MWT was significantly increased, the TWL was prolonged, and the expression of 5-HT and GABA in spinal dorsal horns was up-regulated in group H-NPS (P<0.05). Conclusion The spinal mechanism of endogenous analgesia induced by NPS in the amygdala may be related to up-regulation of the expression of 5-HT and GABA in spinal dorsal horns of rats with neuropathic pain. Key words: Amygdala; Neuralgia; Spinal cord; Serotonin; Gamma-aminobutyric acid; Neuropeptides

Influences of intraperitoneal injection of dexmedetomidine on activation of spinal glial cells in diabetic neuropathic pain rats

Objective Exploring the influences of intraperitoneal injection of dexmedetomidine(Dex) on activation of spinal glial cells and expression of inflammatory factors in rats with diabetic neuropathic pain(DNP). Methods Thirty two health male SD rats, weight 180-200 g, were divided into four groups (n=8) according the random number table method. The four groups included the control group(group C), diabetic neuropathic pain group(group DNP), group Dex and α2 receptor antagonist group(group YOH). Streptozotocin(STZ) was used to establish the DNP model in rats. Starting from 28 d after STZ injection, Dex group was given intraperitoneal injection of Dex(50 μg/kg) for consecutive 7 d, while group YOH was given intraperitoneal injection of Yohimbine(0.1 mg/kg) 30 min before intraperitoneal injection of Dex(50 μg/kg) for consecutive 7 d. Mechanical withdrawal threshold (MWT) was determined in each group of rats 29-35 d after STZ injection. Rats were sacrificed after MWT detection on 35 d. Immunofluorescence double-staining was used to detect activation of microglia and astrocytes in rat spinal cord of each group. ELISA was used to measure TNF-α and IL-1 expression in rat spinal cord of each group. Results Compared with group C, rat body weights were decreased while blood glucose values were increased in group DNP, group Dex and group YOH(P 0.05). Compared with group C, MWT at all time points decreased in group DNP and group YOH(P 0.05). Conclusions Dex can relieve hyperalgesia in rats with diabetic neuropathy pain. The underlying mechanism may be related to inhibition of microglia activation and reduction of the inflammatory reaction in spinal cord. Key words: Dexmedetomidine; Diabetic neuropathic pain; Microglia; Astrocyte; Inflammatory reaction

Study of advanced glycation endproducts and their receptors in Egyptian type 2 diabetic individuals with peripheral neuropathy

Context Diabetic neuropathy is one of the commonest long-term complications of diabetes seen in routine healthcare and considered the most common cause of peripheral neuropathy in developed world.Aim The aim of our work was to measure advanced glycation endproducts (AGEs) and their receptors (RAGEs) in diabetic peripheral neuropathy (DPN), both painful and painless DPN.Patients and methods Our study was conducted on 50 type 2 diabetes mellitus patients with peripheral neuropathy, divided into two subgroups: the first group included 25 patients with painful DPN and the second group included 25 patients with painless DPN. Moreover, a third group included 20 diabetic patients without peripheral neuropathy, and a fourth group that included 20 healthy participants. All groups were subjected to full history taking and clinical examination, anthropometric parameters, the calculation of neuropathy disability score, and nerve conduction studies (peroneal, sural, and tibial nerves). Laboratory investigations included serum AGEs and RAGEs.Results Our study demonstrated that hemoglobin A1c, AGE, and RAGE showed statistically significant difference between the studied groups. Hemoglobin A1c was significantly high in both neuropathic and diabetic groups in comparison with control. Regarding AGE, it was statistically higher in neuropathic group than in control (P<0.011). On the contrary, RAGE was significantly higher in both neuropathic and diabetic groups rather than control (P<0.02). Although the neuropathic group has higher levels of AGE and RAGE than diabetic group, the difference was statistically nonsignificant. Significant difference was found between studied groups regarding nerve conduction studies of sural and tibial nerves. Statistically significant difference was found in the parameters of nerve conduction studies between neuropathic group and both non-neuropathic diabetic and control groups.Conclusion Our study concluded that AGE and RAGE are significantly higher in diabetic patients with neuropathy versus control, with more elevation in neuropathic group than in diabetic without neuropathy.

Investigating Factors Involved in Post Laparoscopic Sleeve Gastrectomy (LSG) Neuropathy.

Laparoscopic sleeve gastrectomy (LSG) has gained popularity as the leading bariatric procedure for the treatment of morbid obesity. Due to the rising numbers of bariatric surgeries, neurologic complications have become increasingly recognized. Our aim was to examine biochemical and hormonal factors that are associated with neuropathy post-LSG. Thirty-two patients were included: 16 patients with neuropathy in the neuropathic group (NG) and 16 patients without neuropathy in the control group (CG). Diagnosis was made by a consultant neurologist, and blood samples were taken to examine vitamin deficiencies and hormones involved in neuropathy. There was no significant difference between the BMI (p=0.1) in both groups as well as excess weight loss percentages post-LSG at 12months (p=0.6). B12 levels were within normal range, but higher in NG (p=0.005). Vitamin B1 and B2 levels were significantly lower in NG; p values are 0.000 and 0.031, respectively. Vitamin B6 levels were significantly higher in NG (p=0.02) and copper levels were lower in NG (p=0.009). There was no significant difference in GLP-1 response in both groups. Our data showed post-LSG neuropathy is associated with lower levels of vitamin B1, B2, and copper, plus patients who are older in age. Vitamin B6 was significantly higher in the NG, which is, at toxic levels, associated with neuropathy. No difference in preoperative BMI, excess weight loss percent at 1year, and GLP-1 levels was found. Larger data is required to validate our results.

Effect of gabapentin on Cav3.2 channels in dorsal root ganglia of rats with neuropathic pain

Objective To evaluate the effect of gabapentin on Cav3.2 channels in the dorsal root ganglia (DRG) of rats with neuropathic pain. Methods Thirty male Sprague-Dawley rats, aged 6-7 weeks, weighing 225-275 g, were divided into 3 groups (n=10 each) using a random number table: sham operation group (S group), neuropathic pain group (NP group) and gabapentin group (G group). In NP and G groups, neuropathic pain was induced by chronic constriction injury to the left sciatic nerve.Starting from 7th day after operation, gabapentin 100 mg/kg in 1 ml of normal saline was injected intraperitoneally twice a day for 7 consecutive days in group G, and the equal volume of normal saline was given twice a day for 7 consecutive days in S and NP groups.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured on day 3 before operation and on postoperative days 3, 7 and 14.After the last measurement of pain thresholds on the postoperative day 14, 4 rats were sacrificed for determination of Cav3.2 mRNA expression (by real-time polymerase chain reaction) and Cav3.2 protein expression (by Western blot) in the DRG. Results Compared with S group, the MWT was significantly decreased, and TWL was significantly shortened on postoperative days 3, 7 and 14, and the expression of Cav3.2 protein and mRNA in the DRG was significantly up-regulated in group NP, and the MWT was significantly decreased, and TWL was significantly shortened on postoperative days 3 and 7 (P 0.05). Compared with NP group, the MWT was significantly increased, and TWL was significantly prolonged on the postoperative day 14, and the expression of Cav3.2 protein and mRNA in the DRG was significantly down-regulated in group G (P<0.05). Conclusion The mechanism by which gabapentin attenuates neuropathic pain may be related to inhibition of the function of Cav3.2 channels in the DRG of rats. Key words: Cyclohexanecarboxylic acids; Neuralgia; Calcium channels; Ganglia, spinal

Mobile phone generated vibrations used to detect diabetic peripheral neuropathy

In the current United Kingdom population the incidence of diabetic peripheral neuropathy is increasing. The presence of diabetic neuropathy affects decision making and treatment options. This study seeks to evaluate if the vibrations generated from a mobile phone can be used to screen patients for diabetic peripheral neuropathy. This study comprised of 61 patients; a control group of 21 patients; a lower limb injury group of 19 patients; a diabetic peripheral neuropathy group of 21 patients. The control and injury group were recruited randomly from fracture clinics. The diabetic peripheral neuropathy group were randomly recruited from the diabetic foot clinic. The 61 patients were examined using a 10g Semmes-Weinstein monofilament, a 128Hz tuning fork and a vibrating mobile phone. The points tested were, index finger, patella, lateral malleoli, medial malleoli, heel, first and fifth metatarsal heads. The most accurate location of all the clinical tests was the head of the 1st metatarsal at 0.86. The overall accuracy of the tuning fork was 0.77, the ten gram monofilament 0.79 and the mobile phone accuracy was 0.88. The control group felt 420 of 441 tests (95%). The injury group felt 349 of 399 tests (87%). The neuropathic group felt 216 of 441 tests (48%). There is a significant difference in the number of tests felt between the control and both the injury and neuropathic groups. p<0.0001 using N-1 Two Proportion Test. A mobile phone is an accurate screening tool for diabetic peripheral neuropathy. The most accurate location to test for diabetic peripheral neuropathy is the head of the 1st metatarsal. Screening for diabetic peripheral neuropathy in the index finger and patella were inaccurate. An injury to the lower limb affects the patient's vibration sensation, we would therefore recommend screening the contralateral limb to the injury. This study represents level II evidence of a new diagnostic investigation.

Effect of hydrogen-rich saline on autophagy in spinal neurons of rats with neuropathic pain

Objective To evaluate the effect of hydrogen-rich saline on autophagy in the spinal neurons of rats with neuropathic pain. Methods Sixty pathogen-free male Sprague-Dawley rats, aged 8-10 weeks, weighing 220-250 g, were randomly assigned into 3 groups (n=20 each)using a random number table: sham operation group (S group), neuropathic pain group (NP group), and hydrogen-rich saline group (H group). Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in the rats anesthetized with chloral hydrate.Hydrogen-rich saline 5 ml/kg was injected intraperitoneally once a day for 7 consecutive days in group H, while the equal volume of normal saline was given instead in S and NP groups.The mechanical paw withdrawal threshold (MWT)and thermal paw withdrawal latency (TWL)were measured at 1 day before operation (T0)and 1, 3, 5 and 7 days after operation (T1-4). The animals were sacrificed after measurement of pain threshold at day 7 after operation.L4-6 segments of the spinal cord were harvested to detect the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 Ⅱ (LC3 Ⅱ), Beclin-1 and p62 by Western blot. Results Compared with group S, the MWT was significantly decreased, and the TWL was significantly shortened at T2-4, and the expression of LC3Ⅱ, Beclin-1 and p62 was significantly up-regulated at T4 in NP and H groups (P<0.05). Compared with group NP, the MWT was significantly increased, and the TWL was significantly prolonged at T2-4, and the expression of LC3Ⅱ and Beclin-1 was significantly up-regulated, and the expression of p62 was significantly down-regulated at T4 in group H (P <0.05). Conclusion The mechanism by which hydrogen-rich saline reduces neuropathic pain is related to induction of autophagy in the spinal neurons of rats. Key words: Hydrogen; Neuralgia; Autophagy; Spinal cord

Effect of polydatin on neuropathic pain in rats

Objective To evaluate the effect of polydatin on neuropathic pain in rats. Methods Forty male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-230 g, were randomly divided into 5 groups (n=8 each)using a random number table: sham operation group (group S), neuropathic pain group (group NP), polydatin 5 mg/kg group (group P1), polydatin 10 mg/kg group (group P2), and polydatin 20 mg/kg group (group P3). Neuropathic pain was induced by chronic constriction injury in NP and P1-3 groups.In group S, the sciatic nerve was only exposed but not ligated.In S and NP groups, normal saline 0.1 ml was injected intraperitoneally immediately after operation and at 1, 3, 5 and 7 days after operation (T1-4). In P1-3 groups, polydatin 5, 10 and 20 mg/kg (in normal saline 0.1 ml)were injected intraperitoneally immediately after operation and at T1-4.At 1 day before operation (T0)and T1-4, the mechanical paw withdrawal threshold (MWT)and thermal paw withdrawal latency (TWL)were measured.After measurement of pain threshold at T4, the rats were sacrificed, and L4-6 segments of the spinal cords were removed for determination of the expression of high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α)and monocyte chemotactic protein-1 (MCP-1)by Western blot. Results Compared with group S, the MWT was significantly decreased, and the TWL was significantly shortened at T1-4 in group NP, the MWT was significantly decreased at T1-4, and the TWL was significantly shortened at T2-4 in group P1, the MWT was significantly decreased at T1-4, and the TWL was significantly shortened at T3, 4 in group P2, the MWT was significantly decreased at T1-4 in group P3, and the expression of HMGB1, TLR4, IL-1β, TNF-α and MCP-1 was significantly up-regulated in NP, P1 and P2 groups (P 0.05). Compared with group P1, the MWT was significantly increased at T4 in group P2, and the MWT was significantly increased at T1-4, the TWL was significantly prolonged at T3, 4, and the expression of HMGB1, TLR4, IL-1β, TNF-α and MCP-1 was significantly down-regulated in group P3 (P<0.05). Compared with group P2, the MWT was significantly increased at T3, 4, and the expression of TLR4, IL-1β, TNF-α and MCP-1 was significantly down-regulated in group P3 (P<0.05). Conclusion Polydatin can alleviate neuropathic pain through inhibiting inflammatory responses in the spinal cord of rats. Key words: Polygonum cuspidatum; Neuralgia

Sex differences in hypothalamic-mediated tonic norepinephrine release for thermal hyperalgesia in rats

Neuropathic pain is treated using serotonin norepinephrine reuptake inhibitors with mixed results. Pain facilitation mediated by α1-adrenoceptors may be involved, but whether norepinephrine (NE) is tonically released is unclear. The aim of this study was to determine whether NE is tonically released from A7 cells following chronic constriction injury (CCI), and if the lateral hypothalamus (LH) plays a role in this release in male and female rats with nociceptive and neuropathic pain types. Neuropathic groups received left CCI while nociceptive groups remained naïve to injury. Fourteen days later, rats were given intrathecal infusion of either the α1-adrenoceptor antagonist WB4101, the α2-adrenoceptor antagonist yohimbine (74μg), or normal saline for control. Paw withdrawal latency (PWL) from a thermal stimulus was measured. The generalized estimated equation method was used for statistical analysis. Nociceptive rats given WB4101 had a PWL significantly longer than saline control (7.89±0.63 vs. 5.87±0.52s), while the PWL of neuropathic rats given WB4101 was 13.20±0.52s compared to 6.78±0.52s for the saline control rats. Yohimbine had no significant effect. Microinjection of cobalt chloride (CoCl) in the A7 catecholamine cell group to prevent synaptic transmission blocked the effect of WB4101 in all groups, supporting the notion that spinally descending A7 cells tonically release NE that contributes to α1-mediated nociceptive facilitation. Microinjection of CoCl into the left LH blocked the effect of WB4101 in nociceptive and neuropathic male rats, but had no effect in female rats of either pain type, suggesting differential innervation. These findings indicate that tonic release of NE acts at pronociceptive α1-adrenoceptors, that this effect is greater in rats with nerve damage, and that, while NE comes primarily from the A7 cell group, LH innervation of the A7 cell group is different between the sexes.

Foot Temperature Trends in Normal, Diabetic, and Neuropathic Foot Populations

INTRODUCTION AND OBJECTIVES: Patients with underlying peripheral neuropathy are subject to changes in foot temperature. (1,2) Of the many forms of neuropathy that affect the lower extremity, the most notable are those types associated with diabetes. The aim of this study was to look for differences in temperatures between uncomplicated diabetic, diabetic neuropathic, and non-diabetic neuropathic feet. METHODS: The feet of 75 subjects were divided into 3 groups: 1) normal (n=50 feet), 2) diabetic (n=50 feet), and 3) neuropathic (n=49 feet). The neuropathic group was further subdivided into diabetic neuropathies (n=20 feet) and non-diabetic neuropathies (n=29 feet). To properly assign subjects to groups, all participants underwent vibratory threshold testing with a biothesiometer. In addition, all diabetic subjects had added glycosylated hemoglobin (hemoglobin A1C) studies performed. Temperature measurements were recorded at nine distinct foot locations (six plantar and three dorsal). Data was statistically analyzed using the Kruskal-Wallis test. RESULTS: For five of the plantar pedal sites tested, temperatures in the diabetic foot were significantly greater than those for the normal controls (p&amp;lt;0.05). At most sites, temperatures in the diabetic foot population tended to be higher than those in both diabetic and non-diabetic neuropathic feet, with the differences between the diabetic foot and non-diabetic neuropathic foot being statistically significant at one dorsal and five plantar sites. Patients in the non-diabetic neuropathic group were not stratified according to their specific neuropathic types. CONCLUSIONS: Diabetic feet, with and without neuropathy, tend to be warmer than the feet of patients with other non-diabetic neuropathies. The finding of no statistical difference between non-neuropathic diabetic and neuropathic diabetic feet is unexpected in that a number of these patients were projected to have an autonomic system component. These null findings suggest the need to further investigate neuropathy solely determined by sensory testing versus tests for autonomic system involvement.

Muscle activation patterns related to diabetic neuropathy in elderly subjects: A Functional Reach Test study

BackgroundThis study was designed to assess, in healthy elderly, non-neuropathic and neuropathic diabetic subjects, the activation patterns of the main muscles involved in the Functional Reach Test, a well-recognized method to identify elderly subjects at risk of balance impairments. MethodsSurface electromyographic analysis of Sternocleidomastoideus, Rectus Abdominis, Erectores Spinae at L4 level, Rectus Femoris, Hamstrings, Tibialis Anterior and Soleus was performed in 10 healthy, 10 diabetic non-neuropathic and 10 diabetic neuropathic subjects. FindingsResults showed that in every group the first motor is Tibialis Anterior, that is recruited before the start of the test. An earlier activation of Tibialis Anterior (P<0.05) was detected in diabetic neuropathic (ON at −24% of the test period), compared with healthy (−11%) and diabetic non-neuropathic (−13%) groups. A significant earlier activation of Sternocleidomastoideus and Rectus Abdominis was found in diabetic neuropathic group, only with respect to healthy subjects. No significant difference was found in Rectus Femoris, Soleus, Hamstrings an Erectores Spinae onset among the three groups. InterpretationResults suggest a trend of diabetic neuropathic patients in earlier anticipation of the activation of the anterior body-muscles. In particular, the earlier onset of Tibialis Anterior is likely to be performed to adjust the movement timing and to compensate for the delay in the recruitment of the motor units. This anticipation might be involved in the altered postural control with increased balance impairment detected in diabetic neuropathic patients, and thereby it might also be proposed as an index of neuropathy, evidenced in a simple and non-invasive manner.

Effect of intrathecal TRESK gene recombinant adenovirus on activities of p38MAPK and ERK in spinal cord of rats with neuropathic pain

Objective To evaluate the effects of intrathecal TRESK gene recombinant adenovirus on the expression of p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-regulated kinase(ERK) in the spinal cord of rats with neuropathic pain. Methods Thirty-six male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into 6 groups (n= 6 each) using a random number table: control group (group C); sham operation group (group S); neuropathic pain group (group NP); TRESK overexpression adenovirus group (group TRESK); negative adenovirus group (group Virus); normal saline group (group NS). The rats underwent spared nerve injury (SNI) to establish the model of neuropathic pain.In TRESK, NS and Virus groups, pAd/CMV/V5-DEST-TRESK 25 μl (109 IU/ml), negative adenovirus 25 μl and normal saline 25 μl were intrathecally injected, respectively, immediately after SNI.At 1 day before SNI (baseline, T0) and 1, 3 and 7 days after SNI (T1-3), the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured.The rats were sacrificed after the last measurement of pain threshold at T3.The lumbar segments (L4, 5) of the spinal cord were removed for determination of phosphorylation of p38MAPK and ERK by Western blot. Results Compared with group C, the MWT was significantly decreased at T1-3, and the phosphorylation of p38MAPK and ERK was increased in NP, TRESK, Virus and NS groups.Compared with group NP, the MWT was significantly increased at T1-3, and the phosphorylation of p38MAPK and ERK was decreased in group TRESK, and no significant change was found in phosphorylation of p38MAPK and ERK in Virus and NS groups.There was no significant difference in TWL between the six groups. Conclusion Inhibited activities of p38MAPK and ERK in the spinal cord may be involved in the mechanism by which intrathecal TRESK gene recombinant adenovirus alleviates neuropathic pain in rats. Key words: Potassium channels; Transfection; Injections, spinal; p38 Mitogen-activated protein kinases; Extracellular signal-regulated MAP kinases; Neuralgia; Spinal cord

Activated autophagy in spinal cord contributes to maintaining diabetic neuropathic pain in rats model

To observe the role of autophagy in maintaining diabetic neuropathic pain in rats model. A total of 44 male Sprague-Dawley rats were randomly divided into diabetic neuropathic (n = 36) and normal control (n = 8) groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg body weight, i.p) freshly dissolved in citrate buffer (pH = 4.5). For assessing the presence of mechanical hyperalgesia in diabetic rats, mechanical paw-withdrawal threshold (MWT) in response to punctuate mechanical stimuli was measured. At Week 4 post-injection, the rats with mechanical pain threshold decreasing over 50% as compared to baseline were designated as diabetic neuropathic pain rats. They were randomly divided into three groups of neuropathic pain (DP), neuropathic pain plus rapamycin (DR) and neuropathic pain plus 3-methyladenine (3-MA) (DA). The DR group received an intraperitoneal injection of rapamycin (1 mg/kg body weight) for Day 1 to Day 14 after grouping. At the same timepoint, the DA group had an intraperitoneal injection of 3-MA (2 mg/kg body weight) and the other group phosphate buffered saline (PBS) (1 ml/kg body weight). MWT was measured at week 1, 2, 3, 4 after STZ injection and at day 1, 3, 5, 7, 9, 14 after rapamycin, 3-MA or PBS injections. Spinal cord tissues were used to examine the expression of LC3, Beclin-1 and P62 protein by Western blot at Day 14 after medication. The mechanical threshold of group DR decreased further from Day 3 to Day 14 after rapamycin injection compared to baseline [(4.8±0.8), (4.3±0.7), (4.1±0.6), (3.6±0.5), (3.3±0.6) vs (5.3±0.9) g, P<0.05]. The mechanical threshold of group DA began to increase from Day 5 to Day 14 after 3-MA injection [(7.0±0.8), (7.7±1.0), (9.1±0.9), (9.6±1.1) vs (5.3±0.6) g, P<0.05]. The expressions of LC3-II and Beclin-1 protein in spinal cord of rapamycin-treated rats was significantly higher than those of non-supplemented diabetics (1.32±0.12 vs 1.02±0.11; 1.03±0.08 vs 0.80±0.06, P<0.05). Otherwise the expressions of these protein in spinal cord of 3-MA-treated rats were significantly lower than those of non-supplemented diabetics (0.70±0.09 vs 1.02±0.11; 0.55±0.05 vs 0.80±0.06, P<0.05). Up-regulated autophagy in spinal cord partially contributes to the maintenance of diabetic neuropathic pain.

Preliminary evaluation of shear wave elastography for median nerve neuropathy

Objective To explore the feasibility of real-time quantitative shear wave elastography (SWE) in median nerve (MN) lesions. Methods Seventy-three healthy volunteers (total 146 nerves) were included as control group (group A). The neuropathic group consisted of 85 patients (total 115 nerves), according their clinical symptoms and electrophysiological results. They were divided into two groups: diabetic peripheral neuropathy group (group B, 57 nerves) and carpal tunnel syndrome group (group C, 58 nerves). The real-time quantitative SWE embedded in Supersonic AixPlorer was used to detect the MN. The mean elasticity modulus of the MN at the wrist (WEmean), at the midpoint of the forearm (FEmean) and the mean elasticity modulus ratio of the MN and the musculus flexor digitorum superficialis in the same interest region at the midpoint of the forearm (FRatio) were calculated. Receiver-operating characteristic (ROC) curve was drawn to assess the diagnostic efficiency. Pearson rank correlation was used to analyze the correlation between the cross-sectional area (CSA) and WEmean of MN at the level of pisiform bone. Results There were significant differences of the elastic parameters between group C and A (P 0.05). The area under the curve(AUC) of elastic parameters indicated that WEmean and FEmean were higher than FRatio in diagnosis of carpal tunnel syndrome(AUC>0.8). No significant difference of diagnostic value was found between WEmean and FEmean(P>0.05). The CSA of MN positively correlated with WEmean (r=0.33, P<0.05). Conclusions SWE technology showed its feasibility in MN evaluation. It could be used to assess the stiffness of nerve neuropathy and may be a quantitative tool for clinical median neuropathy diagnostics. Key words: Ultrasonography; Median neuropathy; Shear wave elastography