Decreased Pain Threshold Research Articles

Dexmedetomidine Reduces Diabetic Neuropathy Pain in Rats through the Wnt 10a/β-Catenin Signaling Pathway.

Diabetic neuropathy pain (DNP), a spontaneous pain with hyperalgesia and allodynia, greatly compromises patients' quality of life. Our previous study suggested that dexmedetomidine (DEX) can relieve hyperalgesia in rats by inhibiting inflammation and apoptosis at the level of the spinal cord. In the present study, we aimed to evaluate the role of Wnt 10a/β-catenin signaling in DEX-induced alleviation of DNP in rats. Forty-eight rats were randomly allocated to four groups (n=12/group): control, DNP, DEX, and yohimbine groups. The DNP model was established by streptozotocin (STZ) injection. The effects of DEX with or without the α2 adrenergic antagonist yohimbine were assessed by behavior tests (mechanical withdrawal threshold and thermal withdrawal latency). Spinal cord tissue was evaluated by immunofluorescence staining of astrocytes as well as for Wnt 10a and β-catenin expression, western blot analysis of Wnt 10a and β-catenin expression, and enzyme-linked immunosorbent assay measurement of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Rats with STZ-induced DNP had a decreased pain threshold, activated astrocytes, increased expression of Wnt 10a and β-catenin, and increased levels of proinflammatory cytokines compared to the control group, and these effects were ameliorated by treatment with DEX. Yohimbine administration partly abolished the protective effects of DEX in the DNP model rats. In conclusion, DEX alleviated DNP in rats by inhibiting inflammation and astrocyte activation, which may be attributed to downregulation of the Wnt 10a/β-catenin signaling pathway.

Benzoxime carbaldehyde prevents rheumatoid arthritis in a rat model by inhibition of oxidative damage

Purpose: To investigate the effect of benzoxime carbaldehyde (BXCD) on rheumatoid arthritis (RA) in a rat model.Methods: Thirty male Sprague-Dawley rats were assigned randomly to 5 groups (6 rats per group): normal control, RA, and three treatment groups. Rats in the normal control and RA groups received normal saline, whereas those in the three treatment groups were given 2, 5 or 10 mg/kg of BXCD daily for 30 days by intraperitoneal injection. Pressure pain was analysed using electronic pressure pain detector, while the expressions of interleukin (IL)-6, interleukin (IL)-1β, nuclear factor (NF)-κB p65 and tumor necrosis factor (TNF)-α in serum were determined using enzyme-linked immunosorbent assay (ELISA) kits.Results: Treatment of RA rats with BXCD for 30 days led to significant (p < 0.05) recovery in pain threshold. At a dose of 10 mg/kg, BXCD decreased pain threshold value to a level comparable to that in normal control rats, and decreased arthritis score to 1, relative to arthritis score of 16 in untreated animals. Malondialdehyde (MDA) level was 4-fold higher in untreated RA rats than in normal and BXCD-treated groups. BXCD treatment increased the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), and blocked increases in the blood levels of IL-6, IL-1β, NF-κB p65 unit, and TNF-α. Western blot assay showed that BXCD treatment prevented increase in the level of cyclooxygenase-2 (COX-2) in RA rat tissues.Conclusion: These results indicate that BXCD prevents RA in a rat model via inhibition of expressions of inflammatory cytokines and decrease in oxidative stress. Thus, BXCD has a strong potential for the management of RA.Keywords: Rheumatoid arthritis, Pain threshold, Antioxidant enzymes, Inflammation, Inflammatory cytokines

Dose related effects of buspirone on pain, learning / memory and food intake

The present study concerned extending the therapeutic use of buspirone for treating pain and improving cognition. Effects of single and repeated administration of buspirone were therefore monitored on pain threshold in the hot plate test and on spatial memory in the water maze test in rats. Effects on cumulative food intake were also monitored. The drug was administered intraperitoneally in doses of 0.1, 0.3, 1.0 and 2.0 mg/kg. We found that single and repeated administration of buspirone in doses of 0.1 mg/kg decreased pain threshold in the hot plate test, while doses of 1.0 and 2.0 mg/kg increased it. Effects of single and repeated administration were not different. A dose of 0.3 mg/kg had no effect. Food intake increased following single as well as repeated administration of 0.1 mg/kg buspirone; higher doses had no effect. Low doses (0.1 and 0.3 mg/kg) improved acquisition and retention of memory in the water maze test, while memory extinction was reduced. Higher doses had either no effect (1.0 mg/kg) or impaired (2.0 mg/kg) performance in this test. The results suggest potential therapeutic use of selected doses of buspirone as an analgesic and nootropic drug.

Nicotine and sleep deprivation: impact on pain sensitivity and immune modulation in rats

Repeated nicotine administration has been associated with increased paradoxical sleep in rats and antinociceptive properties, whereas paradoxical sleep deprivation (PSD) elicits pronociceptive and inflammatory responses. Thus, we aimed to evaluate the effect of repeated nicotine administration and its withdrawal combined with PSD on pain sensitivity and inflammatory markers. Sixty adult male Wistar rats were subjected to repeated injections of saline (SAL) or nicotine (NIC) for 12 days or 7 days of nicotine followed by acute mecamylamine administration on day 8 to precipitate nicotine abstinence (ABST). On day 9, the animals were submitted to PSD for 72 h or remained in control condition (CTRL); on day 12, thermal pain threshold was assessed by the hot plate test. PSD significantly decreased the latency to paw withdrawal in all groups compared to their respective controls. ABST-PSD animals presented higher levels of interleukin (IL)-6 compared to all groups, except ABST-CTRL. After adjustment for weight loss, IL-6, IL-4 and tumor necrosis factor alpha, ABST-PSD was associated with the lowest pain threshold. Nicotine and IL-4 levels were predictors of higher pain threshold. Hyperalgesia induced by PSD prevailed over the antinociceptive action of nicotine, while the association between PSD and ABST synergistically increased IL-6 concentrations and decreased pain threshold.

Сравнительный анализ динамики температурно-болевой чувствительности после коррекции тяжелых и нетяжелых деформаций позвоночника у больных с идиопатическим сколиозом

Introduction Despite a great number of researches on idiopathic scoliosis reported there is still no instrumentation assessment of sensitivity before and after surgical correction of the curve found in literature. The purpose of the work was to explore dynamics in thermal pain sensitivity following correction of severe and mild spinal curves in patients with idiopathic scoliosis. Material and methods The work included results of examination of 25 patients with idiopathic scoliosis. Sampling population was divided into two groups depending on the extent of preoperative curve in major arch: Group I included patients with the curve of ≤ 60o (15 cases); Group II consisted of patients with the curve of > 60o (10 patients). Preoperative neurological examination showed no motor, reflex and sensory impairments. Acute deformity correction and spine stabilization with transpedicular systems were produced in all the cases. Thermal pain sensitivity was explored preoperatively and postoperatively at Th1-S2 dermatomes using electric esthesiometer. Results Disturbed thermal pain sensitivity of various extent was observed preoperatively in the study dermatomes of all patients with idiopathic scoliosis and was not shown to be dependent on the amount of the curve. Positive dynamics in thermal pain sensitivity revealed itself in reduced pain and heat thresholds and restored heat sensitivity and was observed in 41.5 to 54.1 % of the cases Group I following spine deformity correction. Deterioration was seen in 29.2 to 34.7 % of the cases. Group II showed negative dynamics in thermal pain sensitivity in 35.4 to 50 % of the cases with either increased or decreased pain threshold, enhanced heat threshold and loss of heat sensitivity. Sensitivity improved in 29.4 to 31.8 % of the patients. No changes in neurological status were noted in both groups after surgical correction with subclinical changes in thermal pain sensitivity to be considered. Conclusion Positive dynamics in thermal pain sensitivity prevailed in patients with idiopathic scoliosis following baseline curve correction of ≤ 60o. Negative dynamics in thermal pain sensitivity was seen in patients with baseline curve correction of > 60o with a greater risk of neurological complications.

Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine.

Acid-sensing ion channel 3 (ASIC3) is abundant in the trigeminal nervous system and is most sensitive to a slight pH decrease. Recent studies have indicated that ASIC3 in the peripheral trigeminal ganglia is likely involved in the pathogenesis of migraine pain. However, it is unclear whether this receptor plays a role in recurrent migraine, namely, migraine chronicity. Here, we aimed to investigate the role of ASIC3 in an animal model of recurrent migraine (RM). In this study, we established a rat model of RM through repeated administration of inflammatory soup (IS) onto the dura. Then, we tested the mechanical pain thresholds of the face and hindpaws by von Frey filaments. qRT-PCR, Western blot and immunofluorescence labelling were used to detect the expression and localization of ASIC3 in the trigeminal nucleus caudalis (TNC). The protein levels of calcitonin gene-related peptide (CGRP), its receptor component receptor activity modifying protein 1 (RAMP1) and c-Fos were analysed following treatment with the ASIC3 inhibitor APETx2 and activator 2-guanidine-4-methylquinazoline (GMQ). We found decreased pain thresholds after repeated dural inflammatory stimulation, which suggested the establishment of an RM model. Based on this model, we observed elevated expression of ASIC3 in the TNC group compared to that in the Sham group. ASIC3 was primarily expressed in neurons but not in astrocytes of the TNC. Moreover, APETx2 attenuated tactile allodynia and significantly decreased the expression of c-Fos, CGRP and RAMP1, while GMQ aggravated these effects compared to those observed in the IS + vehicle group. These findings indicate a critical role of ASIC3 channels in the pathophysiology of RM, and ASIC3 might represent a potential therapeutic target to prevent the progression of migraine.

Muscular blood flow responses as an early predictor of the severity of diabetic neuropathy at a later stage in streptozotocin-induced type I diabetic rats: a diffuse correlation spectroscopy study.

We propose a novel application of diffuse correlation spectroscopy to evaluate microvascular malfunctions of muscle tissue affected by hyperglycemia and determine their correlation with the severity of diabetic neuropathy at a later stage. Microvascular responses of the thigh muscle and the mechanical pain threshold of the hind paw of streptozotocin-induced type I diabetic rats were continuously monitored once per week for 70 days. Significantly decreased baseline blood flow and reactive hyperemia responses were observed as early as 1 week after hyperglycemia induction. The reactive hyperemia response at 2 weeks of hyperglycemia was highly correlated with the mechanical pain threshold at 8 weeks, at which time a decreased pain threshold was statistically confirmed in hyperglycemic rats relative to controls.

Disrupted physical pain sensation by social exclusion in women with dysmenorrhea

PurposeDysmenorrhea (DM), which involves both acute and chronic pain, is associated with abnormalities in pain modulation. Previous studies have shown that social pain relies on some of the same neural regions that process physical pain, highlighting a possible physical–social pain overlap. However, evidence suggesting that social pain modulates the sensitivity to physical pain remains controversial. The present study aimed to assess the effects of social pain manipulation on sensitivity to physical pain in DM sufferers and healthy female controls (HC).Materials and methodsFifty-nine otherwise healthy patients with DM and 55 HC matched for age, education, calendar age, and gynecological age were randomly assigned to inclusion or exclusion conditions of Cyberball, a virtual ball tossing game used to induce social pain (social exclusion). Pain threshold and pain tolerance in response to nociceptive pressure and cold stimuli were assessed before and after the study condition.ResultsIn response to cold stimulation, pain threshold and tolerance significantly reduced in DM compared to HC participants in the inclusion condition, indicating increased pain sensitivity in DM group. However, exclusion increased the pain threshold and tolerance compared to inclusion in DM but decreased pain threshold and tolerance in HC. Neither inclusion nor exclusion altered pressure pain sensitivity in DM, but, after social exclusion, DM participants were more fearful of being evaluated unfavorably. No significant differences were observed in self-esteem scores between DM and HC after both inclusion and exclusion.ConclusionWe observed altered pain sensation in DM participants in response to social pain manipulation, suggesting that DM not only impacts menstruation but also modulates the perception of pain more generally, especially its affective processes. The present study suggests that the effect of social pain on pain sensation and certain psychometric properties depends on previous pain experience, implicating a reciprocal influence of social and physical pain processes.

Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury

BackgroundHigh-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery.ResultsAnimals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-α and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-α, synaptophysin, and NGF in accordance with the in vivo results.ConclusionImmediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application.

MicroRNA-146a-5p attenuates visceral hypersensitivity through targeting chemokine CCL8 in the spinal cord in a mouse model of colitis

Visceral pain, observed in inflammatory bowel disease (IBD) patients, is a challenging medical problem and remains poorly understood because the mechanisms underlying it are unclear. Emerging evidence indicates that microRNAs (miRNAs) play a crucial role in the pathogenesis of acute and chronic pain. In this study, we aimed to explore the potential role of miR-146a-5p (the mature form of miR-146a) in a mouse model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). We found that induction of colitis resulted in visceral hyperalgesia manifested by a decreased pain threshold to colorectal distension and upregulation of miR-146a-5p expression in the lumbosacral spinal cord. In situ hybridization and immunohistochemistry results showed that miR-146a-5p was colocalized with neuronal marker NeuN, but not with astrocytic marker GFAP or microglial marker IBA-1. Dual-luciferase reporter assay showed that miR-146a-5p directly targeted the 3′-untranslated region (UTR) of CCL8, which was previously identified as an important regulator of visceral pain. In cultured Neuro-2a cells, TNF-α-induced CCL8 upregulation was decreased by transfection of miR-146a-5p mimic dose-dependently. In vivo, exogenous supplementation of miR-146a-5p by intrathecal miR-146a-5p agomir significantly alleviated visceral pain and decreased CCL8 expression in colitis mice. Furthermore, inhibition of CCL8 expression by CCL8 siRNA relieved colitis-induced visceral nociception. Finally, in naïve mice intrathecal miR-146a-5p antagomir upregulated CCL8 expression and induced visceral pain hypersensitivity, which could be partially rescued by neutralization of CCL8. Taken together, the present findings indicate that miR-146a-5p may be an endogenous suppressor of visceral pain and exogenous supplementation of miR-146a-5p could exert an analgesic effect at least partly by targeting spinal CCL8 expression. Thus, miR-146a-5p may serve as a novel therapeutic target for visceral pain intervention in the context of colitis.

The Long-Term Footprint of Endometriosis: Population-Based Cohort Analysis Reveals Increased Pain Symptoms and Decreased Pain Tolerance at Age 46 Years

Previous studies have shown increased pain sensitivity in fertile-aged women with endometriosis in response to mechanical stimuli. As yet, population-based studies on the association of endometriosis with pain sensation and pain symptoms in late fertile age are lacking. The main objective of this population-based cohort study was to investigate whether a history of endometriosis is associated with altered pain sensation and musculoskeletal pain symptoms at age 46 years. Our data are derived from the Northern Finland Birth Cohort 1966, which contains postal questionnaire data (72% response rate) as well as clinical data assessing pressure-pain threshold and maximal pain tolerance. The study population consisted of 284 women with endometriosis and 3,390 controls. Our results showed that at age 46 women with a history of endometriosis had a 5.3% lower pressure-pain threshold and 5.1% lower maximal pain tolerance compared with controls. The most significant contributors besides endometriosis were anxiety, depression, and current smoking status. Women with endometriosis also reported an increased number of pain sites (0 pain sites, 9.6 vs 17.9%; 5-8 pain sites, 24.8 vs 19.1%, endometriosis vs controls respectively; P < .001), and their pain was more troublesome and intense. The results were adjusted for body mass index, smoking, depressive/anxiety symptoms, education, and use of hormonal contraceptives. These unique data revealed an altered pain sensation and a greater likelihood of reporting musculoskeletal pain at age 46 years among women with a history of endometriosis. The results imply that endometriosis has a long-term footprint on affected women, thus underlying the need for psychological support and medical treatment beyond fertile age. PerspectiveThis population-based cohort study showed decreased pain threshold and maximal pain tolerance in women with endometriosis in the late fertile age of 46 years. The pain was also found to be more bothersome and intense compared with controls.

Isoflurane and the Analgesic Effect of Acupuncture and Electroacupuncture in an Animal Model of Neuropathic Pain

The present study aimed to determine whether isoflurane interferes with the analgesic effects of acupuncture (Ac) and electroacupuncture (EA), using a neuropathic pain (NP) rat model. In total, 140 male Wistar rats were used; isoflurane-induced nociceptive response was evaluated using the von Frey test, serum calcium-binding protein β (S100β) levels and nerve growth factor (NGF) levels in the left sciatic nerve. The NP model was induced by chronic constriction injury of the sciatic nerve at 14 days after surgery. Treatment was initiated after NP induction with or without isoflurane anesthesia (20 min/day/8 days). The von Frey test was performed at baseline, 14 days postoperatively, and immediately, 24 h, and 48 h after the last treatment. Results of the nociceptive test and three-way analysis of variance were analyzed by generalized estimating equations, the Bonferroni test, followed by Student–Newman–Keuls or Fisher's least significant difference tests for comparing biochemical parameters (significance defined as p ≤ 0.05). At baseline, no difference was noted in the nociceptive response threshold among all groups. Fourteen days after surgery, compared with other groups, NP groups showed a decreased pain threshold, confirming establishment of NP. Ac and EA enhanced the mechanical pain threshold immediately after the last session in the NP groups, without anesthesia. Isoflurane administration caused increased nociceptive threshold in all groups, and this effect persisted for 48 h after the last treatment. There was an interaction between the independent variables: pain, treatments, and anesthesia in serum S100β levels and NGF levels in the left sciatic nerve. Isoflurane enhanced the analgesic effects of Ac and EA and altered serum S100β and left sciatic nerve NGF levels in rats with NP.

Low-Intensive Electropulse Therapy for Correction of Clinical and Functional Manifestations of Neuropathy in Multiple Myeloma

Polychemotherapeutic drugs can affect neuros system in patients with myeloma, which can worsen their quality of life and promote disease progression. The authors studied the dynamics of pain syndrome, microcirculation status and parameters of quality of life in patients with multiple myeloma complicated by peripheral polyneuropathy under polychemotherapy. In the course of the present study 106 patients were examined and divided into the three groups: in group I the patients were indicated standard polychemotherapy supplemented with the course of dynamic electroneurostimulation, in group II the patients were treated with placebo procedures along with the basic treatment, and in group III the patients received standard treatment. It was established that by the end of the therapy pain syndrome intensity decreased in patients from group I by 1.8 times, initially elevated pain threshold decreased by 24.4% and basal microcirculatory parameters improved by 1.4 times, whereas in the comparison groups significant changes were not observed. The treatment influenced on the quality of life: in group I the score of physical functioning (SF-36 questionnaire) increased by 1.5 times in comparison with the baseline, the score of general health perception and vitality increased by 1.7 and 1.5 times, respectively, which significantly differed from analogue parameters score in the comparison groups. It was established that introduction of dynamic electroneurostimulation into the treatment plan of patients with multiple myeloma reduced pains intensity, decreased pain threshold, stimulated microhemocirculation and contributed to improvement of quality of life that allowed the patients to continue their specific polychemotherapy.

Letter to the Editor.

Pain is an important aspect of pediatric dentistry. Phlenophobia or fear for needle is one of the significant factor for reduced apprehensiveness and decreased pain threshold in pediatric patients.How to cite this article: Balasubramanian SK, Gurucharan I, Sekar M. Letters to the Editor. Int J Clin Pediatr Dent, 2018;11(5):357-358

Treatment with NADPH oxidase inhibitor apocynin alleviates diabetic neuropathic pain in rats.

Increased reactive oxygen species by the activation of NADPH oxidase (NOX) contributes to the development of diabetic complications. Apocynin, a NOX inhibitor, increases sciatic nerve conductance and blood flow in diabetic rats. We investigated potential protective effect of apocynin in rat diabetic neuropathy and its precise mechanism of action at molecular level. Rat models of streptozotocin-induced diabetes were treated with apocynin (30 and 100 mg/kg per day, intragastrically) for 4 weeks. Mechanical hyperalgesia and allodynia were determined weekly using analgesimeter and dynamic plantar aesthesiometer. Western blot analysis and histochemistry/immunohistochemistry were performed in the lumbar spinal cord and sciatic nerve respectively. Streptozotocin injection reduced pain threshold in analgesimeter, but not in aesthesiometer. Apocynin treatment increased pain threshold dose-dependently. Western blot analysis showed an increase in catalase and NOX-p47phox protein expression in the spinal cord. However, protein expressions of neuronal and inducible nitric oxide synthase (nNOS, iNOS), superoxide dismutase, glutathion peroxidase, nitrotyrosine, tumor necrosis factor-α, interleukin-6, interleukin-1β, aldose reductase, cyclooxygenase-2 or MAC-1 (marker for increased microgliosis) in the spinal cord remained unchanged. Western blot analysis results also demonstrated that apocynin decreased NOX-p47phox expression at both doses and catalase expression at 100 mg/kg per day. Histochemistry of diabetic sciatic nerve revealed marked degeneration. nNOS and iNOS immunoreactivities were increased, while S-100 immunoreactivity (Schwann cell marker) was decreased in sciatic nerve. Apocynin treatment reversed these changes dose-dependently. In conclusion, decreased pain threshold of diabetic rats was accompanied by increased NOX and catalase expression in the spinal cord and increased degeneration in the sciatic nerve characterized by increased NOS expression and Schwann cell loss. Apocynin treatment attenuates neuropathic pain by decelerating the increased oxidative stress-mediated pathogenesis in diabetic rats.

Changes in expression of H3K9Ac and MeCP2 in spinal cord and dorsal root ganglion of rats with diabetic neuropathic pain

Objective To evaluate the changes in the expression of acetylated histone 3 lysine 9(H3K9Ac)and methyl-CpG-binding protein 2(MeCP2)in the spinal cord and dorsal root ganglion(DRG)of rats with diabetic neuropathic pain(DNP). Methods Pathogen-free male Sprague-Dawley rats, weighing 120-160 g, were fed a high-fat and high-sucrose diet for 8 weeks, then streptozocin 35 mg/kg was intraperitoneally injected, and type 2 diabetes mellitus was confirmed by blood glucose level≥16.7 mmol/L 3 days later.DNP model was considered successful when the decrease in pain threshold <85% of the baseline value on 14 days after injection, otherwise it was considered as non-DNP(NDNP). Eighteen rats with DNP and NDNP served as DNP and NDNP groups, respectively, and another 18 normal rats served as control group(group C). At 3, 7 and 14 days after successful establishment of the model, the mechanical paw withdrawal threshold and thermal paw withdrawal latency were measured in group DNP and at the corresponding time points in C and NDNP groups, and then rats were sacrificed, and the lumbar segment of the spinal cord and DRGs were removed for determination of the expression of H3K9Ac and MeCP2 by Western blot. Results Compared with C and NDNP groups, mechanical paw withdrawal threshold was significantly decreased, thermal paw withdrawal latency was shortened, the expression of H3K9Ac in the spinal cord and DRGs was up-regulated, and the expression of MeCP2 in the spinal cord and DRGs was down-regulated at 3, 7 and 14 days after successful establishment of the model in group DNP(P<0.05). Conclusion The maintenance mechanism of DNP may be related to up-regulated expression of H3K9Ac and down-regulated expression of MeCP2 in rats with DNP. Key words: Diabetes Mellitus; Neuralgia; Histones; Methyl-CpG-binding protein 2; Spinal cord; Ganglia, spinal

Transcranial direct current stimulation (tDCS) prevents chronic stress-induced hyperalgesia in rats

BackgroundChronic stress (CS) is associated with a decrease in pain threshold caused by the changes in neural pain circuits. It can be associated to glucocorticoid imbalance with alterations in neural circuitry. Inhibition of stress-induced pain-related neural changes by using techniques that safely induce neuroplasticity such as transcranial direct current stimulation (tDCS) may prevent hyperalgesia triggered by CS. ObjectiveThis study aimed to verify the effect of tDCS performed prior to CS exposure on nociceptive response. MethodsThirty-two rats were distributed in the following groups: control; stress; sham-tDCS + stress; and tDCS + stress. Bicephalic active tDCS was performed for 8 consecutive days before the CS exposure. The pain threshold was evaluated using a hot plate and tail flick latency (TFL) tests. ResultsThe tDCS exposure increased the pain threshold on stressed rats. ConclusionThe data obtained indicate that the treatment with bicephalic active tDCS before chronic stress exposure prevents stress-induced hyperalgesia.

Calcitonin potentiates the anticonvulsant and antinociceptive effects of valproic acid and pregabalin in pentylenetetrazole-kindled mice

Antiepileptic drugs are the backbone for epilepsy management. Epilepsy may be accompanied by decreased pain threshold. Thus, anticonvulsant agents with antinociceptive properties are of great importance. This study investigated the possible anticonvulsant and antinociceptive effects of calcitonin in combination with either valproic acid or pregabalin and whether these effects might occur through γ-aminobutyric acid (GABA) modulation.Eighty-four male Balb/C mice were divided into 7 groups: control-naïve, pentylenetetrazole (PTZ)-induced seizures, PTZ-calcitonin, PTZ-valproic acid, PTZ-pregabalin, PTZ-calcitonin-valproic acid (PCV) combination, and PTZ-calcitonin-pregabalin (PCP) combination. PTZ was used in a sub-convulsive dosage, every other day for 11 injections. Drugs were given i.p. 30min before PTZ. After each PTZ injection, mice were put under observation and PTZ-provoked seizures were assessed. After the last dose of PTZ, the hot plate test was used to assess antinociceptive properties. Also, brain GABA neurotransmitter was evaluated by immunoassay.Repeated injection of PTZ induced chemical kindling. Calcitonin was found to have significant antinociceptive property as shown by hot plate latency. The beneficial effects of PCV and PCP combination were statistically significant in epilepsy and pain models as compared to valproic acid and pregabalin. The antiepileptic and antinociceptive activity of calcitonin may not relate to the GABAergic system.Calcitonin enhanced the anticonvulsant and antinociceptive effects of either valproic acid or pregabalin. This new treatment “calcitonin add-on” may provide an improved range of options for patients with refractory epilepsy which is still an important risk factor for sudden death.

Investigation of Spinal nerve Ligation Effect on Muscular Neurotrophin-4 Gene Expression in Male Wistar Rats

Introduction: Motor neurons in spinal cord dictate the structural and contractile properties of muscles. Damage to motor neurons change muscles gene expression pattern. Given that Neurotrophin-4 (NT-4) is required for survival and normal function of muscle fibers, the aim of present study is investigation effect of Decreased activity model as Spinal Nerve Ligation on muscular NT-4 gene expression. Materials & methods: Ten adult male wistar rats in the weight range of 250±20 gr randomly were divided into two groups including healthy control (C), Spinal nerve ligation (SNL). Over the six weeks after SNL, neuropathic pain behavior tests were conducted continually in groups. In the end of Sixth weeks, change of NT-4 gene expression in soleus muscle was measured with Real time technique. Findings: Behavioral tests demonstrated that spinal nerve ligation induce thermal Hyperalgesia and mechanical Allodynia in the SNL group which decreased pain threshold seen in allover period of study (P≤0.05). Also, compared to the C group, NT-4 gene expression in soleus muscle was higher in SNL group significantly (P≤0.05). Discussion & conclusions: The present study demonstrated that decreased activity in the form of SNL is associated with increased NT-4 gene expression in soleus muscle. However, the mechanisms and pathophysiologic issues of this increase are remaining elusive.

DEVELOPMENT OF A SCREENING PROTOCOL TO IDENTIFY INDIVIDUALS WITH DYSFUNCTIONAL BREATHING

Dysfunctional breathing (DB) has been linked to health conditions including low back pain and neck pain and adversely effects the musculoskeletal system. Individuals with DB often have decreased pain thresholds and impaired motor control, balance, and movement. No single test or screen identifies DB, which is multi-dimensional, and includes biochemical, biomechanical, and psychophysiological components. Several tools assess and test for DB, but no screen exists to determine whether additional testing and assessment are indicated. The purpose of this study was to develop a breathing screening procedure that could be utilized by fitness and healthcare providers to screen for the presence of disordered breathing. A diagnostic test study approach was utilized to establish the diagnostic accuracy of the newly developed screen for DB. A convenience sample of 51 subjects (27 females, 27.0 years, BMI 23.3) were included. To test for DB related to the biochemical dimension, end-tidal CO2 (ETCO2) was measured with a capnography unit. To test for DB related to biomechanical dimension, the Hi-Lo test was utilized. To test for DB related to the psychophysiological dimension, the Self Evaluation of Breathing Symptoms Questionnaire (SEBQ) and Nijmegen questionnaires were utilized. Potential screening items that have been shown to be related to DB in previous research and that could be performed by non-health care personnel were utilized to create the index test including activity level, breath hold time (BHT), respiration rate, and the Functional Movement Screen (FMS™). There were no strong correlations between the three measures of DB. Five subjects had normal breathing, 14 failed at least one measure, 20 failed at least two, and 12 failed all three. To develop screening items for each dimension, data were examined for association with failure. BHT and a four-item mini-questionnaire were identified as the most closely associated variables with failure of all three dimensions. A BHT of < 25 seconds and four questions were combined and yielded a sensitivity of 0.89 (0.85-0.93) and a specificity of 0.60 (0.18-0.92) for clinical identification of DB. Easily obtained clinical measures of BHT and four questions can be utilized to screen for the presence of DB. If the screen is passed, there is an 89% chance that DB is not present. If the screen is failed, further assessment is recommended. 2b.