Thermal Nociceptive Thresholds Research Articles

A novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers.

The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.

Pharmacokinetics, pharmacodynamics and antinociceptive effects of buprenorphine following transdermal administration to horses

ObjectiveThis study describes the pharmacokinetics and pharmacodynamics, including antinociceptive effects, of a transdermal buprenorphine solution in horses. It was hypothesized that transdermal application would lead to sustained blood concentrations and antinociceptive effects with fewer adverse effects compared with intravenous (IV) injection. Study designProspective nonrandomized four-part parallel experimental study. AnimalsA group of eight horses (three mares and five geldings) aged 6–12 years. MethodsHorses were administered incremental doses of 15, 30 and 45 μg kg–1 of buprenorphine transdermal solution and a single IV dose of 5 μg kg–1 of buprenorphine with a 2 week washout period between treatments. Concentrations of buprenorphine were determined in plasma using liquid chromatography–tandem mass spectrometry and modeled using a nonlinear mixed effects population pharmacokinetic model to determine pharmacokinetic parameters. Pharmacodynamic effects, including changes in locomotor activity, heart rate, body temperature, gastrointestinal borborygmi, thermal and mechanical nociceptive thresholds were recorded. Mixed effects analysis of variance and post hoc comparisons were performed using a Bonferroni multiple comparison adjustment to assess differences in pharmacodynamic parameters between baseline and each time point within each dose group and between dose groups at the same time point. ResultsTransdermal application of buprenorphine resulted in low systemic concentrations relative to IV injection. Bioavailability after transdermal application was 11%. Thermal nociceptive thresholds were significantly (p < 0.05) increased (4.3–10.7% relative to baseline) for up to 72 hours in the IV dose group, but only sporadically in the transdermal dose groups (2.5–9.9% relative to baseline). Changes in locomotor activity, heart rate and borborygmi varied over time and with dose. Conclusions and clinical relevanceLimited thermal antinociceptive effects were observed at the transdermal doses studied likely owing to limited absorption relative to IV dosing. Future studies may be directed toward investigating antinociceptive effects of higher transdermal doses and different application sites.

Mode of delivery alters sensitivity to thermal and chemical stimuli in adult rats: An experimental study.

The mode of delivery might prompt a long-lasting alteration in physiological and behavioral responsiveness in offspring. This study was intended to evaluate if the mode of delivery could alter sensitivity to thermal and chemical stimuli in female rats. 56 adult female Wistar rats (200-220 gr) that were born by vaginal or cesarean section (C-section) were used (n = 28/each). Inflammatory pain was induced by subcutaneous injection of formalin into the hind paw. The thermal nociceptive threshold was determined by tail-flick and hot plate tests. Besides, the Western blot test was used to evaluate the spinal cord levels of c-Fos and c-Jun proteins. Formalin-induced inflammation was significantly decreased in C-section group as compared to vaginally born rats (p 0.001). The baseline nociceptive threshed and morphine-induced analgesia were significantly increased in C-section groups in comparison to vaginally born rats. In addition, the levels of c-Fos and c-Jun proteins were significantly decreased in the spinal cord of C-section rats as compared to vaginally born animals (p 0.01). Morphine treatment could decrease the expression of c-Fos and c-Jun in the C-section group (p 0.05). Overall, C-section rats showed lower spinal nociceptive processing and neuronal activity later in life, compared to the vaginal born rats.

Evaluation of physical variables, thermal nociceptive threshold testing and pharmacokinetics during placement of transdermal buprenorphine matrix-type patch in healthy adult horses.

Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization. Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 μg h-1 and 40 μg h-1 dosing) in healthy adult horses. Randomised experimental study with a Latin-square design. Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 μg h-1) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 μg kg-1 h-1. BUP40 horses received two patches placed alongside each other (40 μg h-1) on the tail base resulting in a dose of 0.07-0.09 μg kg-1 h-1. Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content. Between the three groups, there was no change in physiological variables across timepoints as compared to baseline (p > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 μg h-1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h. 20 μg h-1 and 40 μg h-1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 μg h-1 dosing as compared to control.

Hydroethanolic Extract of Capparis spinosa Amends Vincristine-Induced Peripheral Neuropathy in Rats

Background: Peripheral neuropathy is a common side effect of chemotherapeutic agents. This study aimed to assess the impact of hydroalcoholic extract from Capparis spinosa fruit on mechanical allodynia and heat hyperalgesia induced by vincristine. Methods: Vincristine (0.1 mg/kg/day, intraperitoneally) was used to induce peripheral neuropathy in rats for 2 weeks. The rats received treatment with the hydroalcoholic extract of Capparis spinosa fruit (100, 200, and 400 mg/kg, orally) or pregabalin (20 mg/kg, orally) for 2 weeks. Assessments of thermal and mechanical hyperalgesia were conducted using the hot plate, open field, footprint, grip strength, and von Frey hair tests. To investigate the roles of opioid and serotonergic pathways in anti-nociceptive and locomotor activities, naloxone (1 mg/kg) and cyproheptadine (5 mg/kg) were administered in conjunction with the extract. Results: Two weeks post vincristine administration, there was a significant decrease in thermal and mechanical nociceptive thresholds, muscle strength, and locomotor activity in rats compared to untreated groups. In all tests, pregabalin mitigated vincristine's effects; notably, the Capparis spinosa extract at a dose of 400 mg/kg significantly reduced neuropathic behavioral changes compared to animals that received vincristine. The efficacy of the extract at the 400 mg/kg dose was diminished by naloxone in the von Frey filament test (P &lt; 0.01), hot plate test (P &lt; 0.05), and grip strength test (P &lt; 0.001). Additionally, cyproheptadine reversed the extract's effect in the grip strength (P &lt; 0.0001) and von Frey filament tests (P &lt; 0.01). Conclusions: The findings suggest that the hydroalcoholic extract of Capparis spinosa fruit may counteract vincristine-induced neuropathic pain through opioidergic and serotonergic pathways. The extract's beneficial effects are likely due to its flavonoid and phenolic compound content.

Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice

Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics.

Huntingtin-associated protein 1 ameliorates neurological function rehabilitation by facilitating neurite elongation through TrKA-MAPK pathway in mice spinal cord injury.

Huntingtin-associated protein 1 (HAP1) is a neuronal protein closely associated with microtubules and might facilitate neurological function rehabilitation. This study aimed to investigate the effects of HAP1 on SCI and the underlying mechanisms. the spinal cord injury (SCI) mouse model was induced by Allen's method. Then recombinant-HAP1 (r-HAP1) was administrated by intrathecal injection, and the BMS, Thermal nociceptive thresholds, tactile nociceptive thresholds, and neurofibrillary regeneration were identified to inspect the therapy outcome. Then NSCs were isolated from mice on embryonic day 14.5 and induced to differentiate into neurons. The efficiency of axon growth was calculated. Signaling pathway array was conducted to examine the signaling pathways in NSCs treated with r-HAP1. Antagonists and activators of TrkA were used to confirm the role of TrkA of HAP1 intervention both in vitro and in vivo. r-HAP1 ameliorates the neurological function rehabilitation after SCI, and benefits the regain of Tuj in injury spinal cord. Also significantly enhances neurite growth during neuronal differentiation of NSCs; Signaling pathway array and Western blot revealed that r-HAP1 significantly activates the phosphorylation of TrkA-MAPK/ERK in NSCs. TrkA selective inhibitor GW441756 blocks r-HAP1 on TrkA-MAPK/ERK signaling pathway and detracts from axonal growth after neuronal differentiation. TrkA selective activator gambogic amide can mimic the function of r-HAP1 by activating the foregoing pathway. ERK activator U-46619 reverses the blocking effect of GW441756 on r-HAP1. HAP1 activates the TrkA-MAPK signaling pathway and is conducive to neurite elongation during NSC neuronal differentiation; by which to improve the prognosis of spinal cord injury in mice.

Sex-specific biobehavioral regulation of persistent inflammatory pain by alcohol.

Although a large percentage of chronic pain patients consume alcohol to manage their pain, there is a significant gap in knowledge regarding the mechanisms underlying the antinociceptive effects of alcohol. To determine the longitudinal analgesic effects of alcohol, we utilized the complete Freund's adjuvant (CFA) model of inflammatory pain in adult female and male Wistar rats. Both somatic and negative motivational aspects of pain were measured using the electronic von Frey (mechanical nociception) system, thermal probe test (thermal nociception), and mechanical conflict avoidance task (pain avoidance-like behavior). Tests were conducted at baseline and 1 and 3 weeks following intraplantar CFA or saline administration. At both time points post-CFA, animals were treated with each of three doses of alcohol (intraperitoneal; 0, 0.5, and 1.0 g/kg) over separate days in a Latin square design. Alcohol produced dose-dependent mechanical analgesia and antihyperalgesia in females but only antihyperalgesia in males. Although alcohol continued to attenuate CFA-induced decreases in both thermal and mechanical nociceptive thresholds between 1 and 3 weeks post-CFA, it appeared less effective at increasing thresholds 3 weeks after CFA induction. These data suggest that individuals may develop tolerance to alcohol's ability to alleviate both somatic and negative motivational symptoms of chronic pain over time. We also discovered sex-specific neuroadaptations in protein kinase A-dependent phosphorylation of GluR1 subunits and extracellular signal-regulated kinase (ERK 1/2) phosphorylation in nociceptive brain centers of animals receiving an alcohol challenge 1 week post-CFA. Together, these findings illustrate a sex-specific regulation of behavioral and neurobiological indices of persistent pain by alcohol.

The effects of voluntary exercise on histological and stereological changes of sciatic nerve, nitric oxide levels, and peripheral neuropathy caused by high-fat diet-induced type 2 diabetes in male rats

This research was conducted to investigate the possible beneficial impacts of voluntary exercise on sciatic tissue, nitric oxide levels, stereological changes, and peripheral neuropathy caused by "high-fat-diet (HFD)"-induced "type 2 diabetes mellitus (T2DM)" in male rats. Rats were put into four experimental groups at random: "healthy control (C), voluntary exercise (VE), diabetic (D), and diabetic rats treated by voluntary exercise (VED)"; each group contain eight animals. Animals in VE and VED groups performed "voluntary exercise (VE)" for ten weeks. Animals in D and VED groups became diabetic after receiving a HFD for four weeks and an intraperitoneal injection (IP) of "streptozotocin (STZ)" (35 mg/kg). In order to evaluate mechanical and thermal algesia, hot plate, tail withdrawal, and von Frey tests were carried out. At the end of this study, serum NOx levels were assessed, and histological and stereological analyses were conducted. Mechanical nociceptive thresholds indicated considerable reduction (p < 0.001) which was followed by a remarkable enhance (p < 0.001) in thermal nociceptive threshold of D group. Tissue changes were also seen in sciatic nerve of D group. Voluntary exercise modified thermal and mechanical sensitivity in diabetic rats. It also improved the damaged sciatic nerve in diabetic animals.

The Antinociceptive Effect of Magnesium Sulphate Administered in the Epidural Space in Standing Horses.

To study the antinociceptive properties of epidural magnesium sulphate (MgSO4) in standing horses Experimental, placebo-controlled, masked, cross-over A group of six healthy horses Through an epidural catheter, 1 mg kg -1 MgSO4 (treatment Mg) diluted to a volume of 15 mL or the same volume of saline (treatment S) was administered over 15 minutes. Electrical, thermal and mechanical nociceptive thresholds were determined on the pelvic limb before and 20, 40, 60, 80, 100, 120, 140, 160 and 180 minutes after the start of the injection. Heart rate (HR) and respiratory frequency (fR) were recorded every 10 minutes. Blood samples were collected before treatment and every 30 minutes throughout the study period. Data were assessed for normality using a Shapiro-Wilk test. A linear mixed model with horse as random effect and time, treatment and their interaction as fixed effects was used. Treatments were compared at 20, 60, 120 and 180 minutes using the Wilcoxon rank sum test stratified for horse (global α=0.05, with Bonferroni correction α=0.0125). Epidural MgSO4 caused a significant increase in the electrical threshold (mA) (P=.0001), but no significant differences in thermal and mechanical nociceptive thresholds. During the injection of MgSO4, two horses collapsed. One stood up within 20 minutes and was able to continue the study, the second one was excluded. A significant difference was found for HR at T180 (Mg 44 ± 23 beats minute-1; S 32 ± 9 beats minute-1) (P=.0090). Epidural administration of MgSO4 caused an increase in the electrical threshold of the pelvic limbs of horses. Caution is warranted however, as with the current dose, 2 horses collapsed.

Focused ultrasound-induced inhibition of peripheral nerve fibers in an animal model of acute pain

BackgroundModerate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient...

Evaluation of physical examination and thermal nociceptive threshold testing during placement of transdermal buprenorphine patch in healthy adult horses

Introduction: Transdermal buprenorphine patches have not previously been investigated in horses and could potentially be used for long-term analgesia without needing venous catheterization.

Assessment of the anti-nociceptive effects of fetal ventral mesencephalic tissue allografts in a rat model of hemi-Parkinson's disease using fMRI.

Extensive studies showed increased subjective pain sensitivity in Parkinson's disease (PD), which appeared to be partially reversed by dopaminergic (DA) treatment. Although cell replacement represents an attractive therapeutic strategy, its potential for PD-related hyperalgesia remains unclear. We investigated re-establishment of DA function via allografting exogenic DA cells on pain hypersensitivity in a rat model of PD. We evaluated the anti-nociceptive effects of fetal ventral mesencephalic (rVM) tissue allografts in PD rats after unilateral 6-OHDA-induced toxicity in the medial forebrain bundle. The drug -induced rotation test was used to validate the severity of the nigrostriatal lesion; von Frey and thermal pain tests were employed to evaluate nociceptive function. Nociception-induced cerebral blood volume (CBV) response was measured using a 4.7-T MR system. Finally, the immunohistochemical (IHC) studies were performed and the results were compared with the imaging findings from functional magnetic resonance imaging (fMRI). The grafts significantly improved drug-induced rotation behavior and increased mechanical and thermal nociceptive thresholds in PD rats. The elevation of CBV signals significantly recovered on the grafted striatum, whereas this effect was inhibited by the D2R antagonist eticlopride in each striatum. Quantitative IHC analysis revealed the transplantation markedly increased the numbers of tyrosine hydroxylase immunoreactive cells. Therefore, we concluded transplantation of rVM tissue results in anti-nociceptive effects and improves motor function. Moreover, in vivo CBV response confirmed the key role of D2R-mediated pain modulation. Therefore, we demonstrate fMRI as a reliable imaging index in evaluating the anti-nociceptive therapeutic effects of fetal rVM transplantation in the rat model of PD.

Trigeminal‐mediated headshaking: A diagnostic challenge

Trigeminal‐mediated headshaking: A diagnostic challenge

Intravenous Magnesium Sulphate in Standing Horses: Effects on Physiological Parameters, Plasma Concentration of Magnesium and Nociceptive Threshold Tests☆

A bolus of 50 mg kg −1 MgSO4 (treatment Mg) or the same volume of saline (treatment S) was infused over 15 minutes in 5 adult healthy horses. T0 was the end of the infusion. Physiological parameters were recorded throughout the study period. Measurements of electrical, thermal, and mechanical nociceptive thresholds were performed at the pelvic limbs at baseline (before T0), and at specific timepoints. Blood samples were taken at fixed timepoints before, during and until 12 hours after the infusion. For statistical analysis, the 95% confidence intervals (CI's) for the differences in nociceptive thresholds between treatments were calculated. Physiological parameters were compared using a linear mixed model (global α = 0.05, with Bonferroni correction α = 0.0125). The concentrations of ions were also compared with the baseline values at specific timepoints, using a linear mixed model. The Pearson's correlation coefficient was derived between the ion concentrations. The 95% CI's of thermal, mechanical and electrical thresholds were [-1; +2]°C, [0; +3] N and [-1; +1] mA (positive differences indicate higher thresholds for treatment Mg), respectively. Heart rate was significantly higher (P < .0001) and non-invasive systolic arterial pressure (P < .0001) and respiratory rate (P = .0002) significantly lower after treatment Mg compared to treatment S. Additionally, non-invasive systolic arterial pressure was significantly different at T45 (P < .001). Although mild changes in cardiovascular parameters and plasma concentrations were seen with intravenous administration of MgSO4, no changes in nociceptive thresholds were detected in standing non-sedated horses.

Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat

Arginine vasopressin (AVP) is a hypothalamic neurosecretory hormone well known as an antidiuretic, and recently reported to be involved in pain modulation. The expression kinetics of AVP and its potential involvement in the descending pain modulation system (DPMS) in neuropathic pain (NP) remains unclear. We investigated AVP expression and its effects on mechanical and thermal nociceptive thresholds using a unilateral spinal nerve ligation (SNL) model. All rats with SNL developed NP. Intensities of enhanced green fluorescent protein (eGFP) in the supraoptic and paraventricular nuclei, median eminence, and posterior pituitary were significantly increased at 7 and 14 days post-SNL in AVP-eGFP rats. In situ hybridisation histochemistry revealed significantly increased AVP mRNA expression at 14 days post-SNL compared with the sham control group. The chemogenetic activation of AVP neurones significantly attenuated mechanical and thermal hyperalgesia with elevated plasma AVP concentration. These analgesic effects were suppressed by pre-administration with V1a receptor antagonist. AVP neurones increased the neuronal activity of serotonergic dorsal raphe, noradrenergic locus coeruleus, and inhibitory interneurones in the spinal dorsal horn. These results suggest that the hypothalamo-neurohypophysial system of AVP is upregulated in NP and activated endogenous AVP exerts analgesic effects via the V1a receptors. AVP neurones may activate the DPMS.

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

BackgroundThe noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.MethodsThe Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.ResultsActivation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.ConclusionThese findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice.

Burn injury is a trauma resulting in tissue degradation and severe pain, which is processed first by neuronal circuits in the spinal dorsal horn. We have recently shown that in mice, excitatory dynorphinergic (Pdyn) neurons play a pivotal role in the response to burn-injury-associated tissue damage via histone H3.1 phosphorylation-dependent signaling. As Pdyn neurons were mostly associated with mechanical allodynia, their involvement in thermonociception had to be further elucidated. Using a custom-made AAV9_mutH3.1 virus combined with the CRISPR/cas9 system, here we provide evidence that blocking histone H3.1 phosphorylation at position serine 10 (S10) in spinal Pdyn neurons significantly increases the thermal nociceptive threshold in mice. In contrast, neither mechanosensation nor acute chemonociception was affected by the transgenic manipulation of histone H3.1. These results suggest that blocking rapid epigenetic tagging of S10H3 in spinal Pdyn neurons alters acute thermosensation and thus explains the involvement of Pdyn cells in the immediate response to burn-injury-associated tissue damage.

The Role of Long Noncoding RNA MALAT1 in Diabetic Polyneuropathy and the Impact of Its Silencing in the Dorsal Root Ganglion by a DNA/RNA Heteroduplex Oligonucleotide.

Diabetic polyneuropathy (DPN) is the most common complication of diabetes, yet its pathophysiology has not been established. Accumulating evidence suggests that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays pivotal roles in the regulation of cell growth and survival during diabetic complications. This study aimed to investigate the impact of MALAT1 silencing in dorsal root ganglion (DRG) sensory neurons, using an α-tocopherol-conjugated DNA/RNA heteroduplex oligonucleotide (Toc-HDO), on the peripheral nervous system of diabetic mice. We identified MALAT1 upregulation in the DRG of chronic diabetic mice that suggested either a pathological change or one that might be protective, and systemic intravenous injection of Toc-HDO effectively inhibited its gene expression. However, we unexpectedly noted that this intervention paradoxically exacerbated disease with increased thermal and mechanical nociceptive thresholds, indicating further sensory loss, greater sciatic-tibial nerve conduction slowing, and additional declines of intraepidermal nerve fiber density in the hind paw footpads. Serine/arginine-rich splicing factors, which are involved in pre-mRNA splicing by interacting with MALAT1, reside in nuclear speckles in wild-type and diabetic DRG neurons; MALAT1 silencing was associated with their disruption. The findings provide evidence for an important role that MALAT1 plays in DPN, suggesting neuroprotection and regulation of pre-mRNA splicing in nuclear speckles. This is also the first example in which a systemically delivered nucleotide therapy had a direct impact on DRG diabetic neurons and their axons.

Peripheral neuropathy in the pre-diabetic state of the type 2 diabetes mouse model (TSOD mice) involves TRPV1 expression in dorsal root ganglions.

Peripheral neuropathy, which is a complication of diabetes mellitus (DM), is thought to occur in the pre-DM state, being known as impaired glucose tolerance (IGT) neuropathy, although its pathogenesis is unknown. Since it is reversible, an effective treatment at the pre-DM stage could stop the progression of peripheral neuropathy and improve patients’ quality of life and reduce medical costs. We investigated the hypersensitivity to mechanical and thermal stimuli during the pre-DM state in Tsumura Suzuki Obese Diabetes (TSOD) mice, a type 2 DM mouse model. The expression pattern of the Transient Receptor Potential Vanilloid 1 (TRPV1)-positive cells in the dorsal root ganglia (DRG) was examined in TSOD mice, which showed a pre-DM state at 5–12 weeks of age and decreased mechanical and thermal nociceptive thresholds. Additionally, the size of TRPV1-positive cells in TSOD mice increased compared with that in non-diabetic controls (Tsumura Suzuki Non-Obesity; TSNO). Furthermore, the expression of TRPV1 on myelinated nerve fibers (neurofilament heavy-positive cells) had significantly increased. Thus, TSOD mice in the pre-DM state at 5–12 weeks of age could be a useful animal model of IGT neuropathy. We also hypothesized that the development of IGT neuropathy may involve a switch in TRPV1 expression from small, unmyelinated neurons to large, myelinated neurons in the DRG.