Acetone Test Research Articles

Nociceptive, emotional and electrophysiological characterization of the chronic constriction injury model of experimental traumatic neuropathic pain in female Wistar Han rats.

Event Abstract Back to Event Nociceptive, emotional and electrophysiological characterization of the chronic constriction injury model of experimental traumatic neuropathic pain in female Wistar Han rats. Diana M. Rodrigues1, 2*, Inês M. Laranjeira1, 2, João Barbosa1, 2, 3, Diana Amorim1, 2, Armando Almeida1, 2 and Filipa Pinto-Ribeiro1, 2 1 Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Portugal 2 PT Associate Laboratory ICVS/3B’s, Portugal 3 Polytechnic Institute of Viana do Castelo, Portugal Chronic neuropathic pain, affecting 7-10% of the population, is often accompanied by comorbid emotional impairments (depression/anxiety) that adversely affect pain by enhancing nociceptive symptomatology. This condition greatly reduces the quality of life of the patients, as it impairs physical, cognitive, emotional and social functioning, consequently interfering with treatment. Importantly, although chronic pain and emotional disorders are more prevalent in women, only a few publications focus on female animals. While the chronic constriction injury (CCI) model has been shown to mimic human neuropathies in terms of mechanical/thermal hyperalgesia, allodynia and spontaneous pain in both sexes, data on CCI-induced emotional impairments on female rats remains scarce. In this work, young adult female rats (Wistar Han) were divided into four groups (n=8 per group): gonadally intact females (SHAM/SHAM), ovariectomized females (SHAM/OVX), ovariectomized females with CCI (CCI/OVX) and gonadally intact females with CCI (CCI/SHAM) and the CCI model was induced by placing 4 chromic catgut constrictive ligatures in the common sciatic nerve. Nociceptive testing began before CCI surgery and was performed weekly throughout 5 weeks post-surgery after which the anxiodepressive-like behaviours were also assessed. In the postoperative period, CCI animals displayed visible gait abnormalities, limping and guarding the affected hind paw, and the development of mechanical (VonFrey test) and cold allodynia (acetone test) from week 1 onwards. While no differences were found between CCI and SHAM animals concerning anxiety-like (elevated plus maze and open field tests) and depressive-like (forced swimming and sucrose preference tests) behaviours, OVX females displayed anhedonic-like behaviour regardless of CCI surgery. Single cell electrophysiological recordings showed changes, in the neuronal activity of areas mediating nociceptive and emotional processing (the rostral ventromedial medulla and the amygdala), in accordance with our behavioural data. Keywords: Neuropathic pain (NP), Anxiety, Depression, Chronic constriction injury (CCI), Electrophysiology Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019. Presentation Type: Poster presentation Topic: Sensory Processing Citation: Rodrigues DM, Laranjeira IM, Barbosa J, Amorim D, Almeida A and Pinto-Ribeiro F (2019). Nociceptive, emotional and electrophysiological characterization of the chronic constriction injury model of experimental traumatic neuropathic pain in female Wistar Han rats.. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00016 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Feb 2019; Published Online: 27 Sep 2019. * Correspondence: Miss. Diana M Rodrigues, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal, diannamarina@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Diana M Rodrigues Inês M Laranjeira João Barbosa Diana Amorim Armando Almeida Filipa Pinto-Ribeiro Google Diana M Rodrigues Inês M Laranjeira João Barbosa Diana Amorim Armando Almeida Filipa Pinto-Ribeiro Google Scholar Diana M Rodrigues Inês M Laranjeira João Barbosa Diana Amorim Armando Almeida Filipa Pinto-Ribeiro PubMed Diana M Rodrigues Inês M Laranjeira João Barbosa Diana Amorim Armando Almeida Filipa Pinto-Ribeiro Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats

It seems that histamine release in the site of neuronal injury could contribute to the neuropathic pain mechanism. In the present study, we investigated the anti-allodynic effects of chronic administration of different classes of histamine H1 and H2 receptor antagonists on neuropathic nociceptive behavior following tibial nerve transection (TNT) in rats.Peripheral neuropathy was induced by TNT surgery. We performed acetone tests (AT) to record cold allodynia, Von Frey tests (VFT) to measure mechanical allodynia, double plate test (DPT) to evaluate thermal place preference/avoidance and open field test (OFT) for evaluation of animal activity.TNT rats showed a significant mechanical and cold allodynia compared to the sham group. Chlorpheniramine (5 and 15 mg/kg, i.p) significantly attenuated cold allodynia and prevented cold plate avoidance behavior and at the dose of 15 mg/kg remarkably decreased mechanical allodynia. Fexofenadine (10 and 30 mg/kg, p.o) significantly attenuated the mechanical allodynia and prevented cold plate avoidance. Ranitidine (5 and 15 mg/kg, i.p) significantly prevented cold plate avoidance behavior and at the dose of 15 mg/kg notably improved mechanical and cold allodynia. Famotidine (1 and 3 mg/kg, p.o) was ineffective on all nociceptive tests. Gabapantin (100 mg/kg, p.o) significantly improved all types of nociceptive behaviors.These results indicate that both blood brain barrier penetrating (chlorpheniramine) and poorly penetrating (fexofenadine) histamine H1 receptor antagonists could improve the neuropathic pain sign, but only the blood brain barrier penetrating histamine H2 receptor antagonist (ranitidine) could produce anti-allodynic effects in the TNT model of neuropathic pain in rats.

Low back pain and disc degeneration are decreased following chronic toll-like receptor 4 inhibition in a mouse model

Intervertebral disc degeneration is a leading cause of chronic low back pain (LBP) but current treatment is limited. Toll-like receptors (TLRs) on disc cells are activated by endogenous extracellular matrix (ECM) fragments and modulate degeneration invitro. This study investigated whether inhibiting TLR4 slows disc degeneration and reduces behavioral signs of LBP invivo. 7-9-month old wild-type and secreted protein acidic and rich in cysteine (SPARC)-null (a model of disc degeneration and LBP) male mice were treated with TAK-242 (TLR4 inhibitor) once, and following a 10-day washout, mice were treated 3 times/week for 8 weeks. Behavioral signs of axial discomfort and radiating leg pain were assessed weekly with the grip force assay and acetone test, respectively. Following treatment, pain-related spinal cord changes were evaluated and lumbar discs were excised and cultured. Cytokine secretion from discs was evaluated with protein arrays. SPARC-null mice displayed elevated signs of axial and radiating pain at baseline compared to wild-type. Chronic, but not acute, TLR4 inhibition reduced behavioral signs of pain compared to vehicle. SPARC-null mice have increased calcitonin gene-related peptide (CGRP)- and glial fibrillary acidic protein (GFAP)-immunoreactivity (astrocyte marker) in the dorsal horn compared to wild-type, which is reduced by chronic TLR4 inhibition. Exvivo degenerating discs from SPARC-null mice secrete increased levels of many pro-inflammatory cytokines, which chronic TLR4 inhibition reduced. Chronic TLR4 inhibition decreased behavioral signs of LBP, pain-related neuroplasticity and disc inflammation in SPARC-null mice. TAK-242 inhibits TLR4 activation within discs, as evidenced by decreases in cytokine release. Therefore, TLRs are potential therapeutic targets to slow disc degeneration and reduce pain.

Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats

Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.

Minocycline through attenuation of oxidative stress and inflammatory response reduces the neuropathic pain in a rat model of chronic constriction injury.

Objective(s):Several lines of evidence showed that minocycline possesses antioxidant and anti-inflammatory properties. This study aimed to demonstrate the effects of minocycline in rats subjected to chronic constriction injury (CCI).Materials and Methods:In this study four groups (n = 6–8) of rats were used as follows: Sham, CCI, CCI + minocycline (MIN) 10 mg/Kg (IP) and CCI + MIN 30 mg/Kg (IP). On days 3, 7, 14, and 21 post-surgery hot-plate, acetone, and von Frey tests were carried out. Finally, Motor Nerve Conduction Velocity Evaluation (MNCV) assessment was performed and spinal cords were harvested in order to measure tissue concentrations of TNF_α, IL-1β, Glutathione peroxidase (GPx), Superoxide dismutase (SOD) and Malondialdehyde (MDA). Extent of perineural inflammation and damage around the sciatic nerve was histopathologically evaluated.Results:Our results demonstrated that CCI significantly caused hyperalgesia and allodynia twenty-one days after CCI. MIN attenuated heat hyperalgesia, cold and mechanical allodynia and MNCV in animals. MIN also decreased the levels of TNF_α and IL-1β. Antioxidative enzymes (SOD, MDA, and GPx) were restored following MIN treatment. Our findings showed that MIN decreased perineural inflammation around the sciatic nerve. According to the results, the neuropathic pain reduced in the CCI hyperalgesia model using 30 mg/kg of minocycline.Conclusion:It is suggested that antinociceptive effects of minocycline might be mediated through the inhibition of inflammatory response and attenuation of oxidative stress.

Validation of an algorithm for identifying type 1 diabetes in adults based on electronic health record data.

Algorithms using information from electronic health records to identify adults with type 1 diabetes have not been well studied. Such algorithms would have applications in pharmacoepidemiology, drug safety research, clinical trials, surveillance, and quality improvement. Our main objectives were to determine the positive predictive value for identifying type 1 diabetes in adults using a published algorithm (developed by Klompas et al) and to compare it to a simple requirement that the majority of diabetes diagnosis codes be type 1. We applied the Klompas algorithm and the diagnosis code criterion to a cohort of 66690 adult Kaiser Permanente Colorado members with diabetes. We reviewed 220 charts of those identified as having type 1 diabetes and calculated positive predictive values. The Klompas algorithm identified 3286 (4.9% of 66690) adults with diabetes as having type 1 diabetes. Based on chart reviews, the overall positive predictive value was 94.5%. The requirement that the majority of diabetes diagnosis codes be type 1 identified 3000 (4.5%) as having type 1 diabetes and had a positive predictive value of 96.4%. However, the algorithm criterion involving dispensing of urine acetone test strips performed poorly, with a positive predictive value of 20.0%. Data from electronic health records can be used to accurately identify adults with type 1 diabetes. When identifying adults with type 1 diabetes, we recommend either a modified version of the Klompas algorithm without the urine acetone test strips criterion or the requirement that the majority of diabetes diagnosis codes be type 1 codes.

Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents.

Oxaliplatin is a widely used chemotherapy agent, but induces serious peripheral neuropathy. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine, and is shown to be effective against pain. However, whether and how duloxetine can attenuate oxaliplatin-induced allodynia in rodents is not clearly understood. A single injection of oxaliplatin (6 mg/kg, intraperitoneal; i.p.) induced a cold and mechanical allodynia, which was assessed by acetone and von Frey filament tests, respectively. When significant allodynic signs were observed, three different doses of duloxetine (10, 30, and 60 mg/kg, i.p.) were injected. Administration of 30 and 60 mg/kg of duloxetine significantly reduced the allodynia, whereas 10 mg/kg did not. By using an in vivo extracellular recording method, we further confirmed that 30 mg/kg of duloxetine could significantly inhibit the hyperexcitability of spinal wide dynamic range (WDR) cells. The anti-allodynic effect of duloxetine was completely blocked by an intrathecal injection of phentolamine (non-selective α-adrenergic receptor antagonist, 20 μg), or prazosin (α1-adrenergic receptor antagonists, 10 μg); however, idazoxan (α2-adrenergic receptor antagonist, 10 μg) did not block it. In conclusion, we suggest that duloxetine may have an effective protective action against oxaliplatin-induced neuropathic pain and spinal hyperexcitability, which is mediated by spinal α1-adrenergic receptors.

Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats.

Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats. Rats were administered intravenous L-OHP, once a week for 4weeks, at doses of 3, 5, or 8mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period. The mean AUC0-∞ values for L-OHP were 0.4±0.2, 2.4±0.4, and 3.5±0.9ngh/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0-∞ values of 0.6±0.2, 4.0±1.0, and 14.1±9.8 ng·h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment.

Single oral dose of cannabinoid derivate loaded PLGA nanocarriers relieves neuropathic pain for eleven days

Neuropathic pain, resistant to opiates and other drugs, is a chronic/persistent state with a complex treatment and often poor efficacy. In this scenario, cannabinoids are increasingly regarded as a genuine alternative. In this paper, and in an experimental animal model of neuropathic pain, we studied the efficacy of three kinds of PLGA nanoparticles containing synthetic cannabinoid CB13: (i) plain nanoparticles (PLGA); (ii) particles coated with PEG chains (PLGA+PEG) and (iii) particles possessing hydrophilic surfaces obtained by covalently binding PEG chains (PLGA–PEG). The optimized formulation, CB13–PLGA–PEG, showed high drug loading (13%) and small size (<300nm) with a narrow distribution and controlled surface properties (near-neutral zeta potential and stable PEG corona). Animal nociceptive behavioral studies were conducted by paw pressure and acetone tests. Versus the free CB13, CB13–PLGA–PEG nanoparticles showed a very noticeable analgesic efficacy with the longest sustained pain-relieving effect, lasting up to eleven days after one oral dose.

Involvement of Charcot-Marie-Tooth disease gene mitofusin 2 expression in paclitaxel-induced mechanical allodynia in rats.

Paclitaxel induces peripheral neuropathy, which is dose-limiting and results in loss of quality of life. Therefore, the prevention and treatment of paclitaxel-induced peripheral neuropathy are major concerns in clinical cancer therapy. However, the detailed mechanisms have not been fully elucidated. It has recently been reported that allelic variability in the Charcot-Marie-Tooth disease (CMT) genes, mitofusin 2 (MFN2), Rho guanine nucleotide exchange factor 10 (ARHGEF10), and periaxin (PRX), affected paclitaxel-induced peripheral neuropathy in clinical cases. Therefore, we hypothesized that paclitaxel may induce peripheral neuropathy due to changes in Mfn2, Arhgef10, and Prx mRNA expression. Paclitaxel (6mg/kg) was administered intraperitoneally, on two consecutive days per week for 4 weeks in rats. Paclitaxel-induced peripheral neuropathy was measured by the von Frey test and acetone test, mechanical allodynia, and cold hyperalgesia, respectively, on days 0, 3, 10, 17, and 24. Mfn2, Arhgef10, and Prx mRNA expression in the spinal cord were analyzed by qRT-PCR on days 3 and 24. Paclitaxel induced mechanical allodynia from days 17-24, but did not induce cold hyperalgesia. In addition, paclitaxel reduced Mfn2 mRNA expression, but not Arhgef10 or Prx mRNA expression, on days 3 and 24. In addition, Mfn2 mRNA level was decreased before the appearance of mechanical allodynia. The results of the present study suggest that a reduction in Mfn2 mRNA expression contributes to paclitaxel-induced mechanical allodynia.

Enhancement of Antinociceptive Effect by Co-administration of Amitriptyline and Crocus Sativus in a Rat Model of Neuropathic Pain.

The aim of this study was to evaluate the anti-nociceptive effects of a low, sub-effective dose of amitriptyline, in combination with the different doses of ethanolic and aqueous extracts of Crocus sativus following sciatic nerve chronic constriction injury (CCI) in rats. Amitriptyline (3, 10 and 30 mg/Kg, i.p.) and the extracts (25, 50 and 100 mg/Kg, i.p.), were separately administered at the time of CCI for 7 consecutive days. In combination therapy, the sub-antinociceptive dose of amitriptyline (3 mg/Kg) was given with the three different doses of extracts for seven days. Mechanical allodynia, thermal allodynia and thermal hyperalgesia were evaluated by von Frey, acetone and radiant heat tests, respectively, 1 day before and on days 3, 5 and 7 after surgery. Co-administration of amitriptyline (3 mg/Kg) with aqueous extract (50, 100 mg/Kg,) produced more potent cold anti-allodynic (P < 0.01 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects than that produced by each of them. Amitriptyline (3 mg/Kg) plus ethanolic extract (50, 100 mg/Kg) produced more potent cold anti-allodynic (P < 0.05 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects as compared with the sum effects produced by each of them. Mechanical anti-allodynia effect was only potentiated with the co-administration of amitriptyline with the high dose of aqueous extract (100 mg/Kg, P < 0.001). Our study supports the use of saffron as an adjunctive to amitriptyline to improve the therapeutic outcome in the management of neuropathic pain.

S.35.04 - Immune factors as biomarkers for stress-related psychiatric and pain disorders

Evidence for a role of immune system in hyperalgesic pain states is increasing. Recent work in neuroimmunology suggests that the immune system does more than simply perform its well known functions of recognizing and removing invading pathogens and tumors. Interest in neuroinflammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system inflammatiom and immune responses in the aetiology of pain states. Among various theories, the role of inflammatory responses of the injured nerve has recently received attention. Cytokines are heterogenous group of polypeptides that activate the immune system and mediate inflammatory responses, acting on a variety of tissue, including the peripheral and central nervous system. Interleukin-6 (IL-6) a pro-inflammatory cytokine, is potentially important in pain aetiology, have pronociceptive actions. Neuropathic pain may be due to a primary insult to the peripheral or central nervous system. Substances released during inflammation from immune cells play an important role in the development and maintenance of chronic pain. Nimesulide, a highly selective cox-2 inhibitor, effectively reduces hyperalgesia due to peripherally administration of inflammatory agents like formalin. The safety of nimesulide was reported for some conditions in which other NSAIDs are contraindicated. Here we have determined the effect of nimesulide on pain behaviour and serum IL-6 level in chronic constriction injury (CCI) model of neuropathic pain.Experiments were carried out on male Wistar rats, (weight 150–200 g, n = 8). Rats were divided into 3 different groups: 1- CCI + saline 0.9% 2- Sham + saline 0.9% (control) 3- CCI + drug. Nimesulide (1.25, 2.5, 5 mg/kg, i.p.) was injected 1h before surgery and continued daily to day 14 post-ligation. 42 °C water for thermal hyperalgesia, von Frey filaments for mechanical allodynia, acetone test for cool allodynia and 10 °C water for cold hyperalgesia were respectively used as pain behavioural tests. Behavioural tests were recorded before surgery and on postoperative days 1, 3, 5, 7, 10, 14 and the serum concentration of IL-6 was determined at the day 14.The results of this study showed a decrease in hyperalgesia and allodynia following nimesulide administration.It appears that nimesulide was able to reduce pain behaviour due to nerve inflammation and a parallel decrease in the serum IL-6 concentration was observed.The immune system is an important mediator in the cascade of events that ultimately results in hyperalgesia. Cytokines contribute to the patheogenesis of neuropathic pain, therefore drugs that inhibit cytokine release from immune cells may reduce inflammatory pain states.

Fabrication and capillary characterization of micro-grooved wicks with reentrant cavity array

Micro-grooved wicks with reentrant cavity array (MGRAs) were fabricated with orthogonal Ploughing/Extrusion method for the application in the ultra-thin aluminum vapor chambers. Capillary rise tests using both ethanol and acetone as the working fluid were conducted by a novel IR-thermal imaging method. The experimental results indicated that the MGRAs yielded larger capillary height than the micro-grooved wicks (MGs) and the MGRA-1 exhibited the highest capillary rise rate of all samples studied. In addition, the permeability was characterized in the force flow tests. It was found that the MGRAs obtained comparable permeability to that for the MGs, revealing that they were able to enhance the capillary rise with little penalty of pressure drop. With regard to the capillary limited heat flux, the capillary parameter K·ΔPcap was employed to evaluate the performance of the wicks comprehensively. The comparison of K·ΔPcap between the prediction with/without the gravitational effect showed that the Washburn’s Law greatly underestimated the K·ΔPcap after the initial stage, so the gravitational effect should be taken into account when comparing the samples. In this case, K·ΔPcap determined in the ethanol and acetone tests were similar. Besides, the MGRAs yielded higher K·ΔPcap than that for the MGs, except for the MGRA-3/MG-3 couple, justifying the prominent performance of the MGRAs. Despite the fact that the MGRA-2 failed to obtain the largest capillary height, it showed the largest K·ΔPcap among all MGRAs due to the good balance between the capillary pressure and permeability. Thus, it may be the optimum choice of all MGRAs in this study.

The Antinociceptive Effects of Tramadol and/or Gabapentin on Rat Neuropathic Pain Induced by a Chronic Constriction Injury.

Preclinical Research The current work evaluates the interaction between two commonly used drugs, tramadol (Tra) and gabapentin (Gbp). Dose-response curves (DRC) and isobolographic analysis were used to confirm their synergistic antihyperalgesic and anti-allodynic responses in a rat neuropathic pain model involving chronic constriction injury of the sciatic nerve and in von Frey and acetone tests. Tra and Gbp produced dose-dependent antihyperalgesic and anti-allodynic effects. Dose-response studies of combinations of Tra and Gbp in combination showed the DRC was leftward-shifted compared to the DRCs for each compound alone. One combination demonstrated both antihyperalgesic and anti-allodynic effects greater than those observed after individual administration. The remaining combinations demonstrated an additive effect. The Tra+Gbp combination demonstrated a potentiative effect with smaller doses of Tra. Additionally, it was determined lethal dose 50 (LD50 ) of Tra alone and tramadol + Gbp 10 using mice to 48 h post administration. The DRC (death) were similar for Tra alone and in Tra in combination, despite the improved effectiveness of Tra in the presence of GBP, 10 mg/kg. A combination of these drugs could be effective in neuropathic pain therapy because they can produce potentiative (at a low dose) or additive effects. Drug Dev Res 77 : 217-226, 2016. © 2016 Wiley Periodicals, Inc.

Effect of DSP4 and desipramine in the sensorial and affective component of neuropathic pain in rats

Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2weeks after injury by administering the antidepressant desipramine (10mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independently.

Antinociceptive Interactions Between Meloxicam and Gabapentin in Neuropathic Pain Depend on the Ratio used in Combination in Rats.

Preclinical Research Neuropathic pain is particularly difficult to treat because of its diverse etiologies and underlying pathophysiological mechanisms. Drug combinations have been proposed to effectively treat some neuropathies. In the present study the interaction of five combinations of meloxicam and gabapentin, were studied to assess the possible synergistic antinociceptive response in neuropathic pain using the von Frey and acetone tests in rat models. Coadministration of meloxicam and gabapentin increased the antihyperalgesic or antiallodynic effects as compared with the compounds administered alone. The area under the curve (AUC) of the antihyperalgesic effects produced by the combination of the two drugs was generally similar to the theoretical sum of effects produced by each drug alone. However, the AUC of the antiallodynic effect produced by one combination (meloxicam 1.0 mg/kg + gabapentin 10 mg/kg) was greater than the theoretical sum of the effects produced by each drug alone. The type of final interaction on the drug combinations can be additive or cause potentiation of antinociceptive effects and depends on the proportion of each compound used in dosing. Drug Dev Res 77 : 134-142, 2016. © 2016 Wiley Periodicals, Inc.

Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain

Ethnopharmacological relevanceProcessed aconite root (PA, the root of Aconitum carmichaeli, Ranunculaceae) is a crude drug used in traditional Chinese or Japanese kampo medicine to generate heat in the body and to treat pain associated with coldness. Oxaliplatin (L-OHP) is a platinum-based anticancer drug that frequently causes acute and chronic peripheral neuropathies, including cold and mechanical hyperalgesia. Aim of the studyWe investigated the effects of PA on L-OHP-induced peripheral neuropathies and identified the active ingredient within PA extract. Materials and methodsL-OHP was intraperitoneally injected into mice, and PA boiled water extract was orally administered. Cold and mechanical hyperalgesia were evaluated using the acetone test and the von Frey filament method, respectively. Dorsal root ganglion (DRG) neurons were isolated from normal mice and cultured with L-OHP with or without PA extract. Cell viability and neurite elongation were evaluated. ResultsPA extract significantly attenuated cold and mechanical hyperalgesia induced by L-OHP in mice. In cultured DRG neurons, L-OHP reduced cell viability and neurite elongation in a dose-dependent manner. Treatment with PA extract significantly alleviated the L-OHP-induced reduction of neurite elongation, while the cytotoxicity of L-OHP was not affected. Using activity-guided fractionation, we isolated neoline from PA extract as the active ingredient. Neoline significantly alleviated L-OHP-induced reduction of neurite elongation in cultured DRG neurons in a concentration-dependent manner. Moreover, subcutaneous injection of neoline attenuated cold and mechanical hyperalgesia in L-OHP-treated mice. PA extract and neoline did not show sedation and motor impairment. ConclusionsThe present study indicates that PA and its active ingredient neoline are promising agents to alleviate L-OHP-induced neuropathic pain.

Involvement of c-Myc-mediated transient receptor potential melastatin 8 expression in oxaliplatin-induced cold allodynia in mice.

Oxaliplatin, a platinum-based chemotherapeutic agent, induces acute cold allodynia and dysesthesia. Cold-sensitive transient receptor potential channels (TRPM8 and TRPA1) have been implicated as candidates to mediate oxaliplatin-induced cold allodynia and hyperalgesia, but precise roles of these channels remain unclear. In this study, we investigated the role of TRPM8 in oxaliplatin-induced cold allodynia. Oxaliplatin was injected intraperitoneally in mice. Cold allodynia was evaluated by the acetone test. Expression levels of TRPM8 mRNA and protein were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively. Oxaliplatin-induced cold allodynia was alleviated by the TRPM8 blockers N-(2-aminoethyl)-N-[4-(benzyloxy)-3-methoxybenzyl]-N'-(1S)-1-(phenyl) ethyl] urea and TC-I 2014. Oxaliplatin increased the expression levels of TRPM8 mRNA and protein in the dorsal root ganglia and plantar skin, respectively. Prophylactic administration of the c-Myc inhibitor 10058-F4 prevented cold allodynia and the increase of TRPM8 mRNA after oxaliplatin injection. These results suggest that oxaliplatin induces cold allodynia through the increase of c-Myc-mediated TRPM8 expression in primary sensory neurons.

Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: An evidence of behavioral and biochemical examination

The present study was designed to investigate the effect of ferulic acid (FA) in vincristine-induced neuropathic pain in rats. Vincristine (50 µg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy in rats. Various pain sensitive tests, viz., pinprick, hot plate, paint-brush, and acetone test were performed on different days (1, 6, 14, and 21) to assess the degree of mechanical hyperalgesia, heat hyperalgesia, mechanical dynamic allodynia, and cold allodynia, respectively. The electrophysiological and histopathological evaluations were also investigated. The tissue thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and total calcium were measured as the markers of inflammation and oxidative stress. FA (50 and 100 mg/kg, i.p.) and gabapentin (10 mg/kg, p.o.) were administered for 11 days. Administration of FA attenuated the vincristine-induced behavioral alteration along with electrophysiological and histopathological changes significantly (P < 0.05). FA also attenuated the vincristine-induced oxidative stress (TBARS, GSH, and total calcium levels) and inflammation (MPO, TNF-alpha, IL-6, and IL-10). It may be concluded that FA has ameliorative potential in mitigation of the painful states associated with vincristine-induced painful neuropathy that may further be attributed to anti-inflammatory actions with subsequent reduction in oxidative stress.

Effects of glia metabolism inhibition on nociceptive behavioral testing in rats.

Fluoroacetate has been widely used to inhibit glia metabolism in vivo. It has yet to be shown what the effects of chronic intrathecal infusion of fluoroacetate on nociceptive behavioral testing are. The effects of chronic infusion of fluoroacetate (5 nmoles/h) for 2 weeks were examined in normal rats. Chronic intrathecal fluoroacetate did not alter mechanical threshold (von Frey filaments), responses to supra-threshold mechanical stimuli (von Frey filaments), responses to hot (hot plate) or cool (acetone test) stimuli and did not affect motor performance of the animals, which was tested with rotarod. This suggests that fluoroacetate at appropriate dose did not suppress neuronal activity in the spinal cord.