Nociceptive Threshold Research Articles

Rolipram and pentoxifylline combination ameliorates the morphological abnormalities of dorsal root ganglion neurons in experimental diabetic neuropathy by reducing mitochondrial dysfunction and apoptosis.

Diabetic neuropathy (DN) is the most prevalent complication of diabetes. Pharmacological treatments for DN are often limited in efficacy, so the development of new agents to alleviate DN is essential. The aim of this study was to evaluate the effects of rolipram, a selective phosphodiesterase-4 inhibitor(PDE-4I), and pentoxifylline, a general PDE inhibitor, using a rat model of DN. In this study, a diabetic rat model was established by i.p. injection of STZ (55 mg/kg). Rats were treated with rolipram (1 mg/kg), pentoxifylline (100 mg/kg), and combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for 5 weeks. After treatments, sensory function was assessed by hot plate test. Then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP, adenosine diphosphate and mitochondrial membrane potential (MMP) levels, Cytochrome c release, Bax, Bcl-2, caspase-3 proteins expression in DRG neurons were assessed by biochemical and ELISA methods, and western blot analysis. DRG neurons were histologically examined using hematoxylin and eosin (H&E) staining method. Rolipram and/or pentoxifylline significantly attenuated sensory dysfunction by modulating nociceptive threshold. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, prevented mitochondrial dysfunction, apoptosis and degeneration of DRG neurons, which appears to be mediated by inducing ATP and MMP, improving cytochrome c release, as well as regulating the expression of Bax, Bcl-2, and caspase-3 proteins, and improving morphological abnormalities of DRG neurons. We found maximum effectiveness with rolipram and pentoxifylline combination on mentioned factors. These findings encourage the use of rolipram and pentoxifylline combination as a novel experimental evidence for further clinical investigations in the treatment of DN.

A Cre Driver Line for Genetic Targeting of Kappa Opioid Receptor Expressing Cells.

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3'UTR of the κ opioid receptor gene (Oprk1) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also attenuated KOR agonist-induced conditioned place aversion (CPA) in male Oprk1-Cre mice. Overall, these results suggest a potential role for BLAKOR cells in regulating anxiety-like behaviors and KOR-agonist mediated CPA. In summary, these results provide evidence for the utility of the newly generated Oprk1-Cre mice in assessing localization, anatomy, and function of KOR circuits throughout the brain.

Effects of S-ketamine on Postoperative Recovery Quality and Inflammatory Response in Patients Undergoing Modified Radical Mastectomy.

S-ketamine plays an important role in reducing postoperative pain, but its impact on the quality of recovery in breast cancer has not been clarified. We designed this trial to explore the effects of s-ketamine on the quality of postoperative recovery and inflammatory response in modified radical mastectomy. A total of 138 patients were randomly assigned to group C (group control), group K1 (group of s-ketamine dose 1) and group K2 (group of s-ketamine dose 2). Groups K1 and K2 were given 0.1mg/kg, 0.2mg/kg s-ketamine intravenous (IV) after induction, followed by 0.1mg/kg/h or 0.2mg/kg/h continuous intravenous infusion, respectively. Group C received the same volume of saline. A 40-item Quality of Recovery Questionnaire (QoR-40) was used to assess the quality of recovery at 24h postoperatively. Changes in inflammatory markers, nociceptive thresholds, and the occurrence of adverse events were recorded at 24h postoperatively. The QoR-40 scores at 24h postoperatively were higher in group K2 [182.00 (179.00-185.00)] compared to group K1 [174.00 (169.50-180.50)] and group C [169.00 (163.75-174.25)] (group K2 vs. group K1, P < 0.001; group K2 vs. group C, P < 0.001). At 24h postoperatively, the neutrophil count, NLR (neutrophil-lymphocyte ratio), and CRP (C-creative protein) were all significantly lower in group K2 than group C(P < 0.05), no differences were observed between group K1 and C(P > 0.05), group K1 and K2(P > 0.05), respectively. There was no significant difference in the incidence of adverse effects among the three groups (P > 0.05). A high dose of s-ketamine improved the quality of recovery at 24h after surgery, as well as alleviated the inflammatory response without increasing the incidence of adverse effects.

The Effectiveness of Liposome-Encapsulated Bupivacaine Compared to Standard Bupivacaine for Anesthesia of the Maxilla in Dogs.

Medical and surgical procedures involving the canine maxilla can be painful both during and for several hours post-procedure. The length of this pain may exceed the predicted duration of standard bupivacaine or lidocaine. The goal of this study was to determine the duration and efficacy of sensory blockade of the maxilla produced by liposome-encapsulated bupivacaine (LB), compared to standard bupivacaine (B) or saline (0.9% NaCl) (S), when administered as a modified maxillary nerve block in dogs. Eight maxillae were studied bilaterally from 4 healthy dogs of the same breed and similar age. This prospective, randomized, crossover, blinded study evaluated a modified maxillary nerve block using 1.3% LB at 0.1 mL/kg, 0.5% B, or S at an equivalent volume. An electronic von Frey aesthesiometer (VFA) was used to evaluate mechanical nociceptive thresholds at 4 locations on each hemimaxilla at baseline and at specific intervals up to 72-h post-treatment. Both B and LB treatments resulted in significantly higher VFA thresholds when compared to S. Dogs that received B had VFA thresholds significantly higher than S for 5 to 6 h. Dogs that received LB had thresholds significantly higher than S for 6 to 12 h depending on the site of measurement. No complications were observed. Maxillary nerve block with B provided up to 6 h, and LB 12 h, of sensory blockade depending on the site tested.

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. MethodsAutistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. ConclusionsIbudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

Exercise Improves Orofacial Pain and Modifies Neuropeptide Expression in a Rat Model of Parkinson's Disease.

Pain is a common non-motor symptom of Parkinson's disease (PD), which often occurs in the early disease stages. Despite the high prevalence, it remains inadequately treated. In a hemi-parkinsonian rat model, we aimed to investigate the neurochemical factors involved in orofacial pain development, with a specific focus on pain-related peptides and cannabinoid receptors. We also evaluated whether treadmill exercise could improve orofacial pain and modulate these mechanisms. Rats were unilaterally injected in the striatum with either 6-hydroxydopamine (6-OHDA) or saline. Fifteen days after stereotactic surgery, the animals were submitted to treadmill exercise (EX), or remained sedentary (SED). Pain assessment was performed before the surgical procedure and prior to each training session. Pain-related peptides, substance P (SP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid type 1 (TRPV1) activation and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated in the trigeminal nucleus. In order to confirm the possible involvement of cannabinoid receptors, we also injected antagonists of CB1 and CB2 receptors. We confirmed the presence of orofacial pain after unilateral 6-OHDA-injection, which improved after aerobic exercise training. We also observed increased pain-related expression of SP, CGRP and TRPV1 and decreased CB1 and CB2 in the trigeminal ganglion and caudal spinal trigeminal nucleus in animals with PD, which was reversed after aerobic exercise training. In addition, we confirm the involvement of cannabinoid receptors since both antagonists decreased the nociceptive threshold of PD animals. These data suggest that aerobic exercise effectively improved the orofacial pain associated with the PD model, and may be mediated by pain-related neuropeptides and cannabinoid receptors in the trigeminal system.

Treadmill exercise modulates nigral and hippocampal cannabinoid receptor type 1 in the 6-OHDA model of Parkinson’s disease

Physical exercise benefits Parkinson’s disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and animal models. We test the hypothesis that binding of the CB1R inverse agonist, [3H]SR141716A, is normalized by treadmill exercise in the toxin-induced 6-hydroxydopamine (6-OHDA) model of PD. Male rats had unilateral striatal injections of 6-OHDA or saline. After 15 days, half were submitted to treadmill exercise and half remained sedentary. [3H]SR141716A autoradiography was performed in postmortem tissue from striatum, substantia nigra (SN) and hippocampus. There was a 41% decrease of [3H]SR141716A specific binding in the ipsilateral SN of 6-OHDA-injected sedentary animals which was attenuated to 15% by exercise, when compared to saline-injected animals. No striatal differences were observed. A 30% bilateral hippocampal increase was observed in both healthy and 6-OHDA exercised groups. In addition, a positive correlation between nigral [3H]SR141716A binding and nociceptive threshold was observed in PD-exercised animals (p = 0.0008), suggesting a beneficial effect of exercise in the pain associated with the model. Chronic exercise can reduce the detrimental effects of PD on nigral [3H]SR141716A binding, similar to the reported reduction after dopamine replacement therapy, so should be considered as an adjunct therapy for PD.

Wound healing and pain sensitivity following caustic paste disbudding in dairy calves

Caustic paste disbudding is increasing in popularity on commercial dairy farms in the US, but little research has explored the pain and welfare implications beyond the acute period of this procedure. Researchers have reported it takes 7 to 9 wk, on average, for hot-iron disbudding wounds to re-epithelialize in dairy calves. Our objective was to describe wound healing and sensitivity following caustic paste disbudding. Jersey and Holstein female calves were disbudded using Dr. Naylor's caustic paste at 3 d of age (n = 18) while control calves received a sham procedure (n = 15). Before disbudding, calves received a local block and an NSAID. Calves ≥34 kg and <34 kg at birth had 0.3 or 0.25 mL of paste applied per unshaved horn bud, respectively. Following disbudding, wounds were scored 2x/wk for the presence/absence of 8 tissue categories including the final stages: new epithelium and fully healed. Control calves were removed from the experiment after 6 wk to be hot-iron disbudded and avoid more invasive procedures. Mechanical nociceptive threshold (MNT) measures were collected weekly to evaluate wound sensitivity until calves were removed from the study or wounds were healed. Wounds were slow to re-epithelialize (16.2 ± 5.7 wk, mean ± SD; range: 6.2-32.5 wk) and contract to be considered fully healed (18.8 ± 6 wk, mean ± SD; range: 8.7-34.1 wk). Compared with non-disbudded controls, paste calves exhibited lower MNT values for all 6 wk (mean ± SE, Control:1.46 ± 0.16; Paste:1.18 ± 0.12 N). These data indicate that wounds from caustic paste disbudding are more sensitive than undamaged tissue for at least 6 wk and take twice as long to heal compared with cautery methods described in the literature. In conclusion, caustic paste disbudding wounds took 18.8 wk to fully heal and were more sensitive than intact horn buds for 6 wk. Future work should examine if aspects of paste application (e.g., amount, time rubbed in, age, pain mitigation), could improve healing time and sensitivity.

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.

Validation of Standing and Locomotion Scoring, Behavioral Assessments, and Mechanical Nociceptive Threshold Testing on Naturally Occurring Sow Lameness.

The objective of this study was to validate standing and locomotion lameness scoring, mechanical nociceptive threshold testing, and behavioral profile tools for the diagnosis of naturally occurring lameness etiologies in pigs. A total of 55 crossbred gilts and sows obtained from a commercial farm were enrolled in the study; with sound pigs classified as controls (8) and the remainder as lame due to integumentary (20), musculoskeletal (15), and combinations of integumentary and musculoskeletal (12) etiologies. Standing and locomotion lameness, mechanical nociceptive threshold (MNT) test, pig-human interventions, and latency to complete an obstacle course were evaluated. Standing and locomotion lameness scoring systems, MNT, and pig behavior (latency) were capable of discriminating between animals with mild organic lameness and animals that were sound and may have utility on the farm for staff to use to identify and manage lame animals. In rare instances, the tools used here were able to discriminate between broad categories of lameness etiology.

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.

Insulin-like Growth Factor-1 (IGF-1) Related Drugs in Pain Management.

Objective. The aim of this review is to explore the role of IGF-1 and IGF-1R inhibitors in pain-related conditions and assess the effectiveness of IGF-1-related drugs in pain management. Specifically, this paper investigates the potential involvement of IGF-1 in nociception, nerve regeneration, and the development of neuropathic pain. Methods. We conducted a search of the PUBMED/MEDLINE database, Scopus, and the Cochrane Library for all reports published in English on IGF-1 in pain management from origination through November 2022. The resulting 545 articles were screened, and 18 articles were found to be relevant after reading abstracts. After further examination of the full text of these articles, ten were included in the analysis and discussion. The levels of clinical evidence and implications for recommendations of all the included human studies were graded. Results. The search yielded 545 articles, of which 316 articles were deemed irrelevant by reading the titles. There were 18 articles deemed relevant after reading abstracts, of which 8 of the reports were excluded due to lack of IGF-1-related drug treatment after reviewing the full text of the articles. All ten articles were retrieved for analysis and discussion. We found that IGF-1 may have several positive effects on pain management, including promoting the resolution of hyperalgesia, preventing chemotherapy-induced neuropathy, reversing neuronal hyperactivity, and elevating the nociceptive threshold. On the other hand, IGF-1R inhibitors may alleviate pain in mice with injury of the sciatic nerve, bone cancer pain, and endometriosis-induced hyperalgesia. While one study showed marked improvement in thyroid-associated ophthalmopathy in humans treated with IGF-1R inhibitor, two other studies did not find any benefits from IGF-1 treatment. Conclusions. This review highlights the potential of IGF-1 and IGF-1R inhibitors in pain management, but further research is needed to fully understand their efficacy and potential side effects.

On determining the mechanical nociceptive threshold in pigs: a reliability study.

A pressure algometer is a valuable tool for assessing the mechanical nociceptive threshold (MNT) in clinical pain studies. Recent research has turned to large animal models of pain because of the closer anatomy and physiology to humans. Although the reliability and usefulness of the MNT have been extensively validated in humans, similar data from large animals is still sparse. Therefore, the aim of the current study was to evaluate the reliability (within- and between-session) of MNT in the forelimb of pigs using a pressure algometer. Nine animals were used (23-40 kg), and MNTs were measured at both the right and left limbs at three different sessions, with three repetitions per session. The intraclass correlation coefficient (ICC) was used as a metric for relative reliability. The standard error of measurement (SEM) and coefficient of variation (CV) was used to assess absolute reliability. Systematic bias was also evaluated. The average ICC was found to be 0.71 and 0.45 for the between-session and within-session, respectively. CV ranged from 17.9% to 20.5%, with a grand average of 19.1%. The grand average SEM was 249.5 kPa (16.6%). No systematic differences were found for the MNT between sessions, which suggests that there was no habituation to the stimulus. The reliability indices obtained in this study are comparable to results obtained in other species or anatomical regions and substantiate the use of the pressure algometer as a valuable tool to investigate the nociceptive system in pigs and translation to the human nociceptive withdrawal reflex.

Medial septum glutamatergic neurons modulate nociception in chronic neuropathic pain via projections to lateral hypothalamus.

The medial septum (MS) contributes in pain processing and regulation, especially concerning persistent nociception. However, the role of MS glutamatergic neurons in pain and the underlying neural circuit mechanisms in pain remain poorly understood. In this study, chronic constrictive injury of the sciatic nerve (CCI) surgery was performed to induce thermal and mechanical hyperalgesia in mice. The chemogenetic activation of MS glutamatergic neurons decreased pain thresholds in naïve mice. In contrast, inhibition or ablation of these neurons has improved nociception thresholds in naïve mice and relieved thermal and mechanical hyperalgesia in CCI mice. Anterograde viral tracing revealed that MS glutamatergic neurons had projections to the lateral hypothalamus (LH) and supramammillary nucleus (SuM). We further demonstrated that MS glutamatergic neurons regulate pain thresholds by projecting to LH but not SuM, because the inhibition of MS-LH glutamatergic projections suppressed pain thresholds in CCI and naïve mice, yet, optogenetic activation or inhibition of MS-SuM glutamatergic projections had no effect on pain thresholds in naïve mice. In conclusion, our results reveal that MS glutamatergic neurons play a significant role in regulating pain perception and decipher that MS glutamatergic neurons modulate nociception via projections to LH.

Cannabidiol reduces LPS-induced nociception via endocannabinoid system activation.

Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious etiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS-induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD-induced endocannabinoids upregulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.

Evaluation of the Analgesic Efficacy of Undiluted Intraperitoneal and Incisional Ropivacaine for Postoperative Analgesia in Dogs after Major Abdominal Surgery.

Recommendations for intraperitoneal (IP) and incisional (INC) administration of local anaesthetics after visceral surgery exist, but evidence is scarce. This prospective, randomized, blinded, controlled, clinical trial compared postoperative pain in dogs undergoing major abdominal surgery. Sixteen client-owned dogs were anaesthetized with a standardized balanced protocol including opioids and received either 2 mg/kg ropivacaine IP (0.27 mL/kg) and a 1 mg/kg INC splash (0.13 mL/kg) or equal volumes of saline. Influence of the treatment on heart rate (HR) and postoperative pain was assessed using the Short Form of the Glasgow Composite Pain Scale (GCPS-SF), a dynamic interactive visual analogue scale (DIVAS) and mechanical nociceptive threshold testing (MNT). Data was tested with mixed ordinal regression and log linear mixed models for 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h after extubation. Rescue analgesia was given to 3/8 dogs after ropivacaine and 0/8 dogs after saline. GCPS-SF and MNT were not different between groups. DIVAS was slightly higher after ropivacaine (odds increased by 5.44 (confidence interval (CI) 1.17-9.96, p = 0.012)), and HR after ropivacaine was 0.76 * that after saline (CI 0.61-0.96, p = 0.02) with no effect of time (p = 0.1). Undiluted ropivacaine IP and INC was not beneficial for postoperative analgesia.

Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague-Dawley rats (200-250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca 2+ ] i in dorsal root ganglia (DRG) neurons ex vivo . Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.

Effect of kinesio-taping on the acute phase of the post-operative reconstruction of the anterior cruciate ligament: A randomized controlled trial

ObjectivesEvaluate the Kinesio taping (KT) effects on reducing pain and edema on postoperative (PO) after anterior cruciate ligament (ACL) reconstruction. DesignControlled and randomized clinical study. SettingsIndividuals of both sexes, aged 18–45, underwent ACL reconstruction were randomized into intervention (IG; n = 19) and control (CG; n = 19) groups. MethodsIntervention consisted of KT bandage applications at hospital discharge for seven days, and on the 7th PO day, which was removed on the 14th PO. CG received specific instructions from the physiotherapy service. All volunteers were evaluations before and immediately after surgery, on the 7th and 14th PO day. Pain threshold (KgF), evaluated by algometer; edema (cm), evaluated by the perimetry measurements and volume of the lower limbs and the truncated cone test (ml) were the evaluated variables. The Student's t-test and Mann-Whitney U test were used to evaluate intergroup, analysis of variance (ANOVA) and Dunnett's test to evaluate intragroup. ResultsEdema reduction and increased nociceptive threshold were significant in the 7th (p < 0.001; p = 0.003) and 14th (p < 0.001; p = 0.006) PO day in IG when compared to CG patients. IG perimetry levels, on the 7th and 14th PO were similar to preoperative period (p = 0.229; p = 1.000). IG nociceptive threshold value was similar on the 14th PO to before the surgery (p = 0.987). The same pattern did not occur in CG. ConclusionKT treatment reduced edema and increased nociceptive threshold in the 7th and 14th PO ACL reconstruction.

Determination of minimum infusion rate of propofol in combination with electroacupuncture in goats

Total intravenous anesthesia (TIVA) is frequently used anesthetic protocol in animals when inhalation anesthesia is not available. To date, it has not yet been known whether electroacupuncture (EA) can affect propofol-based TIVA in goats. Therefore, the present paper aims to determine the minimum infusion rate (MIR) of propofol, in combination with EA, required to preclude purposeful movement of the extremities in response to standardized noxious stimulation in goats. Twelve clinically healthy goats weighing 17.45 ± 2.15 kg were randomly allocated into two groups with six goats each. Propofol alone (P group) and propofol combined with EA (EA-P group). In the EA-P, propofol was given 30 min after EA stimulation. For induction of anesthesia, a bolus of propofol was administered at 4 mg/kg IV, and an infusion dose of 0.4 mg/kg/min was initially set for maintenance. The MIR of propofol in both groups was determined by testing for responses to stimulation (clamping on a digit with Vulsellum forceps) at 10-min intervals after inducing anesthesia until the end period of the experiment. Cardiorespiratory variables and nociceptive threshold were measured throughout anesthesia. The median propofol MIR was significantly lower in the EA-P group than the P group [0.520 (0.467–0.572) and 0.650 (0.600–0.677)], respectively; p = 0.0013). In the P group, goats anesthetized with MIR showed a significant increase in heart rate and cardiac index (p = 0.0010 and p < 0.0001, respectively), and a decrease in respiratory rate (p = 0.0001). Additionally, the EA-P showed a significant decrease in hemoglobin oxygen saturation following the initial infusion rate at 2 min (p = 0.0023) and 10 min (p = 0.0007) as compared to the P group. A significant increase in nociceptive threshold was recorded in the EA-P threshold than that of the P group (p < 0.005). EA combined with propofol provides antinociception, decreases the MIR of propofol-based TIVA, and subsequently lessens the negative cardiorespiratory consequences related to propofol anesthesia in goats.

Life experiences of boars can shape the survival, aggression, and nociception responses of their offspring

IntroductionBoars are often housed in stressful environments on commercial farms, experiencing poor welfare. These conditions may cause epigenetic changes in the boars' gametes, which could potentially be transmitted to their offspring. We aimed to investigate the effect of three different boars housing environments on the survival, aggression, and nociceptive responses of their offspring.MethodsFor four weeks, 18 boars were housed in three different systems: crates (C;n=6), pens (P;n=6), and enriched pens (E;n=6). The environmental enrichment was provided twice daily (brushing, shower, and hay). Thirteen gilts were housed in outdoor paddocks and inseminated with pooled semen from the boars kept in the three treatments. We evaluated the number of live-born, stillborn, and weaned piglets, sex, and mortality rate. Weaning was performed at 29 days of age. For each piglet, six body photographs were taken for five days postweaning to measure skin lesions (n=138). On Day 34, the nociceptive pressure threshold was assessed using an analgesimeter (n=138). DNA paternity tests were carried out at the end of the study (n=181). A generalized linear model with a negative binomial distribution was used to compare the number of live-born/weaned piglets and skin lesions among the treatment groups. We used a Kruskal‒Wallis test to analyze nociceptive data.ResultsMore live-born and weaned piglets were fathered from boars kept in the E group than the P group (p=0.002;p=0.001, respectively). A trend was observed in the number of skin lesions on the left side of piglets (P&amp;lt;C;p=0.053). For nociceptive assessments, offspring from P boars showed less right leg withdrawal than piglets from E and C boars (p=0.008); the P group had a higher average nociceptive value than the C group (p=0.002). All treatments differed in the region adjacent to the tail for nociceptive pressure threshold (P&amp;gt;E&amp;gt;C;p&amp;lt;0.001).Discussion and conclusionOur results suggest that providing an enriched environment for boars can increase the number of live-born and weaned piglets. Moreover, the boars housing conditions can influence nociceptive threshold in their offspring. Further research must be performed to understand the underlying mechanism associated with these changes using epigenetics protocols and measuring physiological indicators and other molecular markers in semen and/or sperm cell samples.