Mechanical Nociceptive Thresholds Research Articles

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.

Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.

Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation

BackgroundMigraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated.MethodsWe established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1β, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C.ResultsAt the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2.ConclusionsOur data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.Graphical

Transcranial direct current stimulation is more effective than pregabalin in controlling nociceptive and anxiety-like behaviors in a rat fibromyalgia-like model.

Despite the fact that fibromyalgia, a widespread disease of the musculoskeletal system, has no specific treatment, patients have shown improvement after pharmacological intervention. Pregabalin has demonstrated efficacy; however, its adverse effects may reduce treatment adherence. In this context, neuromodulatory techniques such as transcranial direct current stimulation (tDCS) may be employed as a complementary pain-relieving method. Consequently, the purpose of this study was to evaluate the effect of pregabalin and tDCS treatments on the behavioral and biomarker parameters of rats submitted to a fibromyalgia-like model. Forty adult male Wistar rats were divided into two groups: control and reserpine. Five days after the end of the administration of reserpine (1 mg/kg/3 days) to induce a fibromyalgia-like model, rats were randomly assigned to receive either vehicle or pregabalin (30 mg/kg) along with sham or active- tDCS treatments. The evaluated behavioral parameters included mechanical allodynia by von Frey test and anxiety-like behaviors by elevated plus-maze test (time spent in opened and closed arms, number of entries in opened and closed arms, protected head-dipping, unprotected head-dipping [NPHD], grooming, rearing, fecal boluses). The biomarker analysis (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF-α]) was performed in brainstem and cerebral cortex and in serum. tDCS reversed the reduction in the mechanical nociceptive threshold and the decrease in the serum BDNF levels induced by the model of fibromyalgia; however, there was no effect of pregabalin in the mechanical threshold. There were no effects of pregabalin or tDCS found in TNF-α levels. The pain model induced an increase in grooming time and a decrease in NPHD and rearing; while tDCS reversed the increase in grooming, pregabalin reversed the decrease in NPHD. tDCS was more effective than pregabalin in controlling nociception and anxiety-like behavior in a rat model-like fibromyalgia. Considering the translational aspect, our findings suggest that tDCS could be a potential non-pharmacological treatment for fibromyalgia.

Effects of Meloxicam on the Welfare of Holstein Calves from 6 Weeks to 6 Months Old Undergoing Amputation Dehorning

Amputation dehorning (AD) is a common practice performed on calves, causing harmful effects such as pain, distress, anxiety, and fear. These effects extend to behavioral, physiological, and hematological responses, prompting serious ethical concerns regarding animal welfare, even when performed with local anesthesia. Meloxicam, a non-steroidal anti-inflammatory drug, has been widely used to mitigate the side effects of dehorning and disbudding in calves. However, there is a notable gap in research regarding the effects of meloxicam on calves aged 6 weeks to 6 mo undergoing AD procedures. This study was designed to assess the effectiveness of co-administering meloxicam with lidocaine, a cornual nerve anesthetic, in alleviating the adverse effects caused by the AD procedure in calves within this age range, compared with the use of lidocaine alone. Thirty Holstein calves were enrolled and randomly divided into 2 groups. The first group (Placebo) received a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 0.9% saline at a dose of 0.025 mL/kg in the neck, administered 10 min before the AD procedure. The second group (MX) received a combination of lidocaine and meloxicam: a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 20 mg/mL meloxicam at a dose of 0.025 mL/kg in the neck, also administered 10 min before the AD procedure. To avoid subjective bias, the researchers were blinded to the treatment groups. Pain-related behaviors, including tail flicking, head shaking, ear flicking, head rubbing, head crossing bar, and kicking, were observed, and physiological parameters, including heart rate, rectal temperature, respiration rate, mechanical nociceptive threshold (MNT), daily active steps, and food intake were monitored. Hematological conditions were determined using enzyme-linked immunosorbent assays and routine blood tests. The data were processed using a generalized linear mixed model (GLMM). The outcomes demonstrated that the AD procedure increased the frequencies of ear flicking and resulted in rises in the respiration rate, heart rate, rectal temperature, and daily active steps. It also led to decreases in total food intake, forage intake, hay intake, MNT, and increased concentrations of prostaglandin E2 (PgE2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide (NO), and malondialdehyde, as well as glutathione peroxidase activity. However, calves that received meloxicam treatment showed significant improvements in response to the AD procedure, including lower respiration rates, heart rates, and rectal temperatures; higher MNTs; and lower intermediate cell ratio. They also had higher red blood counts, hemoglobin levels, hematocrit values; larger mean platelet volumes; and lower concentrations of PgE2, IL-1β, TNF-α, and NO. These results suggest that co-administration of lidocaine and meloxicam may aid in mitigating the adverse impacts induced by the AD procedure on these calves, thereby supporting the use of meloxicam in conjunction with a local anesthetic in AD procedures for calves aged 6 weeks to 6 mo.

Clinical evaluation of the sedative, antinociceptive and cardiorespiratory effects of intranasal dexmedetomidine combined with methadone in healthy dogs

In this prospective, randomised, blinded clinical study, we compared the sedative, antinociceptive and cardiorespiratory effects of intranasal (IN) dexmedetomidine at 5 μg/kg (diluted with 0.03 mL/kg NaCl 0.9%, DEX) with or without methadone (0.3 mg/kg; DEXMET), through a mucosal atomization device to one nostril in twenty healthy client-owned dogs. At 5-min intervals over 45 min, sedation score, onset, cardiopulmonary variables, mechanical nociceptive thresholds (MNTs) were assessed, also ease of administration, adverse effects, and response to IV catheterization. Statistical analysis employed t-test, the Mann-Whitney U, repeated measures ANOVA and Chi-square tests as appropriate (P < 0.05).Higher sedation ocurred in DEXMET (7 [5–10]) compared to DEX (5 [2–7]) from 15 to 30 min (P < 0.01, median [interquartile range]). Heart rate was lower in DEXMET (P < 0.01; 65% reduction vs. 41% in DEX, P = 0.001). The MNTs were higher in DEXMET than DEX from 15 to 45 min (P < 0.01), peaking at T30 (17.1 ± 3.8, DEXMET and 8.5 ± 5.4 N, DEX). No differences were observed in mean arterial blood pressure and respiratory rate. Intranasal administration was considered easy for 8 dogs per group. Reverse sneezing (8 dogs; P < 0.001), sialorrhea and retching (4 and 2 dogs, respectively) occurred in DEXMET. Response to catheterisation was lower in DEXMET than DEX (P = 0.039; 2 and 7 dogs, respectively). In conclusion, intranasal methadone (0.3 mg/kg) increased the sedative and antinociceptive effects produced by dexmedetomidine (5 μg/kg) in healthy dogs and resulted in lower heart rate.

Biocompatibility of hydrogel derived from equine tendon extracellular matrix in horses subcutaneous tissue.

Tendinopathies account for a substantial proportion of musculoskeletal injuries. To improve treatment outcomes for partial and total tendon ruptures, new therapies are under investigation. These include the application of mesenchymal stem cells (MSCs) and biocompatible scaffolds derived from the Extracellular Matrix (ECM). Synthetic polymer hydrogels have not demonstrated results as promising as those achieved with ECM hydrogels sourced from the original tissue. This study aimed to evaluate the biocompatibility of a hydrogel formulated from equine tendon ECM. Six horses were administered three subcutaneous doses of the hydrogel, with a saline solution serving as a control. Biopsies were conducted on days 7, 14, and 56 post-application to gauge the hydrogel's impact. Throughout the experiment, the horse's physical condition remained stable. Thermographic analyses revealed a temperature increase in the treated groups compared to the control group within the initial 12h. The von Frey test, used to measure the mechanical nociceptive threshold, also showed significant differences between the treated group and the control group at 6h, 21 days, and 28 days. Histopathological analyses identified an inflammatory response on day 7, which was absent on days 14 and 56. Transmission electron microscopy indicated a decrease in inflammatory cellularity, while immunohistochemistry staining suggested an increased presence of inflammatory factors on day 14. In summary, the hydrogel is easily injectable, triggers a temporary local inflammatory response, and integrates into the adjacent tissue from day 14 onwards.

Effects of elastic therapeutic tape on thoracolumbar epaxial muscle pain in horses

ObjectivesTo evaluate the ability of elastic therapeutic tape to modulate nociception in horses with naturally occurring thoracolumbar epaxial muscle pain. AnimalsTwenty-two horses with naturally occurring thoracolumbar epaxial muscle pain. ProceduresA randomized crossover design study was used to evaluate the efficacy of elastic therapeutic tape compared to control tape application to modulate pain in the thoracolumbar region. Mechanical nociceptive thresholds (MNT) were assessed using a pressure algometer immediately prior to and following tape removal and sequentially at 24 and 48 h after tape removal. ResultsMechanical nociceptive threshold values were significantly (P < 2e-16) different following both elastic therapeutic tape and control tape application at all sites across all time points compared to baseline values. The percent difference in MNT values for the elastic therapeutic tape application ranged from a 15–26 % difference from baseline across the time points at all sites. The percentage difference in MNT values for the control tape application ranged from (-)4–8 % from baseline across the time points at all sites. Clinical relevanceThe outcomes of this study demonstrate that the application of an elastic therapeutic tape at 30 % tension significantly modulates thoracolumbar pain in horses.

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.

Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats

IntroductionWithin the realm of chemogenetics, a particular form of agonists targeting designer receptors exclusively activated by designer drugs (DREADDs) has emerged. Deschloroclozapine (DCZ), a recently introduced DREADDs agonist, demonstrates remarkable potency in activating targeted neurons at a lower dosage compared to clozapine-N-oxide (CNO).MethodsWe conducted a comparative analysis of the effects of subcutaneously administered CNO (1 mg/kg) and DCZ (0.1 mg/kg) in our transgenic rats expressing hM3Dq and mCherry exclusively in oxytocin (OXT) neurons.Results and DiscussionNotably, DCZ exhibited a swift and robust elevation of serum OXT, surpassing the effects of CNO, with a significant increase in the area under the curve (AUC) up to 3 hours post-administration. Comprehensive assessment of brain neuronal activity, using Fos as an indicator, revealed comparable effects between CNO and DCZ. Additionally, in a neuropathic pain model, both CNO and DCZ increased the mechanical nociceptive and thermal thresholds; however, the DCZ-treated group exhibited a significantly accelerated onset of the effects, aligning harmoniously with the observed alterations in serum OXT concentration following DCZ administration. These findings emphasize the remarkable efficacy of DCZ in rats, suggesting its equivalent or potentially superior performance to CNO at considerably lower dosages, thus positioning it as a promising contender among DREADDs agonists.

Dose effect and duration of action of liposomal bupivacaine administered as a perineural analgesic in a reversible and adjustable frog-pressure model of equine lameness.

To determine the dose effect of peri-neural liposomal bupivacaine (LB) in an induced forelimb lameness model. 12 clinically normal adult horses. A randomized cross-over design was performed with 1 limb receiving saline and the other LB: low dose (6), high dose (6). Lameness was induced in 1 forelimb using a frog-pressure model. In the lame limb, peri-neural injection of the palmar nerves at the proximal sesamoid bones was performed using saline, low dose LB (0.25 mg/kg) (LDLB), or high dose LB (0.5mg/kg) (HDLB) in random order with a 1-week washout period between treatments. Distal limb swelling, mechanical nociceptive thresholds (MNT), and objective lameness data were collected before and up to 72 hours after peri-neural anesthesia. Data analysis was performed with mixed model ANOVA, equality of medians test, and Kaplan Meier survival analysis. Compared with baseline, horses treated with LDLB and HDLB had improvements in MNT and lameness (P < .001). In the LDLB group, the median duration of analgesia was 4.5 hours (range = 3-6 hours) and the median return to lameness was 7 hours (range = 4-24 hours). In the HDLB group, the median duration of analgesia was 12 hours (range = 4-48 hours) and the median return to lameness was 9 hours (range = 3-48 hours). Mild to moderate swelling was identified in 11/12 (92%) LB limbs. Both LDLB and HDLB resulted in loss of skin sensation and improvement of lameness. There was high variability among horses in duration of action for both doses.

Effects of two different topographic approaches for combined sciatic and femoral nerve block in calves, guided by ultrasound and neurostimulation

To evaluate the sensory and motor effects promoted by a combined sciatic and femoral nerve block in calves using two approaches. Six calves were used, in a crossover study. Ultrasound combined with neurostimulation, was used to perform the following block combinations: the proximal approach (PA), which consisted of the association of the parasacral approach (sciatic nerve block) and ventral to the ilium approach (femoral nerve block); distal approach (DA) consisted of the association of a lateral approach to the pelvic limb approach (sciatic nerve block), and an inguinal approach, underneath the femoral trigone (femoral nerve block). Pressure algometry and motor function of the limb where evaluated. Mechanical nociceptive threshold (MNT) increase, and ataxia duration means were 9.5 ± 0.7 kg and 10.4 ± 3.9 hr for PA and 10.4 ± 3.9 kg and 12.7 ± 1.9 hr for DA, respectively with no significant difference. There was no significant difference between MNT elevation time and the duration of ataxia using the same approach. The DA treatment showed significant MNT elevation in 72% of the tested regions, while the PA treatment showed an elevation in 100% regions tested. Topographic approaches closer to where the spinal nerves emerge produced a larger desensitised area.

Differential blockade, comparative study of different ropivacaine concentrations (0.75%; 0.2%; 0.12%) for ultrasound guided sciatic and femoral nerve blocks in calves: Prospective cross-over study

Pharmacodynamic understanding of the different local anesthetic concentrations allows adapting their use to diverse clinical/surgical procedures, such as intraoperative and/or postoperative analgesia. A crossover study was performed, where 6 calves (5 male and 1 female), weighing 120 ± 28 Kg, were subjected to combined sciatic and femoral nerve block using three ropivacaine concentrations. The treatments were: R0.75, using 0.75% ropivacaine; R0.2, 0.2% ropivacaine; and R0.12%, 0.12% ropivacaine. All treatments were performed with ultrasound and neurostimulation assistance, and a volume of 0.1 mL/kg of the respective local anesthetic solution was administered in each block point. The sites of mechanical nociceptive threshold (MNT) evaluation were based on the calf pelvic limb dermatomes. The proportion between desensitized areas, MNT elevation time and level of ataxia were registered. Elevation of MNT occurred in 100% of the tested areas in the R0.75 and R0.2 treatments, and in 82% of the R0.12 treatment. Mean MNT elevation times were 9.5 ± 0.7 h for R0.75, 6 ± 0.8 for R.02, and 2.4 ± 2.3 for R0.12, differing significantly between all treatments. No difference was observed between MNT elevation time and ataxia duration time, in each treatment. It is concluded that the duration of sensory-motor effects is dose-dependent, but there was not possible to detect block selectivity as the concentrations was reduced. More desensitized areas and extension were obtained with the use of higher concentrations.

Evaluation of frontal and infratrochlear nerve blocks for standing sedated frontonasal sinusotomy in horses.

To determine if targeted blocking of frontal and infratrochlear nerves provided anesthesia for the approach to a frontonasal sinusotomy. Two part study: Part 1 randomized crossover design; Part 2 proof of concept. N = 12; six each in Parts 1 and 2. Part 1: Each horse had either frontal and infratrochlear nerve blocks or a line block performed with 2% mepivacaine hydrochloride. Mechanical nociceptive thresholds (MNT) were obtained at five sites along a proposed frontonasal sinusotomy prior to injection, and at 10, 60, and 120 min after blocking. After a 4 day washout period, the opposite procedure was performed. Order of procedure and side of face were randomized. MNTs were analyzed using mixed-model ANOVA with p < .05. Part 2: Frontal and infratrochlear nerve blocks were performed followed by creation of a skin/periosteal incision, which was closed at 2 h. Ability to create and suture the incision, and the size of the incision were recorded. For part 1, both line and targeted blocks resulted in at least two times an increase in median MNT values at each of the five sites, as compared to baseline MNT values (p < .0025). In Part 2, incisions could be completed in five of six horses, with median incision size of 6.5 × 5 cm. Following frontal and infratrochlear nerve blocks, MNTs were increased along a proposed frontonasal sinusotomy, and skin incisions could be created in the majority of horses. Frontal and infratrochlear nerve blocks provide an alternative technique to create a frontonasal sinusotomy.

Impact of plane of nutrition and analgesic treatment on wound healing and pain following cautery disbudding in preweaned dairy calves

Nutrition has been reported to be a crucial part of the wound healing process in humans as malnutrition has been well-doc­umented to impede wound healing; however, this has not been evaluated in disbudding wounds in calves. Although it is be­coming more common to feed an increased nutritional plane to young dairy calves, 33% of Canadian producers in a 2015 survey were still feeding calves low levels of milk (&lt; 6 L/d). The objec­tive of this study was to determine the impact of a biologically normal plane of nutrition compared to a limited plane on the primary outcome wound healing, and one dose of nonsteroidal anti-inflammatory drug (NSAID) compared to 2 on the second­ary outcomes: lying behaviour, haptoglobin concentrations, and mechanical nociceptive threshold (MNT) in calves disbud­ded via cautery iron.

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.

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.