Cannabinoids CB2 Receptors,One New Promising Drug Target for Chronic and Degenerative Pain Conditions in Equine Veterinary Patients

Osteoarticular equine disease is a common cause of malady; in general, its therapy is supported on steroids and nonsteroidal anti-inflammatories. Nevertheless, many side effects may develop when these drugs are administered. Nowadays, the use of new alternatives for this pathology attention is demanded; in that sense, cannabinoid CB2 agonists may represent a novel alternative. Cannabinoid belongs to a group of molecules known by their psychoactive properties; they are synthetized by the Cannabis sativa plant, better known as marijuana. The aim of this study was to contribute to understand the pharmacology of cannabinoid CB2 receptors and its potential utilization on equine veterinary patients with a chronic degenerative painful condition. In animals, two main receptors for cannabinoids are recognized, the cannabinoid receptor type 1 and the cannabinoid receptor type 2. Once they are activated, both receptors exert a wide range of physiological responses, as nociception modulation. Recently, it has been proposed the use of synthetic cannabinoid type 2 receptor agonists; those receptors looks to confer antinociceptive properties but without the undesired psychoactive side effects; for that reason, veterinary patients, whit chronical degenerative diseases as osteoarthritis may alleviate one of the most common symptom, the pain, which in some cases for several reasons, as patient individualities, or side effects produced for more conventional treatments cannot be attended in the best way.     

Induction of Noninflammatory Pain in an Experimental Foot Lameness Model in Horses

The mechanism by which nonsteroidal anti-inflammatory drugs mitigate pain caused by a heart bar shoe (HBS) model of lameness is unknown. The purpose of this study was to determine if this HBS model of lameness induces inflammation in horses. Five healthy adult horses from a university teaching herd were enrolled. A custom HBS was applied to the left front foot of each horse, followed by induction of the American Association of Equine Practitioners Lameness Score of 4. Inflammatory markers including serum amyloid A (SAA) concentration, local venous tumor necrosis factor alpha and prostaglandin E2 (PGE2) concentrations, and foot temperature were measured before lameness induction and 1, 3, and 13 hours after lameness induction. Lameness induction using the HBS model did not significantly increase production of plasma SAA, tumor necrosis factor alpha, or PGE2 concentrations at measured time points. Immediately and 1 hour after lameness induction, dorsal coronary band temperatures were higher in the left front foot compared with the right front foot, but there was no difference at 3 or 13 hours. In conclusion, the HBS model did not induce inflammation as assessed by select inflammatory markers, suggesting that the HBS model induces mechanical rather than inflammatory pain. This should be considered when using the HBS model to assess analgesic drugs in horses.     

A Pressure Algometer Is a Useful Tool to Objectively Monitor the Effect of Diagnostic Palpation by a Physiotherapist in Warmblood Horses

There is a lack of scientific evidence for objective evaluation of neck and back musculoskeletal sensitivity in horses, although pressure algometry has been described as an objective tool to quantify musculoskeletal responses by mechanical nociceptive threshold (MNT) values. This study aimed to evaluate the use of pressure algometry for objectively quantifying the effect of diagnostic palpation applied by physiotherapists on the musculoskeletal function of the equine neck and back. The inter-examiner repeatability of animal physiotherapists was tested, and their subjective clinical scores for the vertebral column area were objectively compared with MNT values measured at the same locations to investigate the potential clinical implementation of the pressure algometer in daily equine rehabilitation practice. Six adult Dutch Warmblood riding school mares were randomly assigned to an experimental or a control group. The MNT of all horses was measured on 35 predefined sites on the vertebral column in the morning and in the evening of the same day. In the experimental group (n = 3), neck and back surface “temperature”, “pain”, “muscle tone”, and passive “mobility” were scored through palpation by three certified physiotherapists and related to MNT measurements at the same vertebral column locations. Agreement between the physiotherapists was determined from Spearman's rank correlation coefficients (P < .05). These correlation coefficients showed a significant agreement between the scores of individual physiotherapists and with objective MNT measurements. The three physiotherapists agreed best in their subjective gradings of “pain”, but less for “temperature” and “muscle tone”, and least for “mobility”. There was also a significant difference in MNT between individual horses. The physiotherapeutic diagnostic intervention did not significantly alter the MNT of the experimental group compared with the control group. There was a significant difference, however, between morning (7.4 kg/cm²) and evening (6.9 kg/cm²) MNT-measurements within the combined group (n = 6, P < .05). In conclusion, a pressure algometer proved to be a useful tool to objectively monitor the palpation of individual Warmbloods by individual physiotherapists. The correlation of their scores to the objective MNT measurements elucidated that there were differences on which scale (“pain”, “temperature”, “muscle tone”, “mobility”) they merely relied upon in their palpation. Significant effects of physiotherapeutic diagnostic palpation on MNT, however, were not found. The lower MNT of the horses at the second trial in the evening could be a sensitization of the measurement location because of bruising, a learning effect of the horses, or a diurnal fluctuation. The use of pressure algometry has both a potential to quantify clinical neck and back musculoskeletal sensitivity in horses possibly leading to dysfunction, as well as to objectively evaluate treatment results. Repeated measurements on the same day and on the same location along the vertebral column may influence absolute MNT values. The algometer can be used with success provided that the operator has proper and frequent training.     

Effect of fentanyl on visceral and somatic nociception in conscious horses

BACKGROUND: Transdermal fentanyl is used clinically in horses based on pharmacokinetic data and antinociceptive effects documented in other species. HYPOTHESIS: Fentanyl IV administration increases both visceral and somatic nociceptive threshold in conscious horses. ANIMALS: Six clinically normal horses, each fitted with a permanent gastric cannula. METHODS: Visceral nociception was evaluated with 2 methods of threshold detection--olorectal distention and duodenal distention. Somatic nociception was assessed by measurement of thermal threshold. Fentanyl was administered as an increasing stepwise infusion followed by a continuous-rate infusion for a total of 2 hours. There were 4 doses of fentanyl and 1 dose each of saline and xylazine administered to each horse. Serum fentanyl concentrations were measured and the resulting data were used to determine pharmacokinetic parameters for each horse. All data were analyzed by means of a 3-factor analysis of variance followed by either a simple t test or a Bonferroni t test for multiple comparisons. RESULTS: Fentanyl administration did not result in significant changes in duodenal or colorectal distention threshold. Thermal threshold showed an increased trend at the 15-minute time point for the highest fentanyl group only, with a corresponding mean serum fentanyl concentration of 7.82 +/- 2.10 ng/mL. Two horses in this group became agitated and tachycardic during the first 15 minutes of the infusion. CONCLUSIONS AND CLINICAL IMPORTANCE: Fentanyl did not produce a significant antinociceptive effect at the doses used, 2 of which resulted in serum concentrations above the nociceptive threshold in other species.     

Sedation and Pain Management with Intravenous Romifidine−Butorphanol in Standing Horses

The objective of this study was to determine the sedation, analgesia, and clinical reactions induced by an intravenous combination of romifidine and butorphanol in horses. The study was conducted on six saddle horses weighing 382 to 513 kg (mean ± SD; 449 ± 54 kg) and aged 6 to 14 years. The horses each underwent three treatments: intravenous romifidine 0.1 mg/kg body weight (RM; mean dose, 4.5 mL); intravenous butorphanol 0.05 mg/kg body weight (BT; mean dose, 2.4 mL); and intravenous romifidine 0.1 mg/kg body weight plus butorphanol 0.05 mg/kg body weight (RMBT; mean dose, 7.0 mL). The order of treatments was randomized. Heart rate, arterial pressure, respiratory rate, rectal temperature, sedation, and analgesia were measured at two times before treatments, 15 minutes apart (times –15 and 0) and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, and 180 minutes after drug administration. The onset of sedation was approximately 5 minutes after intravenous injection of RM and RMBT, whereas BT did not present this effect. The duration of complete sedation was approximately 60 minutes for RMBT and approximately 35 minutes for RM. The RMBT treatment provided 30 minutes and the RM treatment 20 minutes of complete analgesia. Heart rate decreased significantly (P < .05) from basal values in the RM and RMBT treatments. Only RM caused significant decreases (P < .05) in the respiratory rate. Arterial pressure did not change significantly (P > .05) in any treatment. Intravenous administration of a romifidine−butorphanol combination to horses resulted in longer duration of sedation and analgesia than administration of romifidine or butorphanol alone. These effects probably resulted from a synergistic effect of the two drugs.     

The Bacteria Isolated from the Skin of 20 Horses at a Veterinary Teaching Hospital

The objective of this study was to isolate bacteria on the skin of the proximal to distal equine limb to guide the practitioner in the selection of prophylactic antimicrobial protocols. This prospective study involved 20 client-owned horses that were admitted to the Veterinary Teaching Hospital for routine elective surgery. Each horse spent between 12 and 36 hours at our hospital before sampling. Samples were collected from the skin of the left mid-thorax and the dorsal aspect of nine joints on the left side of each horse: front and hind coffin and fetlock joints, carpi, elbows, shoulders, hocks, and stifles. Samples were cultured aerobically and speciated when possible. When evaluating bacterial composition by location, a 40% difference was considered clinically significant. When comparing proximal sites above the fetlock to distal sites, the odds of isolating gram-positive bacteria were 1.23 times (P = .0124) higher at proximal sites; the odds of isolating coliform bacteria were 1.32 times (P = .023) higher at distal sites; and the odds of isolating a common septic arthritis pathogen were 1.16 times (P = .018) higher at distal sites. Coagulase-positive Staphylococcus was not isolated in this study. All comparisons between sites and between the proximal and distal limb were <40%, and thus were not considered clinically significant. No coagulase-positive Staphylococcus was isolated from any of the 200 sites in this study, suggesting that iatrogenic infections by that organism may not be because of preexisting flora. These data suggest that antibiotic prophylaxis targeting preexisting normal flora should be similar regardless of the area of interest on the limb.     

Field Trial Validation of the Efficacy and Acceptability of Firocoxib,a Highly Selective Cox-2 Inhibitor,in a Group of 96 Lame Horses

The objective was to generate evidence for clinical efficacy and acceptability of a second generation coxib, firocoxib, administered orally for 14 days to lame horses under field conditions compared with a classic nonsteroidal anti-inflammatory drug, vedaprofen, in a prospective, randomized, controlled, double-blinded, multicenter field trial. Ninety-six client-owned horses with American Association of Equine Practitioners score of at least grade 3 lameness or grade 2 lameness plus at least a score of 2 for either pain on palpation, range of motion, or joint swelling were analyzed. Horses were administered 0.1 mg/kg firocoxib orally at 24 hour intervals (n = 48) or 1.0 mg/kg vedaprofen paste at 12 hour intervals for 14 days (single loading dose of 2.0 mg/kg vedaprofen) (n = 48). Physical examinations and lameness evaluations were conducted on Day 1 (V1, before treatment) and on Days 7 (V2) and 14 (V3). Blood chemistry and hematology profiles were also evaluated. With regard to the primary variable, clinical improvement, 83% of the firocoxib-treated horses improved at V3 compared with 65% of vedaprofen-treated horses improved meeting the criteria defined to demonstrate noninferiority of firocoxib to vedaprofen. Health and behavioral abnormalities for side effect detection occurred at the rate of 2% (1 horse) and 8% (4 horses) for firocoxib- and vedaprofen-treated horses, respectively. Changes in hematology and blood chemistry values from V1 to V3 were not significantly different between treatment groups. Firocoxib, formulated as an oral paste was highly effective, well tolerated, and acceptable for the control of pain and inflammation associated with lameness in horses under field conditions.     

Evaluation of Nociception,Sedation, and Cardiorespiratory Effects of a Constant Rate Infusion of Xylazine Alone or in Combination with Lidocaine in Horses

This study aimed to evaluate the effects of a constant rate infusion (CRI) of xylazine or xylazine in combination with lidocaine on nociception, sedation, and physiologic values in horses. Six horses were given intravenous (IV) administration of a loading dose (LD) of 0.55 mg/kg of xylazine followed by a CRI of 1.1 mg/kg/hr. The horses were randomly assigned to receive three treatments, on different occasions, administered 10 minutes after initiation of the xylazine CRI, as follows: control, physiologic saline; lidocaine low CRI (LLCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.025 mg/kg/min); and lidocaine high CRI (LHCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.05 mg/kg/min). A blinded observer assessed objective and subjective data for 50 minutes during the CRIs. In all treatments, heart and respiratory rates decreased, end-tidal carbon dioxide concentration increased, and moderate to intense sedation was observed, but no significant treatment effect was detected in these variables. Ataxia was significantly higher in LHCRI than in the control treatment at 20 minutes of infusion. Compared with baseline values, nociceptive threshold increased to as much as 79% in the control, 190% in LLCRI, and 158% in LHCRI. Nociceptive threshold was significantly higher in LLCRI (at 10 and 50 minutes) and in LHCRI (at 30 minutes) than in the control treatment. The combination of CRIs of lidocaine with xylazine produced greater increases in nociceptive threshold compared with xylazine alone. The effects of xylazine on sedation and cardiorespiratory variables were not enhanced by the coadministration of lidocaine. The potential to increase ataxia may contraindicate the clinical use of LHCRI, in combination with xylazine, in standing horses.     

Proinflammatory Cytokine and Chemokine Gene Expression Profiles in Subcutaneous and Visceral Adipose Tissue Depots of Insulin‐Resistant and Insulin‐Sensitive Light Breed Horses

Background: Insulin resistance has been associated with risk of laminitis in horses. Genes coding for proinflammatory cytokines and chemokines are expressed more in visceral adipose tissue than in subcutaneous adipose tissue of insulin‐resistant (IR) humans and rodents. Hypothesis/Objectives: To investigate adipose depot‐specific cytokine and chemokine gene expression in horses and its relationship to insulin sensitivity (SI). Animals: Eleven light breed mares. Methods: Animals were classified as IR (SI = 0.58 ± 0.31 × 10^?4 L/min/mU; n = 5) or insulin sensitive (IS; SI = 2.59 ± 1.21 × 10^?4 L/min/mU; n = 6) based on results of a frequently sampled intravenous glucose tolerance test. Omental, retroperitoneal, and mesocolonic fat was collected by ventral midline celiotomy; incisional nuchal ligament and tail head adipose tissue biopsy specimens were collected concurrently. The expression of tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β, IL‐6, plasminogen activator inhibitor‐1 (PAI‐1), and monocyte chemoattractant protein‐1 (MCP‐1) in each depot was measured by real‐time quantitative polymerase chain reaction. Data were analyzed by 2‐way analysis of variance for repeated measures (P < .05). Results: No differences in TNF‐α, IL‐1β, IL‐6, PAI‐1, or MCP‐1 mRNA concentrations were noted between IR and IS groups for each depot. Concentrations of mRNA coding for IL‐1β (P= .0005) and IL‐6 (P= .004) were significantly higher in nuchal ligament adipose tissue than in other depots. Conclusions and Clinical Importance: These data suggest that the nuchal ligament depot has unique biological behavior in the horse and is more likely to adopt an inflammatory phenotype than other depots examined. Visceral fat may not contribute to the pathogenesis of obesity‐related disorders in the horse as in other species.     

Effect of Caudal Traction on Mechanical Nociceptive Thresholds of Epaxial and Pelvic Musculature on a Group of Horses With Signs of Back Pain

Direct muscular attachment from lumbar vertebrae to the caudal vertebrae of the tail suggests that caudal traction, also described as a tail pull, may affect lumbar vertebral segments and/or associated soft tissues in horses. Traction is a commonly used human manual therapy technique used for pain relief and anecdotally observed to relieve pain in horses. However, research is lacking validating the efficacy of manual caudal traction on the horse. The objective of this study was to determine if caudal traction has an effect on mechanical nociceptive thresholds (MNTs) in a group of horses with clinical signs of back pain. Pressure algometry was used to measure MNTs of five bilateral anatomical sites in the epaxial and pelvic musculature of 11 horses referred to physiotherapy because of clinical signs of back pain. Measurements were recorded both before and immediately after traction. A significant difference (P ≤ .05) was identified between mean before and after caudal traction algometry measurements in all described sites. The percentage of MNT increase was highest in the thoracic region (83%) compared with the lumbar (50%) and the pelvic (52.4%) regions. These results support an effect of caudal traction in increasing MNTs in the thoracolumbar and pelvic regions in horses. Further research to determine the clinical effect of this technique is warranted.