Validation of mechanical, electrical and thermal nociceptive stimulation methods in horses

To validate a model for investigating the effects of analgesic drugs on mechanical, thermal and electrical stimulation testing. To investigate repeatability, sensitivity and specificity of nociceptive tests. Randomised experiment with 2 observers in 2 phases. Mechanical (M), thermal (TL) and electrical (E) stimuli were applied to the dorsal metacarpus (M-left and TL-right) and coronary band of the left thoracic limb (E) and a thoracic thermal stimulus (TT) was applied caudal to the withers in 8 horses (405 ± 43 kg). Stimuli intensities were increased until a clear avoidance response was detected without exceeding 20 N (M), 60°C (TL and TT) and 15 V (E). For each set of tests, 3 real stimuli and one sham stimulus were applied (32 per animal) using a blinded, randomised, crossover design repeated after 6 months. A distribution frequency and, for each stimulus, Chi-square and McNemar tests compared both the proportion of positive responses detected by 2 observers and the 2 study phases. The κ coefficients estimated interobserver agreement in determining endpoints. Sensitivity (384 tests) and specificity (128 tests) were evaluated for each nociceptive stimulus to assess the evaluators' accuracy in detecting real and sham stimuli. Nociceptive thresholds were 3.1 ± 2 N (M), 8.1 ± 3.8 V (E), 51.4 ± 5.5°C (TL) and 55.2 ± 5.3°C (TT). The level of agreement after all tests, M, E, TL and TT, was 90, 100, 84, 98 and 75%, respectively. Sensitivity was 89, 100, 89, 98 and 70% and specificity 92, 97, 88, 91 and 94%, respectively. The high interobserver agreement, sensitivity and specificity suggest that M, E and TL tests are valid for pain studies in horses and are suitable tools for investigating antinociceptive effects of analgesics in horses.

Development of a pressure nociceptive threshold testing device for evaluation of analgesics in cats

A pressure analgesiometric device was developed for unrestrained cats. Eleven cats were studied. Stimulation was via three rounded pins within a bracelet on the forearm. The pins were advanced by manual bladder inflation. Bladder pressure was measured using a strain gauge pressure transducer. The threshold was recorded at the behavioural end point. Thresholds were measured at 5 and 15 min intervals for 2-4 h, after removal/replacement of the cuff, for 120 min after SC butorphanol (0.4 mg/kg), and with mild skin inflammation at the testing site. Data were analysed using ANOVA. Pressure thresholds in untreated cats were around 150 mmHg. The minimum interval for testing was established as 15 min. Data were reproducible over 4 h and beyond 24 h. Thresholds in 5 cats increased (P < 0.05) above baseline for 45 min after butorphanol with a maximum increase of 270 +/- 182 mmHg at 10 min. Thresholds decreased with inflammation. The method appears suitable for feline analgesia investigations. (c) 2006 Elsevier Ltd. All rights reserved.

Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats

Objective To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (IV), intramuscular (IM) and subcutaneous (SC) buprenorphine in cats. Study design Randomized, prospective, blinded, three period crossover experiment. Animals Six healthy adult cats weighing 4.1±0.5kg. Methods Buprenorphine (0.02mgkg-1) was administered IV, IM or SC. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the IV data was described using a model combining biophase equilibration and receptor association-dissociation kinetics. Results TT increased above baseline from 15 to 480minutes and at 30 and 60minutes after IV and IM administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60minutes (IV), 4.6±2.8°C at 45minutes (IM) and 1.9±1.9°C at 60minutes (SC). TT was significantly higher at 15, 60, 120 and 180minutes, and at 15, 30, 45, 60 and 120minutes after IV administration compared to IM and SC, respectively. IV and IM buprenorphine concentration-time data decreased curvilinearly. SC PK could not be modeled due to erratic absorption and disposition. IV buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t1/2ke0=47.4minutes) and receptor binding (kon=0.011mL ng-1minute-1). Persistence of thermal antinociception was due to slow receptor dissociation (t1/2koff=18.2minutes). Conclusions and clinical relevance IV and IM data followed classical disposition and elimination in most cats. Plasma concentrations after IV administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the IV route should be preferred over the IM and SC routes when buprenorphine is administered to cats. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Antinociceptive and Behavioral Effects of Methadone Alone or in Combination with Detomidine in Conscious Horses

The antinociceptive and behavioral effects of methadone (MET) alone or combined with detomidine (DET) were studied in horses. Intravenous treatments were randomly administered in a two-phase crossover study. In phase 1, six horses were treated with saline (control) or 0.2 or 0.5 mg/kg methadone (MET0.2; MET0.5, respectively). In phase 2, six horses were treated with 0.01 mg/kg DET alone or with DET combined with 0.2 mg/kg MET (DET/MET0.2). Thermal nociceptive threshold (TNT) and electrical nociceptive thresholds (ENT) were recorded by using a heat projection lamp and electrodes placed in the coronary band of the thoracic limbs, respectively. Spontaneous locomotor activity (SLA) was studied by movement sensors in the stall (phase 1). Chin-to-floor distance was assessed in phase 2. In phase 1, the TNT increased significantly for 30 minute after MET0.5 but not after saline or MET0.2. Hyperesthesia and ataxia were observed in 2 of 6 and 6 of 6 horses after MET0.2 and MET0.5, respectively. SLA increased significantly for 120 minutes after MET in a dose-dependent way, but not after placebo. In phase 2, DET and DET/MET0.2 significantly increased the TNT and ENT above baseline for 15 and 30 minutes, respectively; thresholds were significantly higher with DET/MET0.2 than with DET at the same times. Chin-to-floor distance decreased significantly from baseline for 30 minutes, and no excitatory behavior was observed in both treatments. Although the higher dose of MET induced short-acting antinociception, the associated adverse effects may contraindicate its clinical use. The lower dose of MET potentiated DET-induced antinociception without adverse effects, which might be useful under clinical circumstances. © 2013 Elsevier Inc. All rights reserved.

Effects of meperidine or saline on thermal, mechanical and electrical nociceptive thresholds in cats

Objective To measure cutaneous electrical nociceptive thresholds in relation to known thermal and mechanical stimulation for nociceptive threshold detection in cats.Study design Prospective, blinded, randomized cross-over study with 1-week washout interval.Animals Eight adult cats [bodyweight 5.1 +/- 1.8 kg (mean + SD)].Methods Mechanical nociceptive thresholds were tested using a step-wise manual inflation of a modified blood pressure bladder attached to the cat's thoracic limb. Thermal nociceptive thresholds were measured by increasing the temperature of a probe placed on the thorax. The electrical nociceptive threshold was tested using an escalating current from a constant current generator passed between electrodes placed on the thoracic region. A positive response (threshold) was recorded when cats displayed any or all of the following behaviors: leg shake, head turn, avoidance, or vocalization. Four baseline readings were performed before intramuscular injection of meperidine (5 mg kg(-1)) or an equal volume of saline. Threshold recordings with each modality were made at 15, 30, 45, 60, 90, and 120 minutes post-injection. Data were analyzed using ANOVA and paired t-tests (significance at p < 0.05).Results There were no significant changes in thermal, mechanical, or electrical thresholds after saline. Thermal thresholds increased at 15-60 minutes (p < 0.01) and mechanical threshold increased at 30 and 45 minutes after meperidine (p < 0.05). Maximum thermal threshold was +4.1 +/- 0.3 degrees C above baseline at 15 minutes while maximum mechanical threshold was 296 +/- 265 mmHg above baseline at 30 minutes after meperidine. Electrical thresholds following meperidine were not significantly different than baseline (p > 0.05). Thermal and electrical thresholds after meperidine were significantly higher than saline at 30 and 45 minutes (p < 0.05), and at 120 minutes (p < 0.05), respectively. Mechanical thresholds were significantly higher than saline treatment at 30 minutes (p <= 0.05).Conclusion and clinical relevance Electrical stimulation did not detect meperidine analgesia whereas both thermal and mechanical thresholds changed after meperidine administration in cats.

Efeitos do carprofeno e da buprenorfina no limiar nociceptivo mecânico com ou sem presença de foco inflamatório em gatos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Estudo farmacocinético e farmacodinâmico de cloridrato metadona por via oral, intramuscular e intravenosa e carreadores lipídicos nanoparticulados de metadona via oral em equinos

Pós-graduação em Anestesiologia - FMB

Pre-emptive epidural ketamine or S(+)-ketamine in post-incisional pain in dogs: A comparative study

Objective-To compare the pre-emptive analgesic effects of epidural ketamine or S(+)-ketamine on post-incisional hyperalgesia.Study Design-Prospective randomized study.Animals-Twenty-four mongrel dogs (1-5 years, weighing 11.9 +/- 1.8 kg).Methods-Dogs were anesthetized with propofol (5 mg/kg intravenously) and a lumbosacral epidural catheter was placed. Dogs were randomly allocated to 3 groups, each with 8 dogs. The control group (CG) was administered saline solution (0.3 mL/kg); the ketamine group (KG) ketamine (0.6 mg/kg); and the S(+)-ketamine group (SG) S(+)-ketamine (0.6 mg/kg). The final volume was adjusted to 0.3 mL/kg in all groups. Five minutes after the epidural injection a surgical incision was made in the common pad of the right hind limb and was immediately closed with simple interrupted nylon suture. Respiratory (RR) and heart (HR) rates, rectal temperature (7, sedation (S), lameness score, and mechanical nociceptive threshold by von Frey filaments were evaluated before the propofol anesthesia and at 15, 30, 45, 60, 75, and 90 minutes and then at 2, 4, 6, 8, 12, and 24 hours after epidural injection.Results-There were no differences in RR, HR, T, or S between groups. Motor blockade of the hind limbs was observed during 20 +/- 3.6 minutes in KG and during 30.6 +/- 7.5 minutes in SG (mean SD). Mechanical force applied to obtain an aversive response was higher from 45 minutes to 12 hours in KG and from 60 to 90 minutes in SG, when compared with CG.Conclusions-Pre-emptive epidural ketamine induced no alterations in RR and FIR, and reduced post-incisional hyperalgesia for a longer time than did S(+) ketamine.Clinical Relevance-Although anesthetic and analgesic potency of S(+) ketamine is twice that of ketamine, the racemic form is seemingly better for post-incisional hyperalgesia. (C) Copyright 2004 by the American College of Veterinary Surgeons.

Efeitos antinociceptivos e sedativos da buprenorfina, da acepromazina ou da associação buprenorfina e acepromazina em gatos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Injeção epidural preventiva de xilazina ou amitraz, em eqüinos: efeito antinociceptivo

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Carprofen and buprenorphine prevent hyperalgesia in a model of inflammatory pain in cats

A model of nociceptive threshold determination was developed for evaluation of NSAID analgesia in cats. In a crossover study, eight cats received carprofen (4 mg/kg), buprenorphine (0.01 mg/kg) or saline (0.3 ml) subcutaneously before intradermal kaolin injection on the antebrachium to induce mild inflammation. Pressure thresholds were measured at the injected site using blunt-ended pins advanced by manual inflation of a bladder within a bracelet. Bladder pressure was recorded as threshold (PT) at the behavioural end point. Baseline PT were recorded before kaolin injection (time 0). PT was measured at 2-10 h intervals for 52 h. PT below the lower 95% confidence interval (CI) of baseline values indicated hyperalgesia. After saline, hyperalgesia was detected from 2-6 h, 22-26 h, and at 30 and 36 h. After carprofen, PT remained within the 95% CI. After buprenorphine, PT remained within the 95% CI except at 2 h. Carprofen and to some extent buprenorphine, prevented inflammatory hyperalgesia. (C) 2007 Elsevier Ltd. All rights reserved.

The pre-emptive effect of epidural ketamine on wound sensitivity in horses tested by using von Frey filaments

Objective To evaluate the pre-emptive analgesic effect of pre-incisional epidural ketamine.Study Design A blinded, randomized experimental study.Animals Sixteen mixed breed mares, 17.6 +/- 2.8 years old, weighing 352 +/- 32 kg.Methods In a pilot study, an incision was made on one lateral thigh using a lidocaine block and no further analgesics, and it was verified that the nociceptive threshold was lower on the incised side than nonincised side (p < 0.05), and that von Frey filaments evoked a pain response. The 16 animals were divided into group A (ketamine, n = 9) and B (saline, n = 7). An epidural catheter was inserted 24 hours before the trials, the thigh was shaved bilaterally, and the right side was blocked (incised side) using lidocaine. Twenty-five minutes later, ketamine (A) or saline (B) was administered epidurally. Five minutes later, a 10-cm. skin incision was made on the right side, and then sutured. Nociceptive threshold was determined with von Frey filaments at 1, 3, and 5 cm. around the incision at 15-minute intervals for 2 hours, then at 4, 6, and 8 hours. Behavioral alterations, heart and respiratory rates were recorded. Nociceptive thresholds from these points were averaged to obtain mean values at each time, converted to a logarithmic scale, and submitted to a nonparametric analysis (Mann-Whitney and one-way repeated measures anova test,p less than or equal to 0.05).Results After 8 hours, the global range score revealed reduced hyperalgesia (p < 0.01) around the incision in 92% (4.65-4.27) of evaluated intervals in group A (ketamine). There were no significant changes in behavior, heart and respiratory rates,Conclusions It was concluded that pre-emptive epidural ketamine reduced post-incisional pain in the horse, and that von Frey filaments were able to quantify cutaneous sensitivity after tissue damage.Clinical relevance Epidural ketamine injection can reduce post-incisional sensitivity in the horse.

Molecular Dynamics simulations of track formation at different ensembles

A series of Molecular Dynamics simulations of thermal spikes has been run in zircon. For two different ensembles: microcanonical one and a combination of microcanonical one acting on the simulation core with Langevin one on the side walls of simulation. Depending on the used ensemble, different track-formation threshold energies were found. When the combined ensemble is carried out, the total energy of the simulations varies with the temperature which can influence how annealing fission-track models should deal with the lattice recovery. A fission-track annealing model is tested with the simulation results. © 2012 Elsevier Ltd. All rights reserved.

Efeito da arnica 6D e 30D administradas por via transmucosa oral e subcutânea no controle da dor pós-operatória de gatas submetidas à ovariossalpingohisterectomia

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Efeitos analgésico, hemostático, renal e digestório na administração perioperatória de vedaprofeno, tramadol ou de sua associação em felinos submetidos à ovariosalpingohisterectomia

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)