The influence of lesion type on the duration of hyperalgesia associated with hindlimb lameness in dairy cattle.

The nociceptive thresholds of 42 sound dairy cattle were compared with 53 animals displaying hind-claw lameness. All animals in the study were lameness scored and nociceptive threshold tested. Each animal then received a routine claw trim while the lame cattle also had the cause of lameness determined and treated. Those cattle found to have a unilateral hind-claw lameness (n = 42) were re-evaluated at 28 days after treatment. The lame cattle were found to have a significantly lower nociceptive threshold (P < 0.001) as compared to the sound animals on day 1 and also at retesting on day 28 (P < 0.001). The group which were retested on day 28 were subdivided by lesion type: sole ulcer; white line disease and acute digital tissue infection. Each lesion type caused a decreased nociceptive threshold at day 1. At re-evaluation on day 28 only the thresholds of the acute digital tissue infection group were not significantly different from the sound group but thresholds in sole ulcer and white line disease cows were still depressed.

Comparison of carprofen and pethidine as postoperative analgesics in the cat.

The postoperative analgesia and sedation in cats given carprofen (4.0 mg/kg bodyweight by subcutaneous injection preoperatively) was compared to that in cats given pethidine (3.3 mg/kg bodyweight by intramuscular injection postoperatively) in a controlled, randomised, blinded, multicentre clinical trial. Further dosing with the particular analgesic was allowed if a cat was exhibiting unacceptable pain. In total, 57 carprofen cases and 59 pethidine cases were evaluated. Significantly fewer cats in the carprofen group required additional doses of analgesic, and mean pain scores were significantly lower from four hours after ovariohysterectomy, and at 18 to 24 hours after castration, compared to the pethidine group. In conclusion, carprofen provided as good a level of postoperative analgesia as pethidine, but of a longer duration (at least 24 hours) and was well tolerated. It thus provides an option for 'pre-emptive analgesia' in cats about to undergo surgery.

Associations between locomotion, claw lesions and nociceptive threshold in dairy heifers during the peri-partum period.

The locomotion of 15 heifers was examined at fortnightly intervals over a 4 month peri-partum period. Measurements were made of the development of gait abnormalities, thermal and mechanical nociceptive thresholds, and severity and size of sole lesions observed in the hind claws. All heifers developed lesions at, or shortly after, parturition, and in seven animals this induced marked lameness. Abnormalities of gait were related more to the severity than to the size of the lesion. Lameness was associated with a significant increase in sensitivity to mechanical noxious stimuli applied to the lame leg but not to a thermal stimulus applied to the ear. This study demonstrated interactions between lameness, claw lesions and the development of hyperalgesia in heifers during the post-partum period.

An assessment of the peripheral antinociceptive potential of remoxipride, clonidine and fentanyl in sheep using the forelimb tourniquet.

A modification of the intravenous regional anaesthesia technique was used to assess the peripheral antinociceptive effect of remoxipride, clonidine and fentanyl. Drugs administered intravenously via peripheral catheters were restricted to the distal limb and nociceptive threshold test site by prior inflation of a tourniquet proximal to both the catheter and a threshold-testing device. Lignocaine (1 mg/kg) induced peripheral antinociception during tourniquet inflation. Clonidine (6 micrograms/kg) only induced significant elevations in thresholds after tourniquet deflation. A low dose of remoxipride (2 mg/kg), which had no systemic antinociceptive effect, produced antinociception after its restriction to the periphery. Peripheral administration of saline and tourniquet-induced restriction of blood flow to the distal limb did not alter threshold values. Peripheral administration of fentanyl was used to test a further modification of the injection protocol designed to reduce the incidence of leakage into the systemic circulation. Fentanyl administration (11.2 micrograms/kg) failed to elicit an increase in thresholds when it was restricted to the distal limb test site. The contribution of a peripheral mechanism to the antinociception induced by systemic administration of a higher remoxipride dose (7.5 mg/kg) was investigated using an inflated tourniquet to exclude remoxipride from the periphery. Exclusion of remoxipride from the periphery reduced its antinociceptive effect, i.e. threshold values were lower than if remoxipride was allowed free access to the limb prior to tourniquet inflation. The technique described here was effective in demonstrating that the increase in noninflammatory nociceptive thresholds seen with clonidine and fentanyl is not peripherally mediated whilst that seen with remoxipride has a peripheral component.

Investigation into the antinociceptive potential of remoxipride administered intrathecally in sheep.

Systemic administration of remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p<0.05) increase in nociceptive thresholds as judged by a focused mechanical stimulus (blunt pin) applied to the forelimb of four sheep. However, this dose of remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system. Conversely, intrathecal xylazine (100 and 200 microg), an alpha-adrenergic agonist with antinociceptive properties, did not produce forelimb weakness although the higher dose (200 microg) produced significant sedation. In vitro autoradiography was performed on cervical spinal cord sections taken from sheep. Remoxipride displaced [3H] YM-09151-2, a selective D2 antagonist, from densely-labelled areas in the superficial layer of the dorsal horn, lamina X and ventral horn. Even though there are possible anatomical substrates within the spinal cord for both an antinociceptive and motor disturbance action of remoxipride, the behavioural data suggest that the spinal cord is unlikely to be the primary site of antinociceptive action for systemically-administered doses of remoxipride.

Measurement of mechanical thresholds, plasma cortisol and catecholamines in control and lame cattle: a preliminary study.

The threshold response to a mechanical nociceptive stimulus was significantly lower on the lame hind limb of lame cows than on the same limb of sound cows. There were no significant differences between the concentrations of cortisol, noradrenaline, adrenaline or dopamine in the blood plasma of the sound and lame cows.

Carprofen as an analgesic for postoperative pain in cats: dose titration and assessment of efficacy in comparison to pethidine hydrochloride.

The aim of this study was to titrate the optimal dose of carprofen for single dose usage, for alleviating postoperative pain, under a double-blind and randomised protocol, using both negative and positive controls. Renal tolerance was assessed by screening plasma urea and creatinine. Pre- and postoperative assessment of pain and sedation was made using a dynamic and interactive visual analogue scoring system in 60 cats undergoing ovariohysterectomy. The cats were randomly assigned to one of six groups: (1) carprofen at 1.0 mg/kg subcutaneously (sc); (2) carprofen at 2.0 mg/kg sc; (3) carprofen at 4.0 mg/kg sc; (4) pethidine at 5.0 mg/kg intramuscularly (im), (5) pethidine at 10.0 mg/kg im: and (6) no analgesics (injection of saline). All injections were given postoperatively on tracheal extubation and administered in a double-blind manner. Assessments were made up to 20 hours post extubation. Prior to induction and at 20 hours post extubation, blood samples were taken for laboratory analysis of the urea and creatinine content to check for any adverse effect on renal function. Cats given pethidine did not appear more sedated than the groups receiving carprofen or saline. Cats receiving carprofen were in less pain postoperatively overall, with 4.0 mg/kg being the most effective dose rate (significantly better than the other doses of carprofen at four and eight hours post extubation). The highest dose of pethidine provided significantly better analgesia than the highest dose of carprofen up to two hours post extubation, but from two to 20 hours post extubation carprofen at 4.0 mg/kg provided significantly better analgesia than the pethidine. None of the analgesic regimens appeared to affect renal function adversely, as measured by urea and creatinine levels.

A comparison of the effects of halothane and isoflurane in combination with nitrous oxide on lower oesophageal sphincter pressure and barrier pressure in anaesthetised dogs.

The effects of surgery, and of halothane and isoflurane, on oesophageal pressures were examined in 30 dogs. The dogs were premedicated with a combination of acepromazine maleate (0.1 mg/kg) and pethidine hydrochloride (1 mg/kg), and anaesthesia was induced with thiopentone (10 mg/kg). Ten of the dogs underwent abdominal surgery with halothane, 10 underwent abdominal surgery with isoflurane and 10 underwent non-abdominal surgery with halothane. Gastric pressure, lower oesophageal sphincter pressure and oesophageal barrier pressures were measured at five to 10 minutes after induction, five to 10 minutes after the initial surgical incision, during the abdominal surgery and while the skin was being sutured. There were no significant differences in lower oesophageal sphincter pressure between the groups of dogs but the pressures were greater in all the dogs during the surgical manipulation than shortly after induction or while the skin was being sutured. During abdominal surgery with halothane the barrier pressure was significantly higher (P < 0.05) than during non-abdominal surgery with halothane. The barrier pressure was lower (P < 0.001) during skin suturing after abdominal surgery with isoflurane than after abdominal or non-abdominal surgery with halothane. The lower oesophageal sphincter appears to be more sensitive to isoflurane than halothane.

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 micrograms/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na+ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.

Central sensitization as a result of surgical pain: investigation of the pre-emptive value of pethidine for ovariohysterectomy in the rat.

The development of central hypersensitivity as a result of a routine surgical procedure, midline ovariohysterectomy, was investigated in rats using the paw pressure test (PPT) and tail-flick latency (TFL) tests of spinal reflex activity. In addition, the modulating effect of pre-emptive versus post-operative administration of pethidine (a short-acting pure mu-opioid agonist) on the development of central hypersensitivity was studied. Initial experiments indicated that pethidine (15 mg/kg, i.m.) gave sub-maximal increases in thresholds for 60 min, and also that the administration of an anaesthetic did not unduly prolong the action of pethidine. Subsequently, 24 female Wistar rats were allocated to 1 of 4 treatment protocols: (1) anaesthesia without analgesics; (2) anaesthesia and surgery (midline ovariohysterectomy) without analgesics; (3) anaesthesia and surgery with pre-operative administration of pethidine; (4) anaesthesia and surgery with post-operative administration of pethidine. Thirty-five minutes after the end of anaesthesia thermal and mechanical nociceptive thresholds were measured at stepwise increasing intervals for 480 min. Changes were expressed as percentage changes from baseline (PPT) or deviation from expected values (TFL). Area under the threshold versus time response curves (AUCs) were also calculated for the following time sectors: 30-90, 90-150, 150-270, 270-390 and 390-510 min post-anaesthetic. Results of the TFL testing did not indicate the development of any significant hyperalgesia in any groups, but the results of the PPT did. In the time sectors 150-270 and 270-390 min post-anaesthetic, the AUCs in rats subjected to anaesthesia and surgery with either post-operative administration of pethidine or surgery with no analgesic drug administration, were significantly lower than the AUCs in rats given analgesics pre-operatively or those subjected to general anaesthesia alone (P < 0.01), Mann-Whitney). In summary, it appears that pethidine, in this protocol, prevented the development of surgically induced hyperalgesia when it was given pre-emptively.

A field study of the effect of lameness on mechanical nociceptive thresholds in sheep.

Threshold responses to a mechanical pressure test were measured in two groups of adult female sheep taken from 27 flocks in north Devon. The first group consisted of 470 healthy sheep and the second of 139 sheep suffering from obvious lameness, clinically diagnosed as foot rot. The lame sheep were assessed for the severity of the lesion and the level of lameness and assigned a score. In flocks with sheep with a severe degree of lameness, the sheep had a significantly lower threshold to a mechanical nociceptive stimulus than their matched sound controls and their thresholds remained low when tested three months later, after the apparent resolution of the foot rot lesion. In flocks where the lame sheep were less severely affected there was no difference in the threshold responses to a mechanical stimulus between the sound and lame sheep.

The effects of opioid and alpha 2 adrenergic blockade on non-steroidal anti-inflammatory drug analgesia in sheep.

The analgesic effects of the non-steroidal anti-inflammatory drugs (NSAIDs) flunixin and dipyrone were assessed in healthy sheep with no pre-existing inflammation, and in sheep with a chronic inflammatory lesion, using a mechanical noxious stimulus. Saline and dexamethasone were given as controls. Blood taken from healthy sheep after NSAID administration was assayed for thromboxane B2 (TxB2) to compare the ability of these drugs to inhibit cyclo-oxygenase. Both flunixin and dipyrone produced a small but statistically significant rise in pain thresholds (18% and 21% of maximum possible effect respectively) in the healthy sheep which peaked at 30 min and had returned to pre-drug values by 2-3 h. In the lame sheep a similar effect occurred but the response was smaller, much more variable and tended to be prolonged. Saline and dexamethasone had no effect on thresholds over 6 h in either group of sheep. The rise in thresholds was prevented by pre-treatment with naloxone (an opioid antagonist) or atipamezole (an alpha 2-adrenergic antagonist) in the healthy sheep. Naloxone and atipamezole had no effect on thresholds when given alone to healthy sheep. Both NSAIDs inhibited the production of TxB2 to a similar extent. These results indicate that central mechanisms may be involved in NSAID analgesia.

Effect of body position on oesophageal and gastric pressures in the anaesthetised dog.

The effect of body position on lower oesophageal sphincter pressure (LOSP), gastric pressure and barrier pressure (BrP) was investigated in 40 dogs anaesthetised for neutering procedures. The dogs were placed in lateral recumbency followed by dorsal recumbency (group 1) or vice versa (group 2). LOSP decreased significantly in the animals which were positioned initially in lateral recumbency, when they were then placed in dorsal recumbency, while those initially positioned in dorsal recumbency showed no significant change in their LOSP or BrP when their position was altered to lateral recumbency. When the data from both groups were pooled, LOSP and BrP were significantly lower when the dogs were in dorsal compared to lateral recumbency (P < 0.05).

Antinociceptive activity of midazolam in sheep.

The purpose of this study was to examine the effects of midazolam on the nociceptive threshold responses in sheep. The intravenous administration of midazolam (0.1-0.3 mg/kg) produced a significant dose-dependent elevation of the mechanical and thermal nociceptive thresholds. The intravenous administration of flumazenil (20 micrograms/kg) markedly attenuated the antinociceptive activity of midazolam in the mechanical nociceptive test, whereas intravenous naloxone (0.2 mg/kg) had no significant effect on midazolam-mediated analgesia. The intrathecal administration of midazolam (1 mg), via chronically implanted cervical subarachnoid catheters, produced a significant elevation in the mechanical threshold responses. These results indicate that midazolam has antinociceptive actions in the sheep and suggest that this effect is, at least partially, mediated at the spinal level.

Effect of chronic pain associated with lameness on plasma cortisol concentrations in sheep: a field study.

Plasma cortisol concentrations were measured in two groups of sheep taken from 29 flocks in north Devon. The first group were healthy adult females and the second group were adult females suffering from footrot in one forefoot. These sheep were assessed for the severity of the lesion and the level of lameness and assigned a score. The plasma cortisol concentration was significantly higher in the lame sheep than in the healthy sheep and remained so for up to three months after the apparent resolution of the clinical lesion. There was no correlation between the severity of the footrot and the concentration of plasma cortisol.

Postoperative analgesic and sedative effects of carprofen and pethidine in dogs.

Forty dogs undergoing a variety of orthopaedic surgical procedures were randomly assigned to one of two analgesic protocols, receiving either pethidine at 2 mg/kg pre-operatively and 3 mg/kg postoperatively, or carprofen, a new non-steroidal anti-inflammatory drug at 4 mg/kg pre-operatively. Analgesia and sedation were assessed after the operations under double blind conditions using a discontinuous scoring system and a visual analogue scale. There was good agreement between the two scoring systems, and a statistical analysis of the visual analogue scores showed that carprofen provided slightly better pain relief than pethidine and produced less sedation. Carprofen provided good analgesia during the 18 hours the dogs were in hospital and no adverse side effects were observed.

Quantitative analysis of cyanogen bromide-cleaved peptides for the assessment of type I: type II collagen ratios in equine articular repair tissue.

Cyanogen bromide was used to solubilise and specifically fragment purified equine Type I and II collagen and equine articular surface repair tissue. The resultant peptides were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and quantified by densitometric scanning. Measurement of the relative amounts of the peptides alpha 2(I) CB3, 5 and alpha 1(II)CB10 provided an accurate method of establishing the ratio of Type I to Type II collagen in mixtures of purified equine collagens. The method was sensitive to 6% Type II collagen when the band areas were corrected for peptide molecular weight and the number of chains in the parent tropocollagen molecule which contain that particular peptide. Use of this technique showed that repair tissue in full thickness osteochondral defects in the dorso-distal margins of the intermediate carpal bones of ponies did not contain detectable amounts of Type II collagen 11 weeks after defect induction.