A. Livingston

Techniques for comparison of thermal and mechanical nociceptive stimuli in the sheep

The assessment of analgesia in conscious unrestrained farm animals presents particular problems. In order to provide a reliable nociceptive stimulus, two devices have been constructed, one that provides a threshold reading for a ramped thermal stimulus of the pinna of the ear and another that measures a threshold reading for a pressure stimulus to the foreleg. Both devices allow the rapid termination of the stimulus once a reaction has occurred and allow repeated readings without causing tissue damage. Examples of the analgesic action of alpha 2-adrenoceptor agonists and opioids measured by using the two pieces of apparatus are shown.

The effect of chronic clinical pain on thermal and mechanical thresholds in sheep

&NA; Threshold responses were measured to a thermal skin test and a mechanical pressure test in two groups of conscious unrestrained sheep. The first group of sheep were healthy adult females and formed a control sample, the second group were also adult females, but were all suffering from a condition known as footrot. Footrot is a chronic infective lesion affecting usually one foot which appears to cause severe pain in its worst manifestation. These sheep were assessed for the severity of the lesion and degree of lameness and were divided into high and low severity subgroups. Footrot did not alter the threshold to the thermal test but the mechanical pressure threshold was significantly reduced in both footrot sub‐groups compared to controls. A local anaesthetic block of the affected foot restored values to close to the control level. After treatment of the affected foot, the mechanical threshold in the low severity sub‐group was returned to normal, but in the high severity sub‐group it was still significantly reduced compared to the control animals. However, when retested 3 months later these values had returned to the normal control levels.

Investigation of the antinociceptive activity of buprenorphine in sheep

1 Buprenorphine given intravenously (6 μg kg−1) was examined for its antinociceptive activity in unrestrained sheep using devices to measure thermal and mechanical thresholds 2 The plasma levels of buprenorphine following intravenous injection over the time period of the antinociceptive testing were measured using a radioimmunoassay. 3 Buprenorphine produced a clear antinociceptive effect lasting for up to three and a half hours when measured by the thermal threshold test, but no detectable antinociception in the mechanical test. 4 The plasma levels of buprenorphine indicated that the drug was rapidly distributed in a manner not dissimilar to that reported in man, although individual animals showed a wide variation in some parameters. 5 When plasma levels of the drug were high (< 700 pg ml−1) during the first sixty minutes, no antinociceptive activity in the thermal test could be detected, which may be due to the slow receptor kinetics shown by this drug.

Analgesic activity and respiratory effects of butorphanol in sheep

The analgesic drug butorphanol tartrate has proved useful clinically in horses and dogs but its analgesic profile had not yet been investigated in sheep. This study was initiated to determine the thermal and mechanical antinociceptive activity of butorphanol (at the dose rates 0.05, 0.1 and 0.2 mg kg-1) in sheep. The drug produced significant analgesia in the thermal test system, the duration of which was dose related but no significant elevation in mechanical pressure thresholds could be detected. In a further set of experiments the dose rate was increased to 0.4 mg kg-1 and mechanical testing was repeated. There was still no clinically significant elevation in pressure thresholds. At a dose rate of 0.2 mg kg-1 the drug had no detectable effect on respiratory blood gas tensions. Behavioural changes were severe if a dose rate of 0.2 mg kg-1 was exceeded.

Receptor changes in the spinal cord of sheep associated with exposure to chronic pain

&NA; There is evidence that post‐injury hypersensitivity is partly due to changes in the central nervous system. Sheep with footrot were used to investigate the effect of chronic pain on some receptors thought to be involved in spinal nociceptive processing systems (alpha2 adrenoceptor and mu and delta opioid receptors). Saturation binding studies showed a variable distribution of [3H] clonidine (alpha2 adrenoceptor agonist) in the spinal cord of normal sheep. The number of receptors (Bmax) present in areas thought to be involved in nociceptive processing, laminae I and II and lamina X, increased to 131% and 169% of control sheep values respectively in animals exposed to chronic pain. The affinity of the receptors (KD), however, remained unchanged at approximately 2 nM. There was less [3H]DAGO (mu opioid agonist) and [3H]DPDPE (delta opioid agonist) binding in the sheep spinal cord. Both opioid receptor types being mainly located in the superficial dorsal horn. The [3H]DPDPE binding was unchanged in the sheep with footrot, whilst the number (Bmax), but not the affinity, of the [3H]DAGO binding sites increased in laminae I and II in lame animals to 130% of the control sheep values. Hence, in animals in chronic pain, the number of alpha2 adrenoceptors and mu opioid receptors increased mainly in areas of the sheep spinal cord associated with nociception.

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.

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.

ANALGESIC EFFECTS OF DETOMIDINE IN THOROUGHBRED HORSES WITH CHRONIC TENDON INJURY

This study was undertaken to assess the analgesia provided by detomidine (20 micrograms kg-1 intravenously) in thoroughbred horses. Pain thresholds to a mechanical noxious stimulus were measured before and after a period of mild chronic pain in one foreleg. Detomidine was a good analgesic in control animals; their pain thresholds were significantly elevated for about 60 minutes. After injury, the injured leg had a significantly lower pain threshold and the intensity and duration of analgesia provided by detomidine were significantly reduced. The analgesia in the opposite (sound) leg was also reduced, indicating that there were both central and peripheral aspects to this increased sensitivity to painful stimuli. Detomidine deserves to be considered as a potent analgesic in the horse rather than a sedative with analgesic side effects.

Effects of clinically occurring chronic lameness in sheep on the concentrations of plasma noradrenaline and adrenaline

Plasma adrenaline (AD) and noradrenaline (NA) concentrations were measured by high performance liquid chromatography with electrochemical detection in blood samples from control and lame sheep. The lame sheep suffered from naturally occurring foot rot and showed behavioural characteristics normally associated with chronic pain. The lame sheep were scored both for impairment of gait and pathology of the foot and divided into mild and severely affected groups. Both the mildly and severely lame group showed a significant increase in plasma AD and plasma NA which tended to persist even after clinical resolution of the condition. The measurement of plasma AD and NA may provide information which can be used to assess animals experiencing chronic pain, when taken in conjunction with other parameters, such as nociceptive thresholds and plasma hormone levels.

The spinal antinociceptive activity of the α2‐adrenoceptor agonist, xylazine in sheep

1 The intrathecal administration of xylazine (100 μg), via a chronic indwelling, cervical intrathecal catheter, produced a marked elevation of the mechanical nociceptive thresholds in the sheep. This antinociceptive effect was abolished by the prior intrathecal administration of the α2‐adrenoceptor antagonist, idazoxan. 2 The intrathecal administration of the selective α2‐antagonists, idazoxan (100 μg) and RX811059 (33 μg), significantly attenuated the antinociceptive activity of intravenous xylazine, with a 60–65% reduction in the area under the antinociceptive curve. The intrathecal administration of the antagonists alone had no significant effect on nociceptive thresholds. 3 Examination of the distribution of tritiated idazoxan (25 μCi in 100 μl) indicated that the site of action of the drug was limited to the cervical spinal cord after intrathecal administration. 4 These studies demonstrate that a significant proportion of the antinociceptive effect of systemically administered xylazine is mediated by spinal α2‐adrenoceptors.