Anatomy of the spinal cord and how the spinal cord is affected by local anesthetics and other drugs.

The spinal cord can be affected by several categories of drugs: local anesthetics, opiate agonist, alpha 2 adrenergic agonists, and ketamine. The mechanism of action, side effects, and usefulness of these injections vary with the type of drug used.     

Cardiopulmonary effects of clonidine, diazepam and the peripheral α2 adrenoceptor agonist ST-91 in conscious sheep

The cardiopulmonary effects of the intravenous administration of clonidine (15 μg/kg), ST-91 (30 μg/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of α₂ adrenoceptor agonists are due to sedation, or to peripheral α₂ adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO₂) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO₂ levels of ≈40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO₂ was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO₂) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of α₂ adrenoceptor agonists in sheep are mainly mediated by peripheral α₂ adrenoceptors.     

A review of clinical approaches to antagonism of alpha2‐adrenoreceptor agonists in the horse

Alpha₂‐adrenoceptor agonists xylazine, romifidine, detomidine and, in some cases, medetomidine and dexmedetomidine, are fundamental drugs used in equine practice. There are situations where the undesirable pharmacodynamic effects (ataxia, prolonged sedation, bradycardia and ileus) or accidental overdose of these drugs may need to be antagonised. The α₂‐adrenoceptor antagonists tolazoline, yohimbine and atipamezole can be used to antagonise undesirable effects. However, despite being effective, α₂‐adrenoceptor antagonists are also not without undesirable pharmacodynamic effects. Excitement, muscle trembling and triggered inappropriate stress responses are a few of the more serious undesirable effects. Horses demonstrate a variable response to the antagonists thus recommending dose rates become fraught with difficulty. It is therefore recommended that the α₂‐adrenoceptor antagonist should be titrated to the desired clinical effect. Consequently, other reversal agents, such as anticholinergics (atropine, glycopyrrolate and hyoscine), have been administered for the treatment of α₂‐adrenoceptor agonist‐induced bradycardia. Anticholinergics cannot be recommended for routine use in horses due to the undesirable cardiovascular effects and potentiation of α₂‐adrenoceptor agonist‐induced gastrointestinal hypomotility. Novel peripheral acting α₂‐adrenoceptor antagonists, such as MK‐467, are currently under scrutiny in veterinary anaesthesia in an effort to antagonise the undesirable effects of α₂‐adrenoceptor agonists without compromising on the level of sedation. This review examines the current literature on the α₂‐adrenoceptor antagonists used in horses and makes recommendations on how to use these drugs safely in an attempt to prevent undesirable pharmacodynamic effects.     

Mediation of contraction and relaxation by alpha- and beta-adrenoceptors in the ureterovesical junction of the sheep.

The effects of alpha- and beta-adrenoceptor agonists and antagonists were studied in the sheep ureterovesical junction. Non-specific adrenergic agonists such as adrenaline and noradrenaline induced contraction in the sheep ureterovesical junction, suggesting a predominance of alpha-over beta-adrenoceptors in this functional unity. An inhibition of the noradrenaline-induced contraction was observed after prior blocking with prazosin (10(-7) M) and yohimbine (10(-7) M), the effect of prazosin being more potent than that of yohimbine. The effect of phenylephrine on alpha 1-adrenoceptors was more potent than that of B-HT 920 on alpha 2-adrenoceptors. Isoproterenol caused a concentration-dependent relaxation that was inhibited by propranolol (10(-6) M), pafenolol (10(-5) M) and butoxamine (10(-5) M). These results suggest that ureterovesical junction contraction is mediated by both alpha 1 and alpha 2-adrenoceptors, alpha 1 predominating over alpha 2. Relaxation is mediated by beta-adrenoceptors of the beta 1 and beta 2 subtypes.     

Current Concepts in the Management of Acute Spinal Cord Injury

Acute injury to the spinal cord initiates a sequence of vascular, biochemical, and inflammatory events that result in the development of secondary tissue damage. Experimental studies and clinical trials in humans have demonstrated that the extent of this secondary tissue damage can be limited by pharmacologic intervention at appropriate intervals after injury. High doses of methylprednisolone sodium succinate (MPSS) improve the outcome of acute spinal cord injury in humans if treatment is initiated within 8 hours of injury. Starting therapy more than 8 hours after injury is detrimental to outcome. The clinical efficacy of methylprednisolone in improving the outcome of canine spinal cord injuries has not yet been demonstrated and its use by veterinarians is controversial. Many dogs are not seen by a veterinarian within the 8-hour window after injury, and these dogs frequently are treated with nonsteroidal anti-inflammatory drugs or large doses of dexamethasone or prednisone before methylprednisolone treatment can be initiated, thus increasing the risk of severe adverse effects. Other drugs that may provide safer and more effective alternatives to methylprednisolone include thyrotropin-releasing hormone (TRH), the 21-aminosteroids, and kappa opioid agonists. Recent studies suggest that modulation of the influx of inflammatory cells and activation of endogenous microglial cells may provide another means of improving the outcome of acute spinal cord injuries. Many drugs being developed to treat acute spinal cord injury have shown promising results when evaluated experimentally. However, any proposed therapeutic strategy should be evaluated in prospective blinded clinical trials before being adopted in clinics.     

Large interarcuate spaces in the cervical vertebral column of the tyrolean mountain sheep

Large interarcual spaces have been described between the arcus vertebrae C5/C6 and C6/C7 in the cervical vertebral column of Nubian goats. This aperture enables direct access to spinal cord and rootlets without the need to perform a hemilaminectomy. The present study was performed in order to determine whether these large interarcual spaces can also be found in the vertebral column of the Tyrolean mountain sheep, as this small ruminant, which is anatomically very similar to the Nubian goat, is frequently used for experimental purposes at the Surgical University Clinic in Austria. The carcasses of 10 sheep (six females, four males; range of age: 2.5-6 years, range of weight: 52-89 kg) were dissected and the vertebral column was exposed. All 10 sheep showed elliptic openings between the fourth cervical and the first thoracal vertebrae. Three sheep had additional openings between the first and the second thoracal vertebrae. All openings were covered solitarily by the ligamentum flavum and under this ligamentum lay the spinal cord without any further osseous or ligamentous protection. These findings are not mentioned in the common textbooks of veterinary anatomy and deserve attention, as they can be a step forward towards non-traumatic experimental surgery on the spinal cord.     

The autoradiographic binding of [3H] quinuclidinyl benzilate to muscarinic receptors in the spinal cord of the sheep

Autoradiography of [3H] quinuclidinyl benzilate was used to demonstrate the distribution of muscarinic acetylcholine binding in the spinal cord of sheep. Binding was confined to the grey matter of the cord, and was most densely distributed in the substantia gelatinosa region of the dorsal horn, the lamina X region around the central canal, the intermediolateral columns and in various regions of the ventral horn. The use of specific M1 and M2 receptor subtype ligands, pirenzipine and 4-DAMP indicated that both receptor subtypes were present in most regions of dense binding.     

Alpha 2 agonists and antagonists.

The alpha 2 agonists can produce reliable dose-dependent sedation and analgesia in most species. Nevertheless, they can also produce significant physiological adverse side effects depending on dose, rate, route of administration, and the concurrent use of other CNS depressants. For this reason, it may be best to use a low dose of an alpha 2 agonist as a preanesthetic agent. The alpha 2 agonists are best suited for young, healthy, exercise-tolerant patients. The combining of low doses of alpha 2, opioid, and benzodiazepine agonists results in a synergistic CNS depressant response while minimizing the undesirable side effects of these three classes of drugs. Each group of drugs has specific antagonists available for their reversal, thus allowing veterinarians to reverse one or more of the agonists depending on the desired response. This may represent a significant advantage to the use of low-dose alpha 2 agonists in combination with opioids and benzodiazepines.     

Abnormal turning behaviour, GABAergic inhibition and the degeneration of astrocytes in ovine Tribulus terrestris motor neuron disease

OBJECTIVE: To observe the clinical signs of sheep affected by Tribulus terrestris motor neuron disease, to ascertain their response to striatal dopamine reducing drugs, and to examine their brains and spinal cords for microscopic changes. PROCEDURES: Twenty-eight sheep displaying well developed clinical signs of the disorder were observed. Twenty-two of these and 22 normal sheep were then randomly allocated to three groups and treated with diazepam, chlorpromazine, or xylazine. The time that it took an animal to return to a standing position following drug administration was recorded. The brain and complete spinal cord were removed from each of the other six affected sheep and fixed in formalin. Brains were sectioned throughout at 5 mm intervals and spinal cords at 10 mm intervals. All tissues were paraffin embedded and examined by light microscopy. A few samples were examined by electron microscopy. RESULTS: Clinical signs included postural asymmetry with a right:left body-side dominance within the group of 50:50, unequal flaccid paresis in the pelvic limbs, extensor muscle atrophy and adduction of the weaker pelvic limb, and concurrent abduction of the stronger. Forward motion followed either a fixed left or right hand curved trajectory, the sheep no longer being able to choose which. Twelve animals intermittently displayed rotational behaviour that involved loss of postural balance without locomotor activation. The administration of diazepam, chlorpromazine, or xylazine caused limb paresis and sedation, with affected sheep being slower than normal sheep by factors of 8, 3 and 2 respectively, to return to a standing position. There were scattered areas of mild Wallerian degeneration throughout the spinal cord, and in both the brain and the cord there were small numbers of degenerate astrocytes containing novel cytoplasmic pigment granules. CONCLUSIONS: Affected sheep had a dysfunction in the control of directional change and this provides a new insight into the normal mechanism for 'turning' in quadrupeds. Directional change requires a functional asymmetry or lateralisation within the upper motor neuron to accommodate a difference in the rate of forward progression of each body side and, simultaneously, a lateral shift of the centre of gravity. The sensitivity of affected sheep to diazepam is consistent with a pre-existing elevation in GABAergic neuronal inhibition, probably as a result of a reduction in glutamatergic neuronal excitation. The cytoplasmic pigment found in degenerate astrocytes was novel and its presence in the brain nuclei known to contribute to turning behaviour could have aetiological significance. The motor output of the basal ganglia in Tribulus neurotoxicity appeared to be excessively inhibitory to the pelvic limb extensor muscles and was asymmetric, causing fixation of the turning posture but not locomotor activation. An intoxication of specific purine sensitive, glutamate releasing astrocytes, located in nuclei controlling turning, was suspected.     

Identification and characterisation of beta-adrenoceptors on intact equine peripheral blood lymphocytes with the radioligand (-)-[125I]-iodocyanopindolol

In this study, beta-adrenoceptors of intact equine lymphocytes were identified and subclassified by (-)-[125I]-iodocyanopindolol (ICYP) binding. ICYP binding to intact equine lymphocytes was rapid, saturable (maximal number of binding sites 320 +/- 20 ICYP binding sites/cell, n = 12) and of high affinity (KD value for ICYP 14.4 +/- 1.7 pmol/l, n = 12). Binding was stereospecific as shown by the 10 times greater potency of (-)-propranolol to inhibit binding than its (+)-isomer. Beta-adrenoceptor agonists inhibited ICYP binding with an order of potency: (-)-isoprenaline >(-)-adrenaline >(-)-noradrenaline; the same order of potency was obtained for agonist-induced stimulation of lymphocyte cyclic AMP content. The selective beta2-adrenoceptor antagonist ICI 118,551 was about 1000 times more potent in inhibiting ICYP binding than was the beta1-selective adrenoceptor antagonist CGP 20712A. It is, therefore, concluded that in intact equine lymphocytes, ICYP labels a class of functional beta-adrenoceptors that belong predominantly (>90%) to the beta2-adrenoceptor subtype; a small (<10%) beta1-adrenoceptor component, however, cannot be ruled out completely. ICYP binding to equine lymphocytes might be a suitable model to study function and regulation of the beta-adrenoceptor system in the horse in vivo. The aim of this study was to characterise the beta-adrenoreceptor subtypes present on equine lymphocytes.     

Cerebellar abiotrophy and segmental axonopathy: two syndromes of progressive ataxia of Merino sheep

Findings of a study of 39 sheep with progressive ataxia from 14 farms in the Yass district of New South Wales are described. Microscopic lesions in 25 sheep, 3.5 to 6 years of age, diagnosed as having clinical cerebellar disease, consisted of an apparent primary loss of cerebellar Purkinje neurons, and glial cell accumulation. It is suggested that this previously unreported disorder may be an hereditary cerebellar abiotrophy of Merino sheep. A further 14 sheep, 1 to 4 years of age, had distinguishable clinical signs referable to a spinal cord lesion with widespread segmental axonal ballooning, or "spheroids", in the white matter of the brain and spinal cord. It is suggested that these sheep have a unique form of neuroaxonal dystrophy, described here as segmental axonopathy, and that this is likely to be the same condition described previously as Murrurindi disease (Hartley and Loomis 1981).     

A Rosenthal fiber encephalomyelopathy resembling Alexander's disease in 3 sheep

We report an encephalomyelopathy in three 18-month-old Merino sheep with features of adult-onset Alexander's disease (AD), a human primary astrocytic disorder. The signature histologic finding was the presence of numerous hypereosinophilic, intra-astrocytic inclusions (Rosenthal fibers), mainly in perivascular, subpial, and subependymal sites, especially in the caudal brain stem and spinal cord. Although AD usually results from mutations in the glial fibrillary acidic protein (GFAP) gene, no such mutation was detected in these sheep. However, the annual clinical presentation of this disorder in a few sheep in the affected flock is suggestive of a familial pattern of occurrence.     

Compressive cervical myelopathy in young Texel and Beltex sheep

BACKGROUND: This investigation was prompted by the referral of increasing numbers of young Texel and Beltex rams with ataxia and weakness, or wobbler syndrome. HYPOTHESIS: The study aims were to describe the clinical and pathologic findings in affected sheep. ANIMALS: The animals evaluated in this study included 7 Texel sheep (6 male and 1 female) and 3 Beltex sheep (2 male and 1 female) referred from pedigree flocks. Typically, the sheep were 15-18 months of age at referral. METHODS: Diagnostic investigations included radiographic and computed tomographic (CT) myelography followed by gross postmortem and histopathologic examinations. RESULTS: Clinical findings typical of cervical spinal cord compression were present in all sheep but varied in severity. Myelography confirmed dorsal spinal cord compression in the region of C6-C7. No bony abnormalities were identified as described in cases of canine and equine wobbler syndrome. Postmortem examinations revealed discrete, smooth, nodular to polypoid projections of adipose tissue apparently prolapsing through the dorsolateral intervertebral space at C6-C7 and causing localized spinal cord compression. Histopathology of the nodules confirmed that they were composed of well-differentiated adipocytes typical of fatty tissue. Spinal cord lesions were similar in all sheep with marked Wallerian degeneration at the site of compression and mild Wallerian degeneration present cranial and caudal to the lesion. CONCLUSIONS AND CLINICAL IMPORTANCE: The findings of this study suggest a novel cervical myelopathy in these sheep breeds caused by the presence of fatty nodules encroaching into the dorsal vertebral canal at C6-C7. Additional investigations are required to establish the etiology and possible hereditary risk factors for this unique clinicopathologic syndrome.     

HUMPY BACK OF SHEEP. CLINICAL AND PATHOLOGICAL OBSERVATIONS

Humpy back, a disease of Merino sheep in western Queesland, occurs during mustering for shearing. It is usually seen in summer 6-10 weeks after substantial rainfall and is thought to be caused by the ingestion of a toxic plant. The disease is characterised clinically by a short-stepping, stilted gait of the hind limbs, followed by lowering of the head, arching of the back and inability to continue walking. Histopathological examination of 8 cases from 5 properties revealed a Wallerian degeneration of the white matter throughout the length of the spinal cord with the ventral and lateral columns most severely affected. A similar degenerative change was seen in the posterior cerebellar peduncles of 3 of the sheep. A more severe hind limb incoordination with more extensive degeneration of the white matter of the spinal cord, medulla and cerebellum was seen in a case of humpy back of two years duration. Similar, but much milder, spinal cord lesions were found in apparently unaffected sheep from the same group as the sheep affected with humpy back on 2 properties. Severe myodegeneration of hind limb muscle groups was seen in 3 affected sheep. It was thought to be associated with the long rail journey (1500 km) to the laboratory after the sheep were affected in the field.     

Antinociceptive actions of intravenous a2-adrenoceptor agonists in sheep

The antinociceptive activity of the intravenously administered alpha 2-adrenoceptor agonists, clonidine and xylazine, was measured in sheep using thermal and mechanical pressure threshold detection systems. Both drugs demonstrated clear antinociceptive activity for both forms of threshold stimuli and clonidine at 6 micrograms/kg i.v. was more potent and longer lasting than xylazine at 50 micrograms/kg i.v. The antinociceptive effects were reversed by idazoxan (0.1 mg/kg i.v.), but were not affected by naloxone at 0.2 mg/kg i.v. indicating that these effects were mediated by alpha 2-adrenoceptors.     

Leukoencephalomyelopathy in cats linked to abnormal fatty acid composition of the white matter of the spinal cord and of irradiated dry cat food

Four outbreaks of leukoencephalomyelopathy in colonies of SPF cats on a long‐term diet of irradiated dry cat food were observed in the Netherlands between 1989 and 2001. As a primary defect in myelin formation was suspected to be the cause of the disease and myelin consists mainly of lipids and their fatty acids, we investigated the fatty acid composition of the white matter of the spinal cord of affected and control cats and of irradiated and non‐irradiated food. The irradiated food had low levels of alpha‐linolenic acid compared to linoleic acid as well as a high total omega‐6:omega‐3 ratio of 7:1 in the irradiated and of 2:1 in the non‐irradiated food. The white matter of the spinal cord showed low levels of linoleic acid and absence of alpha‐linolenic acid in affected cats as well as absence of lignoceric and nervonic acid in both affected and control cats. These abnormalities in fatty acid composition of the white matter of the spinal cord may reflect an increased need for alpha‐linolenic acid as a substrate for longer chain omega‐3 fatty acids to compose myelin and thus indicate a particular species sensitivity to dietary deficiency in omega‐3 polyunsaturated fatty acids, particularly alpha‐linolenic acid in cats. Our findings indicate that abnormalities in fatty acid metabolism in myelin play an essential role in the pathogenesis of this acquired form of leukoencephalomyelopathy in cats.     

Evidence for the involvement of alpha 2-adrenoceptors in the emetic action of xylazine in cats

Intramuscular injection of xylazine induced dose-dependent vomiting in cats (ED50 = 0.277 mg/kg); administration of standard dose of xylazine (2 mg/kg, 2 times the 100% emetic dose) induced vomiting in 100% of the cats studied. The xylazine-induced vomiting was antagonized by adrenoceptor antagonists possessing alpha 2-blocking activity, which were yohimbine, tolazoline, and phentolamine. Of these antagonists, yohimbine was the most effective; the maximal antagonistic effect was seen at 1 mg of yohimbine/kg, a dose at which the other drugs had little or no effect. At the doses studied, prazosin and phenoxybenzamine, adrenoceptor antagonists with alpha 1-blocking activity, did not prevent vomiting induced by xylazine. Beta-Adrenoceptor (propranolol), dopamine receptor (domperidone and chlorpromazine), a cholinoceptor (atropine), an opiate receptor (naloxone), and a histamine-receptor (diphenhydramine) antagonists, at the doses studied, did not prevent xylazine-induced vomiting. Pretreatment with 6-hydroxydopamine failed to prevent xylazine-induced vomiting. These results indicated that xylazine-induced vomiting in cats is mediated by alpha 2-adrenoceptors and suggested that the alpha 2-adrenoceptors mediating the vomiting attributable to xylazine may not be presynaptic alpha 2-receptors located on noradrenergic nerve terminals.     

Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.     

Involvement of opioidergic and alpha2-adrenergic mechanisms in the central analgesic effects of non-steroidal anti-inflammatory drugs in sheep

The level within the central nervous system where non-steroidal anti-inflammatory drugs (NSAIDs) produce analgesia and the mechanisms by which they mediate this effect are still uncertain. This study assessed the central analgesic effects of ketoprofen, phenylbutazone, salicylic acid and tolfenamic acid in sheep implanted with indwelling intrathecal (i.t.) catheters and submitted to mechanical noxious stimulation. The sheep received i.t. cumulative concentrations (0.375-200 microM; 100 microL) as well as a single intravenous (i.v.) dose (3, 8, 10 and 2 mg/kg, respectively) of each NSAID. The sheep were also given i.t. naloxone (5.49 mM; 100 microL) and atipamezole (4.03 mM; 100 microL) prior to i.v. ketoprofen. None of the i.t. NSAIDs increased mechanical thresholds. Intravenously, only ketoprofen and tolfenamic acid raised the pain thresholds. The hypoalgesic effect of i.v. ketoprofen was prevented by i.t. naloxone or atipamezole. Although NSAIDs had no direct effect on the spinal cord, their analgesic action appeared to be spinally mediated.     

Influence of idazoxan on the respiratory blood gas changes induced by alpha 2-adrenoceptor agonist drugs in conscious sheep

Administration of either xylazine (50 micrograms/kg) or detomidine (10 micrograms/kg) caused a significant degree of arterial hypoxaemia in six conscious sheep. This effect was independent of any changes produced by changes in posture as all the sheep remained standing. Administration of the specific alpha 2-antagonist drug idazoxan (0.1 mg/kg bodyweight) five minutes before injection of either of the drugs completely abolished the hypoxaemia. These results lend support to the view that the respiratory effect of these drugs is mediated via alpha 2-adrenoceptor activity.