[Continuous intrathecal baclofen in a case of generalized tetanus].
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Baclofen↗
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Sympathetic component of the pressor response to angiotensin II in the pithed rat after pretreatment with disulfiram.
Pressor responses to angiotensin II in the pithed rat were unaffected or slightly increased by procedures such as reserpine pretreatment, alpha and beta adrenoceptor blocking agents or bethanidine which inhibit the sympathetic system. Disulfiram-induced inhibition of angiotensin II pressor responses was unaffected by pretreatment with either alpha-adrenoceptor blockers or bethanidine. Pretreatment with disulfiram prevented infusions of angiotensin II from increasing the responses to spinal sympathetic outflow stimulation. After inhibition of pressor responses to angiotensin II by disulfiram the responses were restored by infusions of noradrenaline, or alpha-methyldopa. The restored responses, unlike control responses, were inhibited by phentolamine. The results suggest that angiotensin II facilitates neuronal release of noradrenaline and that this effect is revealed most clearly when post-synaptic angiotensin II receptors are blocked.
Adrenergic alpha-Antagonists↗
Irreversible conduction block in isolated nerve by high concentrations of local anesthetics.
BACKGROUND: Delivery of large doses of local anesthetics for spinal anesthesia by repeated injections or continuous infusion could expose the cauda equina to concentrations of drug that may be neurotoxic per se. We studied this possible neurotoxic effect by assessing recovery from conduction blockade of desheathed peripheral nerves after exposure to some of the local anesthetic solutions commonly used for spinal anesthesia. METHODS: The reversibility of conduction blockade was studied in desheathed bullfrog sciatic nerves, using the sucrose-gap method for recording compound action potentials, before and during exposure to local anesthetics and during drug washout. The nerves were exposed for 15 min to 5% or 1.5% lidocaine, with or without 7.5% dextrose; 0.5% tetracaine; or 0.75% bupivacaine (the latter two without dextrose). Some nerves were also bathed in 7.5% dextrose (without local anesthetic) or in 0.06% tetracaine, which in this preparation is equipotent to 5% lidocaine. After 15 min in the drug, the nerves were washed for 2-3 h and soaked in Ringer's solution overnight. Nerves exposed only to Ringer's solution served as controls. We also studied neuronal uptake and washout of radiolabeled lidocaine. RESULTS: Exposure of nerves to 5% lidocaine, with or without 7.5% dextrose, or to 0.5% tetracaine resulted in irreversible total conduction blockade, whereas 1.5% lidocaine or 0.75% bupivacaine caused 25-50% residual block after the 2-3 h wash. Nerves exposed to Ringer's solution, 7.5% dextrose or 0.06% tetracaine had 0-10% residual block after 2-3 h wash. The action potential of all nerves declined after overnight soak to between 30-60% of the control value, except for those nerves exposed to 5% lidocaine or 0.5% tetracaine, which showed no activity. Exposure to 5% lidocaine for periods of only 4-5 min produced total, irreversible loss of conduction. The uptake by and washout of radiolabeled lidocaine from the nerves indicate that the maximum amount of residual drug after 2-4 min of exposure to 5% lidocaine and a 3-h wash should cause at most only 50% conduction block. CONCLUSIONS: Solutions of 5% lidocaine and 0.5% tetracaine that have been associated with clinical cases of cauda equina syndrome after continuous spinal anesthesia caused irreversible conduction block in desheathed amphibian nerve. Whether these in vitro actions also occur in mammalian nerves in vivo is an important, clinically relevant question now under investigation in our laboratory.
Analysis of Variance↗
A microstructural study of spinal cord edema.
The experimental spinal cord edema was produced in a cat by the infusion method of Marmarou. Horseradish peroxidase (HRP) dissolved in autoserum of a cat was used as a tracer. After laminectomy, a 30-gauge needle was inserted into the intumescentia cervicalis. A total amount of 20 microliters of a tracer was infused at a rate of 10 microliters/hr. The structural features were studied immediately and 3 days after infusion. Immediately after infusion, HRP was noted in the infused white and gray matters. Though the perivascular space in the white matter at the infused site was widely distended and filled with HRP, the space in the gray matter was not distended but filled with HRP. HRP which was observed along vessels led to the surface of the spinal cord. Swelling of astrocyte was not observed. Three days after infusion, the extracellular space and the perivascular space in the infused white matter were still expanded but were not filled with HRP. The fine structural features were similar to the findings as seen in Marmarou's infusion type of brain edema. Using this model, it seems to be feasible to study the resolution process of spinal cord edema.
Animals↗
Chronic subarachnoid administration of 1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid (indomethacin): an evaluation of its neurotoxic effects in an animal model.
Neuraxial administration of nonsteroid antiinflammatory drugs has been suggested as an alternative in the management of intractable pain, but there is little evidence that the neurotoxic effects of indomethacin by this route of administration have been evaluated. In this study, we evaluated histological neurotoxicity of indomethacin after its subarachnoid administration in guinea pigs. The hypothesis tested was "Does subarachnoid administration of indomethacin produce damage in the spinal cord of guinea pigs?" Ten male guinea pigs were anesthetized, and a polyamide catheter connected to a subcutaneous osmotic micro-pump was implanted at the L2-3 level. Animals were randomly assigned in 2 groups of 5 animals each. Indomethacin or saline solution was administered by continuous infusion (0.5 microL/h) for 14 days. Neurotoxicity was determined by spinal cord histopathology. There was no evidence of toxicity in the histological examinations of either group. These data suggest that subarachnoid administration of indomethacin infusion, at these doses, did not produce lesions typical of neurotoxicity in the spinal cord. We have concluded that epidural administration of indomethacin may be considered an alternative for application in human pain management, although more studies to determine its safety are required.
Animals↗
Role of spinal nitric oxide in the facilitation of the micturition reflex by bladder irritation.
PURPOSE: Nitric oxide (NO) is known to have an important transmitter function at peripheral synapses in the urogenital tract and has also been implicated in the transmission of nociceptive information in the spinal cord. The present study evaluated the role of NO in the central micturition reflex pathway. MATERIALS AND METHODS: We examined the effect of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on micturition reflexes induced by continuous infusion of saline or 0.1% acetic acid (a noxious stimulus) into the bladder in urethane-anesthetized female rats. Bladder and external urethral sphincter function were monitored with a continuous cystometrogram (CMG) and electromyography (EMG). RESULTS: Intrathecal injection of L-NAME (0.01 to 1 mumol.) did not significantly change the CMG or sphincter EMG during saline infusion. Infusion of acetic acid decreased the intercontraction interval (ICI), indicating a decrease in the volume threshold for inducing micturition. Subsequent intrathecal administration of L-NAME partially reversed the decreased ICI in a dose-dependent manner, but did not change the amplitude of bladder contractions: 0.01, 0.1 and 1 mumol. of L-NAME produced increases of 25%, 31% and 56% in the ICI. D-NAME, the inactive stereoisomer had no effect. This effect of L-NAME was reversed by injection of L-arginine (2 mumol. intrathecally) which, by itself, did not alter ICI during saline infusion or acetic acid infusion. CONCLUSIONS: These results indicate that: (1) spinal NO containing pathways do not play a role in the normal micturition reflex, (2) NO is involved at the spinal level in the facilitation of the micturition reflex by nociceptive bladder afferents activated by noxious chemical irritation of the bladder.
Acetates↗
Intrathecal baclofen: does tolerance occur?
Concern over the development of tolerance in patients on continuous intrathecal baclofen therapy has arisen as this new form of treatment for spasticity has gained wider use. We have studied time-dose relationships in 18 spinal cord injured patients who have undergone intrathecal baclofen infusion pump implantation since February 1988 in our facility. Our data show that there was a significant increase in baclofen dosage needed to control spasticity during the first 12 months post implantation. After 12 months, however, no significant changes in dosage requirement was detected. In addition, there was no significant difference between completely and incompletely spinal cord injured patients with regard to both the initial dose and the tolerance trend.
Baclofen↗
Errors and limitations of the multimodality checking methods of defective spinal intrathecal pump systems. Case report.
The loss of benefit from intrathecal baclofen, with increased spasticity and a discrepancy between the residual and the calculated volume content (underinfusion), made us suspect dysfunction of the intrathecal baclofen infusion in a paraplegic patient. Although all possible usual checking methods were used, no failure in the drug administration device (DAD) could be found. Despite some benefit from increasing the daily dose of baclofen, it has not been possible to control the spastic symptoms. Surgery was therefore decided upon, and a small leak at the end of the catheter tip was discovered. Surgeons and physicians should be aware that checking methods of DAD cannot exclude failure of the system. Their errors and limitations are discussed.
Adult↗
Monosynaptic transmission in the cat's spinal cord. A quantitative measure of anesthetic dose.
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Anesthesia, Intravenous↗
[Comparison of the effect of rapid infusion of lactated and that of acetated Ringer's solutions on maternal and fetal metabolism and acid-base balance].
The maternal and neonatal metabolism and acid-base balance were investigated in 20 parturients undergoing combined spinal and epidural anesthesia for cesarean delivery. Patients received intravenous infusion at a rate of either 25 ml.kg-1.h-1 of lactated (LR group, n = 10) or acetated (AR group, n = 10) Ringer's solution before anesthesia, to prevent hypotension during anesthesia. We obtained venous blood samples as follows; maternal control before anesthesia, maternal sample A after the infusion, umbilical sample B, and neonatal pedal sample C 5 h after birth, and determined lactate, pyruvate, bicarbonate, and base excess concentrations, and pH in each sample. In sample A, the lactate level was significantly higher and base excess level was significantly lower in the LR group than in the AR group. The pH of sample A and B was significantly higher in the AR group than in the LR group. However, no differences in all parameters of sample C between the two groups were observed. These results demonstrated that acetated Ringer's solution is better than lactated Ringer's solution in rapid infusion before cesarean section because of the correction of neonatal lactic acidosis.
Acid-Base Equilibrium↗
Effect of methylprednisolone on neuropathic pain and spinal glial activation in rats.
BACKGROUND: Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. METHODS: Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg x kg(-1) x day(-1)) or intrathecal (80 microg x kg(-1) x day(-1)) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. RESULTS: Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. CONCLUSION: : Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.
Animals↗
Conservative management of spinal epidural hematoma in hemophilia.
Two patients with hemophilia and spinal epidural hematoma, who were treated successfully with serial Factor VIII infusions, are reported. This form of conservative therapy may circumvent the need for decompressive laminectomy and its attendant complications in instances in which the neurologic deficit is mild or stable. Somatosensory evoked potential studies were useful in documenting spinal cord dysfunction in 1 of the 2 patients.
Bed Rest↗
Constant infusion of morphine for intractable cancer pain using an implanted pump.
In the past, pain control for chronic pain syndromes using narcotic infusion has been carried out primarily via the intrathecal (subarachnoid) route. This report presents one of the first large series of terminally ill cancer patients with intractable pain treated with continuous epidural morphine infusions by means of implanted pumps and epidural spinal catheters. The purpose of the study was to demonstrate that the epidural route is effective with minimal complications, and that screening with temporary epidural catheter infusions results in a high rate of subsequent pain relief. A multidisciplinary team (neurosurgeon, anesthesiologists, psychiatrists, oncologists, and nurse clinicians) evaluated and treated all of the patients studied. Percutaneous placement of temporary epidural catheters for a trial assessment was performed by the anesthesiologists. Pain evaluations were conducted independently by psychiatrists using both verbal and visual analog scales. From 1982 to 1988, 41 (59.4%) of 69 patients evaluated for eligibility experienced good pain control during trial assessment and were subsequently implanted with Infusaid infusion pumps. Preinfusion pain analog values were 8.6 +/- 0.3 and postimplantation values at 1 month were 3.8 +/- 0.4 (p less than 0.001). Over this same 1-month period. requirements of systemic morphine equivalents decreased by 79.3% with epidural infusions as compared to preinfusion requirements (p less than 0.001). There were no instances of epidural scarring, respiratory depression, epidural infections, meningitis, or catheter blockage. One patient developed apparent drug tolerance and three patients required further catheter manipulations. This series strongly suggests that significant reductions in cancer pain can be obtained with few complications and a low morphine tolerance rate using chronic epidural morphine infusion. Anesthesiology and psychiatry input, along with temporary catheter infusion screening and quantitative pain evaluations using analog scales, are essential.
Adult↗
The influence of hyperthermia on the uptake of cisplatin in the rat cervical spinal cord.
The influence of local hyperthermia on the uptake of cisplatin in the rat cervical spinal cord was investigated. After single intraperitoneal or intravenous injection of cisplatin (5 mg/kg body weight), the spinal cord region cervical 5-thoracic 2 was heated for 60 min at mean (S.D.) 41.2 (0.4) degrees C or 40 min 42.4 (0.3) degrees C using a 434 MHz microwave heating device. One day after treatment with either hyperthermia alone, cisplatin alone or the combination, none of the animals expressed neurological symptoms. The spinal cord was dissected and platinum levels were measured by flameless atomic absorption spectroscopy. No difference was found in uptake of platinum in the spinal cord between control- and heat treated animals. In a second series of experiments, the spinal cord was heated for 30-60 min. during a 2 h infusion of cisplatin. One day after treatment at 42.3 degrees C for 60 min, neither motor nor sensory functions were affected and platinum levels did not differ significantly between control and treated animals. Also, platinum levels measured in the spinal cord immediately after cisplatin infusion were not influenced by heat treatment at 42.1 or 43.0 degrees C for 30 min. However, after a heat dose of 60 min 43 degrees C, cisplatin uptake was significantly increased (P less than 0.001) by a factor of 2.8 (1.3). The data demonstrate that mild hyperthermia has no effect on the uptake of cisplatin in the spinal cord, while an injurious heat dose leads to a significant increase in cisplatin uptake. The present findings indicate that, in case of treatment of tumours of the central nervous system with hyperthermia and cisplatin, a treatment which might be toxic for the tumour is well tolerated by the normal nervous tissue.
Animals↗
Trigeminal and chemoreceptor contributions to bradycardia during voluntary dives in rats.
This study investigates the importance of chemoreceptive and trigeminal information during voluntarily initiated diving in rats. The heart rate responses to simulated diving are unaffected by chemoreceptor drive [McCulloch, P.F., and N. H. West. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1049-R1056, 1992] but are reversibly eliminated by infusion of glutamate receptor antagonists into the spinal trigeminal nuclei [McCulloch, P. F., I. A. Paterson, and N. H. West. Am. J. Physiol. 269 (Regulatory Integrative Comp. Physiol. 38): R669-R677, 1995]. To investigate the role of chemoreceptor drive in conscious dives, rats were made hypercapnic, hyperoxic, or hypoxic predive. The role of trigeminal input was explored by infusing the glutamatergic antagonists D-2-amino-7-phosphoheptanoic acid and 6,7-dinitroquinoxaline-2,3-dione into the region of the trigeminal nuclei. The alteration of arterial blood gases predive had no effect on diving bradycardia. Trigeminal blockade reduced the intensity of the bradycardia but did not abolish it. Chemoreceptor input does not play a significant role in determining heart rate during conscious diving in rats. The attenuation, rather than abolition, of bradycardia on trigeminal blockade suggests either that we achieved incomplete blockade or that an additional spectrum of sensory inputs not present in simulated diving is important in determining the underwater heart rate during conscious diving in rats.
Animals↗
IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.
Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.
Adult↗
Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors.
The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4]morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. beta-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesia↗
Leukemia inhibitory factor induces sympathetic sprouting in intact dorsal root ganglia in the adult rat in vivo.
1. The role of the cytokine leukemia inhibitory factor (LIF) in axotomy-induced sprouting of postganglionic sympathetic fibres into the dorsal root ganglia was examined in the adult rat. 2. Immunocytochemistry was used to study the distribution and density of tyrosine hydroxylase-immunoreactive (TH-IR) fibres within the lumbar dorsal root ganglia and lumbar spinal nerves 14 days following continuous intrathecal infusion of LIF (0.33 mg ml-1), or 14 days following unilateral peripheral nerve axotomy. 3. In LIF-treated animals, numerous pericellular TH-IR basket-like structures were observed surrounding sensory neurones, which were absent from controls. 4. The number of TH-IR fibres within the L3, L4 and L5 spinal nerves was significantly higher in LIF-treated animals than in control or saline-treated animals (P < 0.01, Student's t test). 5. Unilateral ligation of the L4 spinal nerve or unilateral sciatic nerve ligation was also associated with the formation of TH-IR baskets around sensory neurons and a significant increase in the number of TH-IR fibres within the lumbar spinal nerves (P < 0.01, Student's t test). 6. The percentage of neurones surrounded by TH-IR baskets within the L3 and L4 dorsal root ganglia following sciatic axotomy was significantly reduced in animals treated continuously for 2 weeks with a monoclonal antibody against the LIF receptor motif, gp130 (0.833 mg ml-1) (P < 0.05, Mann-Whitney U test). Antibody treatment did not reduce the axotomy-induced increase in TH-IR fibres within lumbar spinal nerves. 7. These results demonstrate that exogenous application of the axotomy-associated cytokine LIF is associated with sprouting of uninjured postganglionic sympathetic neurones around sensory neurones within the dorsal root ganglion. It is likely that increased LIF expression following peripheral axotomy plays an important role in the novel sympathetic sprouting observed within sensory ganglia following peripheral nerve injury.
Adrenergic Fibers↗