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PubMed2003

Cross-tolerance between spinal neostigmine and morphine in the rat.

BACKGROUND: Direct or indirect acting cholinergic muscarinic agonists such as neostigmine, are potent antinociceptives when administered intrathecally (i.t.). This study examines whether spinal neostigmine tolerance and cross-tolerance to spinal morphine occurs. METHODS: Rats (32/group) were implanted with miniosmotic pumps delivering either i.t. saline 1 microl h(-1) (S), morphine 10 nmol microl(-1) h(-1) (M), or neostigmine 3 nmol microl(-1) h(-1) (N). Latencies (infrared thermal withdrawal rear paw) were measured daily for 6 days after which four animals from each group were given one i.t. challenge dose of morphine (m) 0.1, 1, 10, or 100 nmol, or neostigmine (n) 0.3, 3, 10, or 30 nmol. RESULTS: Neostigmine and morphine-infused animals both developed tolerance to spinal neostigmine, but neostigmine-infused animals showed no significant cross-tolerance to spinal morphine; mean ED(50) nmol (CI 95%) dose-response values were Sn 2.6 (1.9-3.5), Mn 15.6 (9.9-24.6)*, Nn 18.7 (11.7-29.8)*, Sm 0.7 (0.4-1.1), Nm 1.2 (0.8-2.0), Mm 152 (50-461)* (*significance vs saline infused control group). CONCLUSION: Thus, unidirectional cross-tolerance from morphine to neostigmine was evident. Previous studies suggest morphine has a cholinergic mechanism of action partially accounting for its antinociceptive effect, which may explain this observed unidirectional cross-tolerance.

Analgesics, Opioid↗
PubMed1982

Centrally mediated enhancement of ouabain cardiotoxicity by angiotensin II in dogs.

The effect of angiotensin II (Ang II) infusion on the doses of ouabain required to induce ventricular arrhythmias and death was investigated in anesthetized dogs. Tritiated ouabain was infused alone i.v. (1 microgram/kg per min) to establish the control toxic doses and the level of ouabain in the heart at death. When Ang II and ouabain were co-infused i.v. the doses of ouabain needed to induce arrhythmias and death were significantly reduced. Spinal transections performed at C-1 prior to drug infusions prevented the effect of Ang II to enhance the toxicity of ouabain. Thus, the action of Ang II to augment ouabain toxicity appeared to be related to its effects on the sympathetic nervous system. To confirm that Ang II was acting within the brain rather than at peripheral sites of the sympathetic system, Ang II was infused into the vertebral artery of spinal cord intact dogs. The infusion rate of Ang II needed to produce a significant enhancement of ouabain toxicity was much lower when given into the vertebral artery than into the femoral vein. These data indicate that Ang II enhances the cardiotoxicity of ouabain via an action produced within the brain and mediated by the sympathetic nervous system.

Angiotensin II↗
PubMed2005

An epidural cooling catheter protects the spinal cord against ischemic injury in pigs.

BACKGROUND: Using swine, we investigated whether epidural placement of a cooling catheter rather than infusing iced saline solution could protect the spinal cord from ischemia during aortic surgery. METHODS: We divided 14 domestic pigs into two groups of 7 each. Each underwent epidural catheter placement preceding 30 minutes of aortic cross-clamping distal to the origin of the left subclavian artery. In group 1, cold water was circulated continuously through the lumen of the catheter connected to an external unit. In group 2, animals received catheter placement without cooling. Spinal cord somatosensory evoked potentials were recorded. Neurologic status involving hind limbs was graded sequentially after surgery. RESULTS: At aortic cross-clamping, spinal temperature in group 1 (31.7 degrees +/- 0.6 degrees C) was significantly lower than in group 2 (37.8 degrees +/- 0.4 degrees C; p < 0.0001). No significant elevation of intrathecal pressure accompanied cooling with the catheter (group 1, 8.1 +/- 1.7 mm Hg; group 2, 8.0 +/- 1.5 mm Hg). Mean duration of total loss of potentials was significantly shorter in group 1 (7.4 +/- 3.8 minutes) than group 2 (19.7 +/- 7.3 minutes; p = 0.0002). Pigs in group 1 exhibited better hind limb function recovery (mean Tarlov score, 4.7 +/- 0.5) than group 2 (0.6 +/- 0.8; p = 0.0017). Group 1 showed normal histologic characteristics, whereas group 2 showed loss of motor neurons in the ventral horns. CONCLUSIONS: Epidural cooling catheter without iced saline infusion can cool the spinal cord without elevating intrathecal pressure, protecting the cord against ischemia.

Animals↗
PubMed1994

Spinal subdural abscess: successful treatment with limited drainage and antibiotics in a patient with AIDS.

The authors present a case of Staphylococcus aureus spinal subdural abscess in a patient with AIDS. Although complete surgical drainage has been strongly advocated in the literature, this patient made a complete neurologic and symptomatic recovery and radiographically demonstrated resolution of the abscess with only limited surgical drainage and parenteral antibiotics. Magnetic resonance imaging findings of this unusual lesion are discussed. Relevant literature in the management of spinal subdural abscesses is reviewed.

AIDS-Related Opportunistic Infections↗
PubMed1999

Brain-derived TNFalpha mediates neuropathic pain.

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague-Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58 degrees C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.

Animals↗
PubMed1990

[Long-term regional infusion of drugs into the arteries of the spine and spinal cord. 2. Experimental and clinical studies].

The present paper is the result of the next stage of the studies devoted to prolonged intraarterial introduction of drugs into the tissues of the thoracic spine. For the solution of the problems of surgical provision of this task the authors have worked out the operative approaches to the secondary departments of the posterior intercostal arteries and the technique of their retrograde catheterization on 14 cadavers in 31 experimental operations. This method has been used in the complex treatment of 12 patients with acute and inveterate injuries of the thoracic and the thoracolumbar departments of the spinal column and of the spine. The proposed method appears to be prospective and may be used in the treatment of the patients with tumours, inflammatory and other diseases of the thoracic spine.

Adult↗
PubMed1988

A comparison of four techniques to establish intraosseous infusion.

This study was designed to determine whether the success rate in establishing intraosseous infusion (IOI) varied with four different types of needles--standard hypodermic, spinal, bone marrow, and Turkel intraosseous infusion needle. Twenty-four second-year residents from various specialties, without prior training or experience in the technique, participated in the study. Each participant attempted to establish an intraosseous infusion in a randomly assigned limb of an anesthetized piglet, using each needle in a randomly assigned order. The overall success rate was 67.7%. Success ratios varied between needles: hypodermic 54%, spinal 75%, bone marrow 75%, and Turkel 67%. Utilizing Cochran's Q-test, there was no statistical difference in success rates between needle types. However, in cases where the resident was successful with all four needles, the average time to successful infusion was significantly less for bone marrow needles.

Animals↗
PubMed1986

Cutaneous vasomotor sensitivity to noradrenalin in spinal and intact man.

It has been suggested that the increased pressor response to noradrenalin found in tetraplegic patients is due to absence of blood pressure restraining reflexes. However, it has also been found that below the lesion in such patients cutaneous vessels, which in intact man are not under baroreflex control, show prolonged vasoconstriction after sympathetic neural discharges. This finding might indicate that cutaneous blood vessels display an increased sensitivity to noradrenalin in spinal patients. To investigate this, photoelectric cutaneous pulse plethysmograms were monitored during i.v. noradrenalin infusions in six patients with spinal cord injuries and in six intact subjects. There were no significant differences between the groups in either extent or duration of vasoconstriction. The findings provide no evidence that increased sensitivity to noradrenalin is a factor of importance for the attacks of hypertension in tetraplegic patients.

Adult↗
PubMed1980

5-Methoxy-N,N-dimethyltryptamine: spinal cord and brainstem mediation of excitatory effects on acoustic startle.

The effects of different doses (0.03, 0.06, 0.12, 0.25, 1.0, 2.0, 4.0, and 8.0 mg/kg body weight) of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) were tested on the acoustic startle reflex in rats. Beginning at 0.12 mg/kg, 5-MeODMT increased startle monotonically up to the highest dose used. 5-MeODMT still increased startle in acutely decerebrate rats or when infused directly onto the spinal cord. The excitatory effects of a high systemic dose of 5-MeODMT were completely blocked by cinanserin, cyproheptadine, and propranolol, but not by parachlorophenylalanine, alpha-methyl-p-tyrosine, haloperidol, sotalol, or phenoxybenzamine. The results were discussed in terms of a new theory, which suggests that stimulation of serotonin receptors in the spinal cord enhance startle whereas serotonin receptors in the forebrain inhibit startle.

Acoustic Stimulation↗
PubMed2005

Effects of epidural hypothermic saline infusion on locomotor outcome and tissue preservation after moderate thoracic spinal cord contusion in rats.

OBJECT: Regionally delivered hypothermia has advantages over systemic hypothermia for clinical application following spinal cord injury (SCI). The effects of local hypothermia on tissue sparing, neuronal preservation, and locomotor outcome were studied in a moderate thoracic spinal cord contusion model. METHODS: Rats were randomized to four treatment groups and data were collected and analyzed in a blinded fashion. Chilled saline was perfused into the epidural space 30 minutes postcontusion to achieve the following epidural temperatures: 24 +/- 2.3 degrees C (16 rats), 30 +/- 2.4 degrees C (13 rats), and 35 +/- 0.9 degrees C (13 rats). Hypothermia was continued for 3 hours when a 45-minute period of rewarming was instituted. In a fourth group a moderate contusion only was induced in 14 animals. Rectal (core) and T9-10 (epidural) temperatures were measured continuously. Locomotor testing, using the Basso-Beattie-Bresnahan (Ba-Be-Br) scale, was performed for 6 weeks, and rats were videotaped for subsequent analysis. The lesion/preserved tissue ratio was calculated throughout the entire lesion cavity and the total lesion, spinal cord, and spared tissue volumes were determined. The rostral and caudal extent of gray matter loss was also measured. At 6 weeks locomotor recovery was similar in all groups (mean Ba-Be-Br Scale scores 14.88 +/- 3.71, 14.83 +/- 2.81, 14.50 +/- 2.24, and 14.07 +/- 2.39 [p = 0.77] for all four groups, respectively). No significant differences in spared tissue volumes were found when control and treatment groups were compared, but gray matter preservation was reduced in the infusion-treated groups. CONCLUSIONS: Regional cooling applied 30 minutes after a moderate contusive SCI was not beneficial in terms of tissue sparing, neuronal preservation, or locomotor outcome. This method of cooling may reduce blood flow in the injured spinal cord and exacerbate secondary injury.

Analysis of Variance↗
PubMed2004

Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation.

The effects of bone marrow stromal cells (BMSCs) on the repair of injured spinal cord and on the behavioral improvement were studied in the rat. The spinal cord was injured by contusion using a weight-drop at the level of T8-9, and the BMSCs from the bone marrow of the same strain were infused into the cerebrospinal fluid (CSF) through the 4th ventricle. BMSCs were conveyed through the CSF to the spinal cord, where most BMSCs attached to the spinal surface although a few invaded the lesion. The BBB score was higher, and the cavity volume was smaller in the rats with transplantation than in the control rats. Transplanted cells gradually decreased in number and disappeared from the spinal cord 3 weeks after injection. The medium supplemented by CSF (250 microl in 3 ml medium) harvested from the rats in which BMSCs had been injected 2 days previously promoted the neurosphere cells to adhere to the culture dish and to spread into the periphery. These results suggest that BMSCs can exert effects by producing some trophic factors into the CSF or by contacting with host spinal tissues on the reduction of cavities and on the improvement of behavioral function in the rat. Considering that BMSCs can be used for autologous transplantation, and that the CSF infusion of transplants imposes a minimal burden on patients, the results of the present study are important and promising for the clinical use of BMSCs in spinal cord injury treatment.

Animals↗
PubMed2003

Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain.

It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF). In this study, we have determined the ability of chronic intrathecal (i.t.) infusion of NGF to reverse neuropathic pain symptoms and to restore morphine's effectiveness in an animal model of neuropathic pain. Seven days after sciatic nerve constriction injury, NGF was administered to the spinal cord by continuous infusion (125 ng/microl/h) via osmotic pumps attached to chronically implanted i.t. catheters. Spinal infusion of NGF did not affect the expression of tactile allodynia or thermal (hot) hyperalgesia in neuropathic rats, although it significantly increased cold water responses frequency at day 14. Following infusion of vehicle, i.t. morphine (20 microg) was ineffective in altering somatosensory thresholds in neuropathic rats. In contrast, morphine substantially attenuated the neuropathy-induced warm and cold hyperalgesia, as well as tactile allodynia, in neuropathic rats chronically infused with i.t. NGF. In addition, we demonstrate that i.t. morphine-induced antinociception was augmented by a cholecystokinin (CCK) antagonist in animals chronically infused with i.t. antibodies directed against NGF. We hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.

Analgesics, Opioid↗
PubMed1992

Evidence that local non-NMDA receptors contribute to functional deficits in contusive spinal cord injury.

To investigate the role of non-N-methyl-D-aspartate (non-NMDA) types of excitatory amino acid (EAA) receptors in traumatic spinal cord injury, we administered 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), a potent and specific antagonist of non-NMDA receptors, to rats with a standardized contusive spinal cord injury. Focal infusion of NBQX into the injury site significantly reduced long-term hindlimb functional deficits as well as decreasing the time required for the rats to establish a reflex bladder. The results suggest that non-NMDA receptors at or near the injury site are involved in producing a portion of the functional deficits that result from contusive spinal cord injury.

Animals↗
PubMed2006

Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene.

We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Intraspinal drug therapy.

Intraspinal drug delivery provides agents directly to their site of action. These sites, receptors within the spinal cord, are bound to a greater degree when drugs are administered intraspinally. The purpose for drug therapy, the acute or chronic nature of delivery, and the drug administration system affect the choice of epidural versus intrathecal route of delivery. Pharmacologic properties, such as solubility, pH, and pKa, aid in dictating the drug chosen for administration. Intraspinal opiates and anesthetics have been used extensively since the 1970s in postoperative, postpartum, and cancer populations. Various delivery systems are in use, including external catheters and implanted ports and pumps. Nursing care includes titration of doses, prevention and management of side effects, and maintenance of delivery systems. Intrathecal baclofen is a new treatment for severe spasticity for patients with multiple sclerosis or spinal cord injury. Candidates include patients who experience persistent spasticity unrelieved by antispasmodics or who experience unacceptable side effects to those oral drugs. Nurses assess spasticity, titrate the intrathecal baclofen to obtain an acceptable degree of spasticity, and manage side effects associated with intrathecal baclofen. A long-term benefit of intraspinal drug delivery, potentially providing benefit to many patients, is the identification of experimental agents that do not cross the blood-brain barrier but prove effective when delivered intraspinally. Pharmacologists and others then might undertake the costly modifications necessary to improve the solubility of the drug. The analogue then might be given orally. "The feasibility of an operation is not an indication for its performance." These words, attributed to the late Lord Cohen, also apply to intraspinal drug delivery. As with any therapy, the simplest and least invasive course should be taken. If, for example, the patient experiences good relief without side effects when given oral opiates or baclofen, there is no good rationale for inserting an intraspinal catheter. The potential for increased morbidity and the escalated expense make this an illogical choice. There are, however, many patients who cannot tolerate oral opiates or baclofen but obtain significant benefit from intraspinal drug delivery. Those who benefit should not be denied this therapy. Much research is necessary as this modality develops. Nurses who comprehend the science of intraspinal drug delivery, as well as the art of patient management, can contribute to this advancing field.

Analgesia, Epidural↗
PubMed1997

Epinephrine increases spinal cord concentrations of [3H]-clonidine hydrochloride in rabbits after epidural infusion.

Epinephrine is often given with epidurally administered drugs to prolong and enhance analgesia, which is partly attributed to alpha-adrenergic processes. This investigation evaluates the effect of epinephrine on the distribution of epidurally administered [3H]-clonidine hydrochloride (clonidine HCl) in serum and in the central nervous system. After placing a lumbar epidural catheter via a laminectomy, rabbits were randomly assigned to receive 20 microCi of clonidine HCl with epinephrine (1:200,000) (n = 5) or without (control; n = 5) for 90 min. During the administration, which included bolus and slow infusion, blood samples were collected at 15-min intervals. At the end of the administration, rabbits were perfused with normal saline, leading to exsanguination. Brain and spinal cord tissues were excised for radiometric analysis. In both groups, the concentration of clonidine HCl was greatest in the lumbar cord. Epinephrine further enhanced accumulation of clonidine HCl into the lumbar cord but did not alter the concentration of clonidine HCl in serum, brain, cervical cord, and thoracic cord. We conclude that lumbar administration of epidural clonidine HCl leads to increased concentrations in the lumbar cord, which is further enhanced by epinephrine. The increased spinal cord accumulation of clonidine may be another mechanism by which epinephrine improves epidural analgesia.

Adrenergic Agonists↗
PubMed2006

Opiate pharmacology of intrathecal granulomas.

BACKGROUND: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Analgesics, Opioid↗
PubMed1990

Intra-cerebral ventricular infusion of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer in the treatment of a rat glioma.

The efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when administered by continuous infusion into the cerebral spinal fluid (CSF) of the lateral cerebral ventricle was evaluated in a 9L gliosarcoma rat brain tumor model. Stereotactic implantation of a 5 x 10(4) tumor cell suspension into the left caudate nucleus was carried out in four groups of 10 rats each. Control animals had a median survival of 16.9 days (range 16-21 days). IUDR, 8.4 mg over 7 days administered by continuous infusion into the left lateral ventricle produced a slight survival advantage (median survival 21.5 days, range 12-56). Irradiation of the entire brain, 8 Gy on days 4, 6 and 7 after tumor cell implantation also produced a slight improvement in survival (median 19.5 days, range 17-34). The combination of radiation and IUDR infusion into the CSF produced a marked survival advantage (median 30.5, range 22-54) compared to the control and single modality treatment groups. This is the first demonstration of the effectiveness of IUDR as a radiosensitizer when administered into the lateral cerebral ventricle in the treatment of an intraparenchymal brain tumor.

Animals↗