naloxone and Paralysis

Spread of neuroadapted Sindbis virus (NSV) to motor neurons (MN) of the spinal cord (SC) causes severe hind limb weakness in C57BL/6 mice and models the paralysis that can accompany alphavirus and flavivirus encephalomyelitis in humans. The fate of spinal MN dictates the severity of NSV-induced paralysis, and recent data suggest that MN damage can occur indirectly via the actions of activated microglial cells. Because the opioid receptor antagonist, naloxone (NAL), blocks microglial-mediated neurodegeneration in other models, we examined its effects during NSV infection. Drug treatment prevented paralysis and enhanced the survival of MN without altering NSV tropism, replication, or clearance from SC tissue. Further studies showed that NAL most effectively inhibited paralysis in a 72-h window after NSV challenge, suggesting that the drug inhibits an early event in SC pathogenesis. Histochemical studies demonstrated that NAL blocked early microglial activation in SC tissue sections, and protein assays showed that the early induction of pathogenic IL-1 beta was blunted in SC homogenates. Finally, loss of glutamate transporter-1 (GLT-1) expression in SC, an astrocyte glutamate reuptake protein responsible for lowering toxic extracellular levels of glutamate and preventing MN damage, was reversed by NAL treatment. This GLT-1 loss proved to be highly IL-1 beta-dependent. Taken together, these data suggest that NAL is neuroprotective in the SC by inhibiting microglial activation that, in turn, maintains normal astrocyte glutamate homeostasis. We propose that drugs targeting such microglial responses may have therapeutic benefit in humans with related viral infections.

Topics: Alphavirus Infections; Animals; Blotting, Western; Cytokines; Encephalomyelitis; Excitatory Amino Acid Transporter 2; Hindlimb; Immunohistochemistry; Interleukin-1beta; Mice; Mice, Inbred C57BL; Motor Neurons; Naloxone; Narcotic Antagonists; Paralysis; Sindbis Virus; Spinal Cord; Tissue Extracts

We studied factors that influence paralysis risk, renal function, and mortality in thoracoabdominal aortic replacement.. We prospectively collected preoperative demographic and intraoperative physiologic data and used univariate and multivariate analyses to correlate this data with risk factors for paralysis. A mathematical model of paraplegia risk was used to study the efficacy of paraplegia reduction strategies. We analyzed preoperative and operative factors for paralysis risk, renal function, and mortality for 217 consecutive patients surgically treated from 1984 through 1996 for 176 thoracoabdominal and 41 thoracic aneurysms at the University of Wisconsin Hospital and Clinics. No patient had intercostal reimplantation or assisted circulation. One hundred fifty patients (group A) received cerebrospinal fluid drainage (CSFD) and low-dose naloxone (1 microg/kg/hour) as adjuncts to reduce the risk of paralysis. Sixty-seven patients (group B) did not receive CSFD and naloxone.. Seventeen deficits occurred in 205 surviving patients: 5 of the 147 in group A (expected deficits = 31) and 12 of the 58 in group B (expected deficits = 13) (p < 0.001). In a multivariate logistic regression model, acute presentation, Crawford type 2 aneurysm, group B membership, and a decrease in cardiac index with aortic occlusion remained significant risk factors for deficit (p < 0.0001). By odds ratio analysis, group A patients had 1/40th the risk of paralysis of group B. The only significant predictor of postoperative renal function was the preoperative creatinine level (p < 0.0001); renal revascularization significantly improved renal function. The mortality rate was 1.6% (2) for patients undergoing elective treatment and 21% (19) for patients who had acute presentations. Acute presentation, age, and the preoperative creatinine level were found to be significant factors for operative mortality in a logistic regression model (p < 0.001) and defined a group at high risk for death.. CSFD and low-dose naloxone significantly reduce the paralysis risk associated with thoracoabdominal aortic replacement. A decrease in the cardiac index with aortic occlusion is a previously unreported variable that defines a subset of patients at higher risk for paralysis.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Blood Vessel Prosthesis Implantation; Cardiac Output; Cerebrospinal Fluid; Creatinine; Demography; Drainage; Female; Heart; Humans; Kidney; Logistic Models; Male; Middle Aged; Monitoring, Intraoperative; Multivariate Analysis; Naloxone; Narcotic Antagonists; Odds Ratio; Paralysis; Paraplegia; Prospective Studies; Reperfusion; Risk Factors; Survival Rate

Intrathecal injection of dynorphin A produced dual effects on sensory and motor functions in the spinal cord of the rat. At a dose of 5 nmol, dynorphin A produced an increase in tail flick latency (TFL) as well as a reversible motor paralysis as assessed by change in the angle of inclined plane. At a dose of 10 or 20 nmol, dynorphin produced a motor paralysis lasting for up to 24 hours. The effect of dynorphin A on the sensory function of the spinal cord was shown by an increase in the vocalization threshold induced by electrical stimulation of the tail, at dose range of 1.25-10 nmol, with a quick onset (5 min) and relatively short duration (within 60 min). Unlike tail flick reaction which involves spinal motor function, tail stimulation-induced vocalization threshold is a relatively pure index for spinal nociceptive activities. The differential effect of dynorphin on sensory and motor function was supported by the evidence that (1) dynorphin-induced analgesic effect (increase in vocalization threshold) was naloxone reversible, whereas dynorphin-induced motor paralysis was naloxone resistant. (2) Nor-BNI, a specific antagonist for kappa opioid receptor, blocked the sensory effect of dynorphin, but had no influence on motor effect of dynorphin. It is thus concluded that dynorphin has both analgesic and paralytic effects in spinal cord. The analgesia shown by an increase of vocalization threshold is an opioid effect, most probably mediated by kappa opioid receptor; the paralytic effect, however, is a non-opioid effect. The increase of TFL induced by dynorphin involves both sensory (analgesia) and motor (paralysis) effects.

Topics: Analgesics; Animals; Dynorphins; Injections, Spinal; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Pain Threshold; Paralysis; Psychomotor Performance; Rats; Rats, Wistar; Reaction Time; Spinal Cord; Vocalization, Animal

A technique of epidural catheterization in rabbits is described. Twelve albino rabbits received a totally implanted epidural catheter system. The system was implanted surgically, and the functioning of the system tested for a period of 3 months. X-ray examinations following epidural contrast injections showed a distribution up to Th4 following 1.5 ml and Th8-9 following 1.0 and 1.25 ml. Epidural injection of lidocaine throughout the study period proved the system to be functioning for all 3 months. Another 12 rabbits were included for the neurotoxicological examinations following epidural catheterization, without any injections (three rabbits), epidural injections of saline (four rabbits) and meptazinol (five rabbits) once a day for 14 days. Histopathological examinations showed a fibrous cocoon, at the tip of the catheter, in all rabbits. In the group of rabbits which did not receive any injections, the cocoon was slightly infiltrated with leukocytes and local depression of the spinal cord was observed in one rabbit. In the saline-injected group this infiltration was more pronounced and in one rabbit it extended into the meninges. Three rabbits showed local depression of the spinal cord and local myelopathy of the white matter in the area adjacent to the cocoon. In the group of rabbits receiving meptazinol, three out of five had local depression and myelopathy of the white matter. In this group these findings were more pronounced. In two rabbits the myelopathy extended transversely through the white matter into the grey matter of the spinal cord. The number of pathological changes in the group receiving meptazinol was significantly higher compared to the control and placebo groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Catheterization; Drug Tolerance; Female; Injections, Epidural; Lidocaine; Lumbar Vertebrae; Meptazinol; Myelitis; Naloxone; Pain; Paralysis; Placebos; Polyradiculopathy; Rabbits; Sodium Chloride; Spinal Cord; Spinal Cord Diseases

The neural injury prevention capabilities of narcotic antagonists have previously been reported. Of the available narcotic antagonists, naloxone has been the most widely studied. Other agents with higher potency, longer half-lives, and greater specificity, however, may be more desirable for the prevention of the "secondary injury" following a primary neural insult. The relative neural injury prevention efficacies of the various narcotic antagonists is not known. The establishment of the relative effectiveness of these drugs is warranted and is of potential clinical importance. Therefore, a study was undertaken to compare the effects of the two narcotic antagonists, naloxone and nalmefene, with respect to their neuro-protective efficacy following experimental spinal cord injury (SCI) in rats. Ninety adult Sprague-Dawley rats were divided into three groups--control; naloxone (2 mg/kg i.p., 45 min following injury); and nalmefene (0.1 mg/kg i.p., 45 min following injury)--following lesioning with the ventral SCI technique. Results were evaluated by the inclined-plane technique and neurologic examination at 1 day and 1 week following injury. Histomorphological evaluation of the injured segment of spinal cord was performed following euthanasia at 1 week following injury. A significant improvement (compared with the control group) was noted in both treatment groups. This was observed with respect to neurological examination and inclined-plane scores in both treatment groups at 24 h and 1 week following lesioning (with a significance level of at least p less than 0.001; analysis of variance). The nalmefene group demonstrated a greater level of function than the naloxone group at both 24 h and 1 week following injury (not significant; p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Drug Evaluation, Preclinical; Intervertebral Disc Displacement; Naloxone; Naltrexone; Nerve Crush; Paralysis; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Spinal Cord Injuries; Spinal Fractures

Injections of high doses of etorphine (0.0625, 0.25, or 1.0 mumol) or equimolar fentanyl into the cerebral ventricles of rats induced a sequence of motor effects including catatonia, a novel flaccid paralysis, and recurrent catatonia. These effects were dose related, naloxone reversible, and reveal an opiate specific organization of a central motor hierarchy.

Topics: Animals; Etorphine; Fentanyl; Injections, Intraventricular; Injections, Spinal; Male; Naloxone; Paralysis; Rats; Rats, Inbred Strains; Receptors, Opioid

Dynorphin A-(1-17) acts through non-opioid mechanisms to produce dose-related neurological deficits following injection into the lumbar spinal subarachnoid space in rats. Hindlimb motor function was examined following subarachnoid injection of dynorphin A fragments and other opioid peptides derived from prodynorphin to establish: (1) which portion(s) of the dynorphin A molecule cause hindlimb motor dysfunction, and (2) whether these paralytic actions are shared by other opioids (dynorphin B, alpha-neo-endorphin, and beta-neo-endorphin) derived from the same promolecule. To minimize the influence of enzymatic inactivation on relative bioactivities, peptides were coinjected with a combination of peptidase inhibitors previously shown to enhance the actions of dynorphin A fragments in vitro. Dynorphin A-(1-17) and -(2-17) produced dose-related neurological deficits with equal potencies and durations. Although without effect when injected alone, dynorphin A-(1-8), -(1-7) and -(3-8) caused transient motor dysfunction when co-injected with peptidase inhibitors. In contrast, dynorphin A-(1-6), -(1-5) and -(6-17) did not disrupt hindlimb motor function with or without peptidase inhibition. Dynorphin B, alpha-neo-endorphin and beta-neo-endorphin also caused hindlimb dysfunction which was potentiated by peptidase inhibition. These deficits appeared to result from non-opioid actions of these three peptides, since they were not blocked by the opioid antagonist naloxone. Thus, the paralytic effects of dynorphin A: (1) result from non-opioid actions involving the 3-7 or 3-8 positions of the molecule, and (2) are shared by other prodynorphin-derived opioid peptides.

Topics: Animals; Dynorphins; Hindlimb; Injections; Male; Naloxone; Paralysis; Rats; Rats, Inbred Strains; Spinal Cord; Subarachnoid Space

Topics: Animals; Cats; Dose-Response Relationship, Drug; Drug Combinations; Female; Methylprednisolone; Motor Activity; Naloxone; Paralysis; Spinal Cord Injuries

Intrathecal administration of dynorphin A in rats produced dose-dependent antinociceptive effects in the tail-flick test to radiant heat and on a limb-flexion test to pressure. The potency of dynorphin A as an analgesic agent on the tail-flick test was dependent upon the duration of cannula implantation. When a short-term procedure was used (drug injected 1 day after catheter implantation) dynorphin A was approximately equipotent to morphine, whereas in animals with long-term implants (drug injected 7 or more days after catheter implantation) dynorphin A was an order of magnitude less potent than morphine. [D-Ala2,D-Leu5]enkephalin was the most potent opioid tested, and in the tail-flick test (long-term procedure) it was about 2 orders of magnitude more potent than dynorphin A and 7 times more potent than morphine. [Leu]enkephalin had no detectable antinociceptive effects. Low doses of naloxone (1 and 2 mg/kg s.c.) completely blocked the antinociceptive effects of morphine and [D-Ala2,D-Leu5]enkephalin, but neither low nor high (40 mg/kg s.c.) doses clearly blocked the antinociceptive effects of dynorphin A. Thus, dynorphin A has an antinociceptive action at the level of the spinal cord, and mu opioid receptors do not mediate these effects. In addition, high doses of dynorphin A (20 nmol or greater) produced long-lasting hindlimb paralysis, which suggests that dynorphin peptides may play a role in motor function in the spinal cord. This paralytic action of dynorphin A was not antagonized by naloxone in doses up to 32 mg/kg s.c.

Topics: Animals; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Morphine; Motor Activity; Naloxone; Nociceptors; Paralysis; Rats; Rats, Inbred Strains

Topics: Aged; Brain; Endorphins; Humans; Naloxone; Paralysis

We compared effects on motor function of four peptides belonging to the dynorphin family--dynorphin-(1-17) (DYN-(1-17], dynorphin-(1-13) (DYN-(1-13], dynorphin-(1-8) (DYN-(1-8] and alpha-neo-endorphin (alpha NE). After intrathecal administration, each of these peptides produced dose-related, flaccid, hindlimb paralysis, with the order of potency being DYN-(1-17) greater than DYN-(1-13) greater than alpha NE congruent to DYN-(1-8). This motor dysfunction was not reversed or blocked by the opiate receptor antagonist naloxone and was not produced by a variety of other kappa-selective agonists. However, paralysis was produced by des-Tyr-dynorphin (DYN-(2-17], which does not act at the opioid receptor. Taken together, the present studies show that dynorphin-related peptides, uniquely amongst opioids, produce motor dysfunction, an action which does not appear to be mediated by opioid receptors.

Topics: Animals; Dose-Response Relationship, Drug; Dynorphins; Endorphins; Male; Motor Activity; Naloxone; Paralysis; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Opioid

Topics: Animals; Biological Assay; Calcium Chloride; Convulsants; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; Isoquinolines; Mice; Muscle Contraction; Naloxone; Narcotics; Paralysis; Salsoline Alkaloids; Seizures; Tetrahydroisoquinolines