strychnine and Muscle-Spasticity

Spastic (spa), spasmodic (spd), and oscillator (ot) mice have naturally occurring glycine receptor (GlyR) mutations, which manifest as motor deficits and an exaggerated "startle response." Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function. Mean glycinergic miniature IPSC (mIPSC) amplitude and frequency were dramatically reduced (>50%) compared with controls for each mutant. mIPSC decay times were unchanged in spa/spa (4.5 +/- 0.3 vs 4.7 +/- 0.2 ms), reduced in spd/spd (2.7 +/- 0.2 vs 4.7 +/- 0.2 ms), and increased in ot/ot (12.3 +/- 1.2 vs 4.8 +/- 0.2 ms). Thus, in spastic, GlyRs are functionally normal but reduced in number, whereas in spasmodic, GlyR kinetics is faster. The oscillator mutation results in complete absence of alpha1-containing GlyRs; however, some non-alpha1-containing GlyRs persist at synapses. Fluctuation analysis of membrane current, induced by glycine application to outside-out patches, showed that mean single-channel conductance was increased in spa/spa (64.2 +/- 4.9 vs 36.1 +/- 1.4 pS), but unchanged in spd/spd (32.4 +/- 2.1 vs 35.3 +/- 2.1 pS). GlyR-mediated whole-cell currents in spa/spa exhibited increased picrotoxin sensitivity (27 vs 71% block for 100 microM), indicating alpha1 homomeric GlyR expression. The picrotoxin sensitivity of evoked glycinergic IPSCs and conductance of synaptic GlyRs, as determined by nonstationary variance analysis, were identical for spa/spa and controls. Together, these findings show the three mutations disrupt GlyR-mediated inhibition via different physiological mechanisms, and the spastic mutation results in "compensatory" alpha1 homomeric GlyRs at extrasynaptic loci.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Biological Clocks; Brain Stem; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; Genotype; Glycine; Glycine Agents; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Motor Neurons; Muscle Spasticity; Neural Inhibition; Patch-Clamp Techniques; Picrotoxin; Receptors, Glycine; Strychnine; Synaptic Transmission; Torticollis

A rare case of suicidal strychnine poisoning that resolved naturally without treatment is presented. The patient first complained of chest pain, which was originally thought to be caused by a dissecting aneurysm; however, nystagmus, dysesthesia, spastic paraplesia, and hyperreactivity to stimuli shortly developed. Diagnosis was difficult because the patient did not disclose the drinking of strychnine or the suicidal intent, and no abnormal signs were seen in the various central nervous system examinations. The natural course was observed without treatment because the patient's circulatory and respiratory condition was good. Movement disturbances in the upper extremities disappeared after 2 days, nystagmus in 3 days, and dysesthesia and spastic paraplesia in 4 days. The patient was able to stand on the fourth day and walk on the seventh. He was discharged on day 10 without any detectable ill effects.

Topics: Central Nervous System Diseases; Diagnosis, Differential; Humans; Hyperesthesia; Male; Middle Aged; Muscle Spasticity; Paraplegia; Poisoning; Strychnine; Suicide, Attempted

1. We previously reported that volatile anaesthetics produce incidences of a transient opisthotonus in mice, a sign of CNS stimulation. This study was performed to investigate mechanisms by which enflurane-induced opisthotonus (EIO) occurs. 2. The effects of pretreatment of N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK-801; DIZ) and ketamine (KET), GABAA antagonists picrotoxin (PIC), pentylenetetrazol (PTZ) and glycine antagonist strychnine (STR) on the incidence of EIO were determined. Prior to exposure to 2.0% enflurane in air, male ddN mice were given intraperitoneal injections of 0.2 mL saline (control), 0.5-5.0 mg/kg DIZ, 20-80 mg/kg KET, 2.9 mg/kg PIC, 40.0 mg/kg PTZ and 0.75 mg/kg STR. After the injection, the behavioural state of the mice was observed for 20 min (the pre-enflurane period). During the exposure to enflurane the time for immobilization, that is, anaesthetic induction time (IT), and the incidence of EIO were measured. 3. Dizocilpine (1.0-5.0 mg/kg) and KET (80 mg/kg) significantly (P < 0.01) reduced both the incidence of EIO and IT in a dose-dependent manner. During the pre-enflurane period DIZ produced incidences (5-40%) of transient seizures in a dose-dependent manner, while KET did not induce them at all. The two GABAA antagonists had no detectable effect on the EIO. Strychnine significantly enhanced the EIO. These CNS stimulants resulted in a 3-10% incidence of transient seizure and/or opisthotonus during the pre-enflurane period, but there was no correlation between DIZ-induced seizure and EIO. 4. These results suggest that the EIO is mediated by the NMDA and the STR-sensitive glycine receptors, but not the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enflurane; Male; Mice; Mice, Inbred Strains; Muscle Spasticity; Pentylenetetrazole; Picrotoxin; Receptors, GABA-A; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Strychnine

Selected examples from three series of isomeric (alkylthio)-1,2,4-triazoles were prepared and examined for anticonvulsant activity versus strychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptopropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthio)-4H-1,2,4-triazoles were selective antagonists of strychnine-induced convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthio)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. The most potent antagonist of strychnine-induced convulsions was 5-(2-fluorophenyl)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selective antagonist was 5-(3-fluorophenyl)-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-1,2,4-triazoles suggested that they were acting functionally like glycine receptor agonists. Since it has recently been postulated that compounds possessing glycine-agonist-like properties might be useful in the treatment of spasticity, we examined 5-phenyl-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3c) in an in vivo model of spasticity. In this regard, 3c reduced the occurrence of hyperreflexia in rats that had received spinal transections 5-10 weeks previously. While triazole 3c appeared to possess glycine-agonist-like properties in vivo, it did not displace [3H]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated 36Cl influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABAA receptor.

Topics: Animals; Anticonvulsants; Cerebellum; Cerebral Cortex; Chlorides; Electroshock; Flumazenil; Male; Mice; Molecular Structure; Muscle Spasticity; Paralysis; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship; Strychnine; Triazoles

A new autosomal recessive mutation, characterized by an early defect in righting reflex and stiffened gait, progression to severe spasticity, tremor and rigidity, and death before weaning, appeared spontaneously on the C57BL/6 background. It was shown to be an allele of the mutant spastic spa, and shall be known as spaAlb. Mutant levels of [3H]strychnine binding are less than 10% of control levels in the brainstem and spinal cord. Autoradiographic examination of the distribution of [3H]strychnine binding sites in the mutant confirm a greatly reduced level of binding compared to control in all areas of the spinal cord, brainstem, and midbrain.

Topics: Alleles; Animals; Central Nervous System; Female; Genetics, Behavioral; Male; Mice; Mice, Neurologic Mutants; Muscle Spasticity; Mutation; Strychnine

Spinal cord reflexes have been examined in a preparation of the mouse spinal cord maintained in vitro. Responses of the motoneurone population of normal and spastic mutant mice to stimulation of a segmental dorsal root were compared. In the normal spinal cord, a monosynaptic response with very little polysynaptic excitation was typical. In the mutant, the monosynaptic response was typically followed by a depolarizing wave on which asynchronous compound action potentials were superimposed. In some spastic cords, an oscillating depolarizing wave was seen, lasting up to 500 ms. The stimulus range from threshold to maximal response was the same for the normal and mutant. The dorsal root reflex (d.r.r.) and dorsal root potential (d.r.p.) were prominent in both normal and mutant, and no consistent difference could be identified. Intracellular recordings were made from motoneurones using electrodes filled with potassium acetate. Mean resting potentials and input resistances were not significantly different in mutant and normal mice. The voltage-dependent conductances, seen as the after-depolarization and after-hyperpolarizations following antidromic action potentials and the responses of motoneurones to depolarizing current injection were similar in both populations. The synaptic responses of motoneurones following stimulation of the segmental dorsal root were clearly abnormal in the mutant. In the normal mice, a monosynaptic excitatory post-synaptic potential (e.p.s.p.), seen at low stimulus intensities, was followed at higher stimulus intensities by polysynaptic activity lasting up to 100 ms, which rarely reached threshold for action potential discharge. In the mutant mice, the monosynaptic response was typically followed by depolarizing synaptic responses which often evoked action potentials before the monosynaptic response reached threshold. At higher stimulus intensities, the monosynaptic response was followed by at least one and often multiple action potentials generated on prolonged depolarizing synaptic activity. When cells were impaled with potassium-acetate-filled electrodes, very little spontaneous synaptic activity was seen in either normal or mutant mice. Spontaneous depolarizing post-synaptic potentials (p.s.p.s) were prominent in normal motoneurones when potassium chloride was used to fill electrodes and were increased in amplitude by ionophoresis of chloride into the cells. Under these conditions stimulation of a ventral root evoked a depolarizin

Topics: Acetates; Acetic Acid; Action Potentials; Animals; In Vitro Techniques; Mice; Motor Neurons; Muscle Spasticity; Potassium Chloride; Reflex, Abnormal; Reflex, Monosynaptic; Spinal Cord; Strychnine; Synapses

Electromyographic (EMG) studies were carried out with the genetically spastic mouse (spa, autosomal recessive), obtained from matings of B6C3a/a, spa/+ heterozygotes. Spastic homozygotes exhibited high amplitude repetitive EMG bursts during spontaneous activity. Following an electrical stimulus to hindlimb or forelimb, high amplitude stereotyped EMG bursts were recorded from contralateral limbs in spastic mice, but were not observed in phenotypically unaffected littermates or normal C57BL/6J mice. The timing and latency of this stereotyped response to an electrical stimulus was consistent with the participation of spinal cord neuronal pathways. In normal C57BL/6J mice the administration of strychnine (0.65 mg/kg), but not picrotoxinin (up to convulsant doses), reproduced all of the behavioral and EMG features observed in spastic homozygotes. We hypothesize that the symptoms in the spastic mutant may result from a deficiency of strychnine-sensitive (presumably glycinergic) inhibition in the spinal cord.

Topics: Animals; Electromyography; Forelimb; gamma-Aminobutyric Acid; Hindlimb; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Muscle Spasticity; Neuromuscular Junction; Strychnine

Strychnine intoxication is manifested by agitation, muscle spasms, and convulsions. We report a case in which intractable convulsions led to severe lactic acidosis which secondarily resulted in visceral (lung, heart, kidney, liver, and brain) collapse and death. Aggressive therapy instituted in the emergency department and aimed at control of seizure activity and lactic acidosis may be lifesaving.

Topics: Acidosis; Adult; Emergency Service, Hospital; Humans; Male; Muscle Spasticity; Seizures; Strychnine

Topics: Aminobutyrates; Animals; Cats; Decerebrate State; Glycine; Humans; Motor Neurons; Muscle Spasticity; Muscle Spindles; Neural Conduction; Neurons, Afferent; Reflex; Spasm; Spinal Cord; Strychnine