strychnine and Chronic-Disease

Isovaline, a nonproteinogenic alpha-amino acid rarely found in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and gamma-aminobutyric acid. Because glycine(A) and gamma-aminobutyric acid receptor agonists are antiallodynic, we hypothesized that isovaline produces antinociception in mice.. All experiments were performed on female CD-1 mice using a blinded, randomized, and controlled design. The effects of RS-isovaline were studied on nociceptive responses to (1) formalin injection into the hindpaw; (2) glutamate injection into the hindpaw; and (3) strychnine injection either into the lumbar intrathecal space or cisterna magna. We determined the effects of IV RS-isovaline (50, 150, or 500 mg/kg; n = 10/dose) or intrathecal RS-, R-, and S-isovaline, glycine, and beta-alanine into the lumbar intrathecal space (5-microL volumes of 60, 125, 250, and 500 mM; n = 9/dose/group) on the response to formalin in the paw. The response to 20 microL intraplantar glutamate (750 mM) was compared with glutamate (750 mM) coadministered with isovaline. We also determined the response to intraplantar strychnine. Lumbar intrathecal (100 microM) or intracisternal (200 microM) injections of strychnine into the lumbar intrathecal space or the cisterna magna were used to induce allodynia as a measure of glycine inhibitory dysfunction. The effects of intrathecal or intracisternal strychnine were compared with isovaline coapplied with the strychnine (n = 8/group).. In the formalin paw test, IV isovaline did not change phase I but decreased phase II responses in a dose-dependent manner (50% effective dose = 66 mg/kg, n = 10, P < 0.01). There was no effect on rotarod performance, appearance, or behavior of the mouse, and no respiratory depression. Intrathecal isovaline, glycine, and beta-alanine attenuated phase I and II responses (P < 0.01 for each drug). In contrast to beta-alanine and glycine, isovaline at maximally effective doses did not produce scratching, biting, or agitation. Intrathecal RS- and S-isovaline attenuated phase I (P < 0.05 for each group) and RS-, R-, and S-isovaline attenuated phase II responses (P < 0.05 for each group), with no significant difference between the efficacies of R- and S-enantiomers. Localized strychnine-induced glycine inhibitory dysfunction was greatly reduced by intracisternal (P < 0.01) and intrathecal (P < 0.01) isovaline. Although intraplantar strychnine did not induce peripheral allodynia, high doses of isovaline did not block the peripheral allodynia induced by glutamate.. Isovaline reduced responses in mouse pain models without producing acute toxicity, possibly by enhancing receptor modulation of nociceptive information.

Topics: Acute Disease; Analgesics, Non-Narcotic; Animals; beta-Alanine; Chronic Disease; Cisterna Magna; Female; Formaldehyde; Glutamic Acid; Glycine; Hypnotics and Sedatives; Injections; Injections, Intravenous; Injections, Spinal; Mice; Models, Molecular; Pain; Pain Measurement; Postural Balance; Receptors, Glutamate; Strychnine; Valine

Although spinal injury is a major cause of chronic disability, the mechanisms responsible for the lesion pathophysiology and their dynamic evolution remain poorly understood. Hence, current treatments aimed at blocking damage extension are unsatisfactory. To unravel the acute spinal injury processes, we have developed a model of the neonatal rat spinal cord in vitro subjected to kainate-evoked excitotoxicity or metabolic perturbation (hypoxia, aglycemia, and free oxygen radicals) or their combination. The study outcome is fictive locomotion one day after the lesion and its relation to histological damage. Excitotoxicity always suppresses locomotor network activity and produces large gray matter damage, while network bursting persists supported by average survival of nearly half premotoneurons and motoneurons. Conversely, metabolic perturbation simply depresses locomotor network activity as damage mainly concerns white rather than gray matter. Coapplication of kainate and metabolic perturbation completely eliminates locomotor network activity. These results indicate distinct cellular targets for excitotoxic versus dysmetabolic damage with differential consequences on locomotor pattern formation. Furthermore, these data enable to estimate the minimal network membership compatible with expression of locomotor activity.

Topics: Animals; Animals, Newborn; Chronic Disease; Convulsants; Excitatory Amino Acid Agonists; Glutamates; Interneurons; Kainic Acid; Locomotion; Lumbar Vertebrae; Nerve Net; Neurons; Neurotoxins; Rats; Spinal Cord Injuries; Strychnine; Wounds and Injuries

We examined the influence of lumbosacral glycinergic neurons on the spinobulbospinal and spinal micturition reflexes. Female rats were divided into intact rats, rats with acute injury to the lower thoracic spinal cord (SCI), and rats with chronic SCI. Under urethane anesthesia, isovolumetric cystometry was performed in each group before and after intrathecal (IT) injection of glycine or strychnine into the lumbosacral cord level. The glutamate and glycine levels of the lumbosacral cord were measured after injection of glycine or strychnine in intact and chronic SCI rats. Expression of strychnine-sensitive glycine receptor alpha-1 (GlyR alpha1) mRNA in the lumbosacral cord was also assessed in both rats. In chronic SCI rats, the interval and amplitude of bladder contractions were shorter and smaller when compared with intact rats. IT glycine (0.1-100 microg) prolonged the interval and decreased the amplitude of bladder contractions in both intact rats and chronic SCI rats. IT strychnine (0.01-10 microg) elevated the baseline pressure in intact rats and induced bladder contraction in acute SCI rats. On amino acid analysis, IT glycine (0.01-100 microg) decreased the glutamate level of the lumbosacral cord in intact rats, but not in chronic SCI rats. The glycine level of the lumbosacral cord was 54% lower in chronic SCI rats when compared with intact rats, while the GlyR alpha1 mRNA level did not change after SCI. These results suggest that glycinergic neurons may have an important inhibitory effect on the spinobulbospinal and spinal micturition reflexes at the level of the lumbosacral cord.

Topics: Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Female; Glutamic Acid; Glycine; Glycine Agents; Injections, Spinal; Lumbosacral Region; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Reflex; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Strychnine; Urinary Bladder; Urination

Strychnine-insensitive glycine binding sites, an absolute requirement of the responses mediated by N-methyl-D-aspartate (NMDA) receptors, were measured in the postmortem brains of 13 chronic schizophrenics and 10 controls, using a radiolabeled receptor assay. Specific [3H]glycine binding was significantly increased in six of the 16 areas of the cerebral cortex that were investigated. Scatchard analysis performed in these areas showed a significant increase in the maximum number of binding sites, with no change in the affinity of binding. Multiple regression analysis confirmed that the increase was not due to age at death or interval from death to freezing. The increase was also observed in the off-drug cases of schizophrenics who had not taken antipsychotics for more than 40 days before death. These results suggest that the increases in NMDA-associated glycine binding sites, possibly ascribed to the postsynaptic compensation for impaired glutamatergic neurotransmission, might be implicated in the pathophysiology of schizophrenia.

Topics: Adult; Aged; Brain Mapping; Cerebral Cortex; Chronic Disease; Female; Glutamates; Glutamic Acid; Glycine; Humans; Male; Middle Aged; Radioligand Assay; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Strychnine; Up-Regulation

Topics: Adolescent; Adult; Anemia, Aplastic; Chronic Disease; Female; Humans; Male; Middle Aged; Strychnine

Topics: Anesthesia, Conduction; Ascorbic Acid; Blood Protein Disorders; Chronic Disease; Humans; Hydrocortisone; Injections, Intravenous; Injections, Subcutaneous; Lipotropic Agents; Methionine; Pancreatic Extracts; Pancreatin; Pancreatitis; Pituitary Hormones, Posterior; Plasma Substitutes; Prednisolone; Procaine; Protein Hydrolysates; Serine; Serum Albumin; Serum Globulins; Strychnine; Thiamine; Water-Electrolyte Balance