morphinans and Nerve-Degeneration

Sinomenine (SIN) has been shown to have protective effects against brain damage following traumatic brain injury (TBI). However, the mechanisms and its role in these effects remain unclear. This study was conducted to investigate the potential mechanisms of the protective effects of SIN.. The weight-drop model of TBI in Institute of Cancer Research (ICR) mice were treated with SIN or a vehicle via intraperitoneal administration 30 min after TBI. All mice were euthanized 24 h after TBI and after neurological scoring, a series of tests were performed, including brain water content and neuronal cell death in the cerebral cortex.. The level of cytochrome. SIN protected neuronal cells by protecting them against apoptosis via mechanisms that involve the mitochondria following TBI.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Brain Edema; Brain Injuries, Traumatic; Cerebral Cortex; Cytochromes c; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione Peroxidase; Male; Malondialdehyde; Mice, Inbred ICR; Mitochondria; Morphinans; Nerve Degeneration; Neurons; Neuroprotective Agents; Oxidative Stress; Signal Transduction; Superoxide Dismutase-1

Neuropsychiatric disorders are one of the main challenges of human medicine with epilepsy being one of the most common serious disorders of the brain. Increasing evidence suggest neuropeptides, particularly the opioids, play an important role in epilepsy. However, little is known about the mechanisms of the endogenous opioid system in epileptogenesis and epilepsy. Therefore, we investigated the role of endogenous prodynorphin-derived peptides in epileptogenesis, acute seizure behaviour and epilepsy in prodynorphin-deficient mice. Compared with wild-type littermates, prodynorphin knockout mice displayed a significantly reduced seizure threshold as assessed by tail-vein infusion of the GABA(A) antagonist pentylenetetrazole. This phenotype could be entirely rescued by the kappa receptor-specific agonist U-50488, but not by the mu receptor-specific agonist DAMGO. The delta-specific agonist SNC80 decreased seizure threshold in both genotypes, wild-type and knockout. Pre-treatment with the kappa selective antagonist GNTI completely blocked the rescue effect of U-50488. Consistent with the reduced seizure threshold, prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after intracisternal injection of kainic acid. Three weeks after local injection of kainic acid into the stratum radiatum CA1 of the dorsal hippocampus, prodynorphin knockout mice displayed an increased extent of granule cell layer dispersion and neuronal loss along the rostrocaudal axis of the ipsi- and partially also of the contralateral hippocampus. In the classical pentylenetetrazole kindling model, dynorphin-deficient mice showed significantly faster kindling progression with six out of eight animals displaying clonic seizures, while none of the nine wild-types exceeded rating 3 (forelimb clonus). Taken together, our data strongly support a critical role for dynorphin in the regulation of hippocampal excitability, indicating an anticonvulsant role of kappa opioid receptors, thereby providing a potential target for antiepileptic drugs.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzamides; Cell Count; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Epilepsy, Temporal Lobe; Guanidines; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphinans; Naltrexone; Nerve Degeneration; Piperazines; Protein Precursors; Receptors, Opioid, kappa; Synaptic Transmission; Time Factors

We investigated alterations in opiate-binding sites in the upper dorsal horn after transection of the related peripheral sensory nerve in rats. The binding of (3H)diprenorphine was measured autoradiographically. The findings indicated a shift of the binding sites, rather than a degenerating disappearance, with a decrease in nerve fibers but an increase in nerve cells. This may be due to latent opiate-binding sites becoming manifest.

Topics: Animals; Autoradiography; Denervation; Diprenorphine; Ganglia, Spinal; Morphinans; Nerve Degeneration; Nociceptors; Rats; Receptors, Opioid; Spinal Nerve Roots