dynorphins and Movement-Disorders

Spinocerebellar ataxia type 23 is caused by mutations in PDYN, which encodes the opioid neuropeptide precursor protein, prodynorphin. Prodynorphin is processed into the opioid peptides, α-neoendorphin, and dynorphins A and B, that normally exhibit opioid-receptor mediated actions in pain signalling and addiction. Dynorphin A is likely a mutational hotspot for spinocerebellar ataxia type 23 mutations, and in vitro data suggested that dynorphin A mutations lead to persistently elevated mutant peptide levels that are cytotoxic and may thus play a crucial role in the pathogenesis of spinocerebellar ataxia type 23. To further test this and study spinocerebellar ataxia type 23 in more detail, we generated a mouse carrying the spinocerebellar ataxia type 23 mutation R212W in PDYN. Analysis of peptide levels using a radioimmunoassay shows that these PDYN(R212W) mice display markedly elevated levels of mutant dynorphin A, which are associated with climber fibre retraction and Purkinje cell loss, visualized with immunohistochemical stainings. The PDYN(R212W) mice reproduced many of the clinical features of spinocerebellar ataxia type 23, with gait deficits starting at 3 months of age revealed by footprint pattern analysis, and progressive loss of motor coordination and balance at the age of 12 months demonstrated by declining performances on the accelerating Rotarod. The pathologically elevated mutant dynorphin A levels in the cerebellum coincided with transcriptionally dysregulated ionotropic and metabotropic glutamate receptors and glutamate transporters, and altered neuronal excitability. In conclusion, the PDYN(R212W) mouse is the first animal model of spinocerebellar ataxia type 23 and our work indicates that the elevated mutant dynorphin A peptide levels are likely responsible for the initiation and progression of the disease, affecting glutamatergic signalling, neuronal excitability, and motor performance. Our novel mouse model defines a critical role for opioid neuropeptides in spinocerebellar ataxia, and suggests that restoring the elevated mutant neuropeptide levels can be explored as a therapeutic intervention.

Topics: Action Potentials; Age Factors; Animals; Animals, Newborn; Cell Count; Cells, Cultured; Cerebellum; Disease Models, Animal; Dynorphins; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement Disorders; Mutation; Patch-Clamp Techniques; Purkinje Cells; Signal Transduction; Spinocerebellar Degenerations; Synapses

The endogenous opioid peptide dynorphin has been implicated in the pathophysiology of secondary tissue injury after central nervous system (CNS) trauma. The detrimental effects of dynorphin appear to be mediated through both opioid receptors (probably kappa-receptors) and nonopioid mechanisms. However, both kappa-opioid agonists and antagonists have been reported to improve outcome in models of CNS trauma. To attempt to clarify this controversy, we examined the effects of centrally or systemically administered kappa-opioid agonists on neurological recovery after experimental fluid-percussion brain injury in the rat. Agonists included dynorphin A-(1-17) [Dyn A-(1-17)], which has actions at both kappa 1- and kappa 2-sites, and the selective kappa 1-agonists U-50,488H and U-69,593. des-Tyr-dynorphin A-(2-17) [Dyn A-(2-17)], which is inactive at opioid receptors, was also used. Microinjection of Dyn A-(1-17), but not Dyn A-(2-17) or U-50,488H, into the lateral ventricle 15 min before brain injury significantly worsened motor deficits over a 2-wk period. However, systemic administration of high doses of the kappa-agonists U-50,488H and U-69,593 also significantly worsened neurological outcome. These results fail to demonstrate any protective actions of kappa 1-agonists in this model of experimental traumatic brain injury and suggest that the opioid-related pathophysiological actions of dynorphin may be mediated by kappa 2-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Benzeneacetamides; Brain; Brain Injuries; Cardiovascular System; Dynorphins; Injections, Intravenous; Injections, Intraventricular; Male; Movement Disorders; Nervous System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Survival Analysis

Levallorphan and dynorphin were effective on the motor dysfunction in the gerbil model of unilateral cerebral ischemia. The effect of opioids, levallorphan (mixed agonist-antagonist), dynorphin (kappa-receptor agonist) and naloxone (mu-receptor antagonist), on neurological impairment was evaluated using the unilateral cerebral ischemia model of gerbil. Motor function was evaluated quantitatively by using the inclined plane method. Both levallorphan-treated group and dynorphin-treated group showed a significant improvement of the motor dysfunction compared with saline-control group. On the other hand, naloxone-treated group did not differ from saline-control group. The beneficial effect of these opioids on motor dysfunction might be mediated by the kappa-opioid receptor. This study also showed the potential usefulness of the inclined plane method for the investigation on the cerebral ischemia.

Topics: Animals; Brain Ischemia; Dynorphins; Female; Kinetics; Levallorphan; Male; Movement Disorders