The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.

We have proposed that neuropathic pain engages emotional learning, suggesting the involvement of the hippocampus. Since cytokines in the periphery contribute to induction and maintenance of neuropathic pain, but might also participate centrally, we used two neuropathic pain models, chronic constriction injury (CCI) and spared nerve injury (SNI), to investigate the temporal profile of hippocampal cytokine gene expression in two rat strains that show different post-injury behavioral threshold sensitivities. SNI induced long-lasting allodynia in both strains, while CCI induced allodynia with time-dependent recovery in Sprague-Dawley (SD) and no allodynia in Wistar Kyoto (WK) rats. In WK rats, only SNI induced sustained upregulation of hippocampal IL-1β, while IL-6 expression was transiently increased and no significant changes in IL-1ra expression were detected. Conversely, in SD rats, SNI resulted in sustained and robust increased hippocampal IL-1β expression, which was only transient in rats with CCI. In this strain, IL-6 expression was not affected in any of the two injury models and IL-1ra expression was significantly increased in rats with SNI or CCI at late phases. The main findings reported are that: 1) the degree and development of neuropathic pain depend on the specific nerve injury model and rat strain; 2) hippocampal IL-1β mRNA levels correlate with neuropathic pain behavior; 3) in contrast to sham-operated animals, there are no correlations between hippocampal IL-1β and IL-1ra or IL-6 in neuropathic rats; and 4) alterations in cytokine expression are restricted to the hippocampus contralateral to the injury side, again implying that the observed changes reflect nociception.

Objective. To explore the hypothesis that, in parallel with alterations in the hypothalamus-pituitaryadrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease.Methods. Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6-hydroxydopamine.Results. Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin-1␤ (IL-1␤) and IL-6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL-1␤ expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease.Conclusion. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen-induced arthritis.The inflammatory/autoimmune process observed during experimentally induced arthritis is paralleled by neuroendocrine alterations, particularly in the activity of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) (for review, see refs.

No abstract

No abstract

No abstract

No abstract

No abstract