News tips from the Journal of Neuroscience

December 23, 2008

1. Interleukin-1β Enhances Sodium Currents in Nociceptors
Alexander M. Binshtok, Haibin Wang, Katharina Zimmermann, Fumimasa Amaya, Daniel Vardeh, Lin Shi, Gary Brenner, Ru-Rong Ji, Bruce P. Bean, Clifford J. Woolf, and Tarek A. Samad

Tissue damage releases factors that activate the immune system and cause inflammation. In addition to recruiting immune cells to damaged tissues, many proinflammatory molecules sensitize nociceptors, causing pain to persist after the initial injury and making previously innocuous stimuli painful. In this issue, Binshtoket al. report that the proinflammatory cytokine interleukin-1β sensitizes nociceptors by reducing slow inactivation of voltage-gated sodium channels at resting membrane potentials and enhancing persistent sodium currents. In cultured rat dorsal root ganglion nociceptors, interleukin-1β increased spontaneous firing and shifted the spike threshold by ~20 mV in the hyperpolarizing direction. This is expected to make nociceptors more sensitive to activation of TRP channels by thermal, chemical, and mechanical stimuli. Indeed, injection of interleukin-1β into rats' paws increased mechanical and thermal pain sensitivity. These effects required phosphorylation of p38 mitogen-activated protein kinase, which might act directly on Nav1.9 and Nav 1.8 sodium channels.

2. Chondroitinase Prevents Lesion-Induced Neuronal Atrophy
Lucy M. Carter, Michelle L. Starkey, Sonia F. Akrimi, Meirion Davies, Stephen B. McMahon, and Elizabeth J. Bradbury

Chondroitin sulfate proteoglycans (CSPGs) are inhibitory extracellular matrix molecules that are upregulated after spinal cord injury and inhibit axonal regeneration. Chondroitinase is a promising treatment for spinal cord injury because it cleaves CSPGs, making the lesion environment more permissive for growth and enhancing functional recovery.To study the effects of chondroitinase on corticospinal tract neurons, Carter et al. crushed the dorsal columns of transgenic mice in which layer 5 cortical neurons were labeled with yellow fluorescent protein. In control mice, nerve crush caused atrophy of corticospinal neuronal somata. Continual intracerebroventricular (ICV) or intrathecal (IT) hondroitinase treatment greatly reduced atrophy. ICV and IT chondroitinase treatment also increased phosphorylation of extracellular signal-regulated kinase 1, a mediator of cell survival, growth, and differentiation in response to growth factors. The authors suggest that chondroitinase treatment releases growth factors bound to CSPGs at the lesion site, and this elicits retrograde signals that promote survival of corticospinal neurons.

3. Receptor Levels May Explain Sex Differences in Morphine Potency
Dayna R. Loyd, Xioaya Wang, and Anne Z. Murphy

The analgesic potency of opiates varies greatly among individuals, and is influenced by many factors, including genotype, sex, and source of pain. Morphine is typically more potent in male laboratory animals than in females, but the opposite might be true in humans. Loyd et al. hypothesized that differences in μ-opioid receptor (MOR) expression underlie sex differences in morphine potency. They found that male rats had greater MOR expression in the caudal ventrolateral periaqueductal gray (PAG) than females. Moreover, morphine injections into the PAG reversed inflammatory thermal hyperalgesia in males, but were significantly less potent in female rats. Finally, selective elimination of MOR-expressing neurons in the PAG reduced the analgesic potency of systemic morphine treatment in male rats, but not in females. Although these results might not have direct implications for sex differences in morphine potency in humans, they suggest that differences in receptor expression contribute to individual variability in morphine sensitivity.

4. Thyroid Hormones Promote Remyelination
Laura-Adela Harsan, Jérôme Steibel, Anita Zaremba, Arnaud Agin, Rémy Sapin, Patrick Poulet, Blandine Guignard, Nathalie Parizel, Daniel Grucker, Nelly Boehm, Robert H. Miller, and M. Said Ghandour

Thyroid hormones are essential regulators of nervous system development, promoting not only axonal and dendritic growth, but also differentiation and maturation of myelinating oligodendrocytes. Harsan et al. reasoned that these effects could be reproduced in adult animals treated with thyroid hormone, providing a potential treatment for demyelinating diseases such as multiple sclerosis. The authors fed mice cuprizone, a gliotoxic copper chelator, and evaluated myelin integrity in vivo using diffusion tensor magnetic resonance imaging (DTMRI). Cuprizone treatment caused severe demyelination in the corpus callosum and cerebellum that persisted after cuprizone withdrawal. Subsequent triiodothyronine (T3) hormone treatment led to complete recoveryofmyelination. Immunohistochemical analysis suggested that T3 increased the generation of oligodendrocyte precursor cells, as well as their migration, differentiation, maturation, and remyelination of axons. Importantly, remyelination processes continued after T3 treatment was terminated, suggesting that prolonged thyroid hormone elevation (and its undesirable side effects) might not be required to produce beneficial effects.
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