Hypertonicity promotes survival of corticospinal motoneurons via mitogen-activated protein kinase p38 signaling.

Extracellular hypertonicity can induce the phosphorylation of mitogen-activated protein kinases (MAPKs). Of these, both extracellular signal-regulated kinases (ERKs) and the stress-activated kinase p38 have been implicated in neuronal cell survival. Resuscitation with hypertonic saline decreases secondary brain injury after trauma, as well as neuronal damage, after ischemia. Since hypertonicity has been shown to support somatic cell survival, we investigated if hypertonicity can also prevent neuronal cell death via MAPK signaling. Death of postnatal rat corticospinal motoneurons (CSMNs) was induced by serum deprivation, and survival in both isotonic and hypertonic media was assessed after 20 h. Addition of NaCl (4-250 mM) to isotonic medium significantly and dose dependently protected CSMN in enriched cultures, increasing cell survival by up to 70% over that in isotonic medium. This response was not restricted to NaCl; addition of KCl, choline chloride, and sucrose had similar effects on cell survival. In addition, hypertonicity supported the survival of pure CSMN populations, albeit with lower potency. In cortical cell suspensions, hypertonic NaCl (20-100 mM) increased basal phosphorylation of p38 and ERK. The activation of both MAPKs, which was induced by 40 mM NaCl, was transient. Cultivation of CSMNs in media containing the specific p38 inhibitor SB203580 abolished the protective effect of hypertonic NaCl, indicating a central role for p38. We therefore conclude that hypertonicity can prevent neuronal cell death via MAPK signaling.

Effects of full-thickness burns on nociceptor sensitization in anesthetized rats.

Burn-induced pain is often inadequately managed and its mechanisms, both peripheral and central, are poorly understood. To examine peripheral mechanisms, the effects of full-thickness burns on individual nociceptive fibers in sural nerve of anesthetized rats were studied. Additionally, the study investigated whether topical post-burn treatment with the mu-opioid receptor agonist loperamide ameliorated burn-induced pathologies. Receptive field (RF) properties of C-fibers were determined for 4h before and after producing burns. Burns caused profound tissue damage with edema extending beyond the injury site. Injury located within or proximal to RFs of nociceptors caused rapid decreases in mechanical responsiveness or complete desensitization at the original test site. However, post-burn, RF size frequently grew to include areas of newly sensitized skin. Transient or prolonged periods of ectopic activity was recorded from some nociceptors; this was most prevalent in fibers with RFs proximal to the injury site where burn induced background firing in 60% of the population. In most cases, loperamide significantly increased mechanical thresholds, prevented sensitization of uninjured skin, and reduced discharge.These data indicate that full-thickness burns activate and/or sensitize C-nociceptors, thus probably leading to pain. As loperamide ameliorates nociceptor activation and sensitization, it is an appropriate candidate for burn pain management.