Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal-regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform-specific function of extracellular signal-regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre-loxP-mediated deletion of Erk2 in the CNS. Still, how extracellular signal-regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin-induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.

Background Rapid fluid infusion resulting in increased hepatic blood flow may decrease the propofol plasma concentration (Cp) because propofol is a high hepatic extraction drug. The authors investigated the effects of rapid colloid and crystalloid infusions on the propofol Cp during target-controlled infusion. Methods Thirty-six patients were randomly assigned to 1 of 3 interventions (12 patients per group). At least 30 min after the start of propofol infusion, patients received either a 6% hydroxyethyl starch (HES) solution at 24 ml·kg−1·h−1 or acetated Ringer’s solution at 24 or 2 ml·kg−1·h−1 during the first 20 min. In all groups, acetated Ringer’s solution was infused at 2 ml·kg−1·h−1 during the next 20 min. The propofol Cp was measured every 2.5 min as the primary outcome. Cardiac output, blood volume, and indocyanine green disappearance rate were determined using a pulse dye densitogram analyzer before and after the start of fluid administration. Effective hepatic blood flow was calculated as the blood volume multiplied by the indocyanine green disappearance rate. Results The rapid HES infusion significantly decreased the propofol Cp by 22 to 37%, compared to the Cp at 0 min, whereas the rapid or maintenance infusion of acetate Ringer’s solution did not decrease the propofol Cp. Rapid HES infusion, but not acetate Ringer’s solution infusion, increased the effective hepatic blood flow. Conclusions Rapid HES infusion increased the effective hepatic blood flow, resulting in a decreased propofol Cp during target-controlled infusion. Rapid HES infusion should be used cautiously as it may decrease the depth of anesthesia.

We prepared a 20% sevoflurane lipid emulsion using caprylic triglyceride (i.e., medium-chain triglyceride). In rats, this emulsion was an effective anesthetic and was not associated with adverse events. The emulsion was stable after consecutive evaluation for 365 days and for 180 minutes after the vial was opened.

The large-conductance Ca 2+-and voltage-activated K + (BK) channel is formed by four pore-forming subunits encoded by a single Slo1 gene and dually regulated by membrane voltage and intracellular Ca 2+ levels. Recently, accumulating evidence using pharmacological methods suggests that the BK channel are associated with nociceptive sensitization. However, mechanisms underlying the effect of the BK channel on the regulation of pain signaling is still largely unknown. Here, we studied the role of the BK channel in the pain signaling in vivo using mice deficient for Slo1. In a partial sciatic nerve ligation (PSNL) model, Slo1 KO mice showed partially restored thermal hyperalgesia compared to their WT littermates. In microglia from WT mice, p38 MAPK phosphorylation was significantly increased after lysophosphatidic acid (LPA) treatment; conversely, it was not significantly upregulated in microglia from Slo1 KO mice, suggesting that the BK channel contributes to the signaling of microglial hyperactivation. Notably, intrathecal (i.t.) injection of microglia derived from WT mice into Slo1 KO mice before PSNL induced the normal development of hyperalgesia in Slo1 KO mice. These results indicate that the BK channel activation in spinal microglia, but not in neuron, contribute to the induction of neuropathic pain in this PSNL model.

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