Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglia (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of incomplete knowledge about the mechanisms underlying painful PDN, current treatment for painful PDN has been limited to somewhat non-specific systemic drugs that have significant side effects or potential for abuse. Recent studies have established that several ion channels in DRG and DH neurons are dysregulated and make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of Type 1 and Type 2 PDN. Furthermore, it has been reported that targeting post-translational modification of nociceptive ion channels such as glycosylation and methylglyoxal metabolism can completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of post-translational regulation of nociceptive channel activity may facilitate development of novel therapies for treatment of painful PDN. We argue that pharmacological targeting of the specific pathogenic mechanism rather than of the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.

Recent evidence strongly supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (NO; laughing gas), as well as sedative drugs such as midazolam are neurotoxic for the developing mammalian brain having deleterious effects on neural circuits involved in cognition, learning and memory. However, to date, very little is known about epigenetic mechanisms involved in GA-induced plasticity of synaptic transmission in the hippocampus, the main memory-processing region in the brain. Here, we used patch-clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) from hippocampal neurons in slice cultures exposed to the clinically relevant GA combination. We found that in vitro exposure to a combination of midazolam, 0.75% Iso, and 70% NO for 6 h leads to lasting increase in frequency of mIPSCs, while amplitudes and kinetics of the events were spared. Importantly, co-application of entinostat (MS-275), a selective inhibitor of class I histone deacetylases (HDAC), completely reversed GA-induced synaptic plasticity. Furthermore, when given in vivo to P7 pups exposed to GA with midazolam, Iso and NO for 6 h, MS-275 reversed GA-induced histone-3 hypoacetylation as shown by an increase in Ac-H3 protein expression in the hippocampus. We conclude that exposure to a combination of Iso with NO and midazolam causes plasticity of mIPSCs in hippocampal neurons by epigenetic mechanisms that target presynaptic sites. We hypothesize that GA-induced epigenetic alterations in inhibitory synaptic transmission in the hippocampus may contribute to altered neuronal excitability and consequently abnormal learning and memory later in life.

Despite the increase of molecular knowledge in anesthesia research over the past decades there is still ongoing discussion about the mechanisms of anesthesia. This article focuses on presenting anesthetic sensitive ligand and voltage gated ion channels. The impact on anesthetic modulated ion channels is summarized for clinically commonly used anesthetics isoflurane, propofol and ketamine. Furthermore, the anesthetic features hypnosis, unresponsiveness to surgical incision and amnesia and their putative relevant anatomical sites in the central nervous system are briefly introduced. KeywordsMechanisms of anesthesia; Ion channels; Isoflurane; Propofol; Ketamine Molekulare MechanismenNarkose kann durch eine breite Vielfalt unterschiedlicher Stoffklassen hervorgerufen werden. Narkosemittel modulieren auf zellulärer Ebene selektiv Ionenkanäle und haben teilweise mehrere molekulare Angriffspunkte in unterschiedlichen anatomischen Strukturen [16,24,28] Klinische EigenschaftenDie klinischen Eigenschaften dieser Narkosemittel sind in Tab. 4 zusammengefasst. Exkurs in die PraxisIm Vergleich zum intraoperativen Schmerzniveau ist der Schmerzreiz gegen Ende einer Operation (Hautnaht, Verbände etc.) zumeist deutlich reduziert. Dies ermöglicht eine