Preemptive analgesic effect of intrathecal applications of neuroactive steroids in a rodent model of post-surgical pain: Evidence for the role of T-type calcium channels

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type C

Further evidence that inhibition of neuronal voltage-gated calcium channels contributes to the hypnotic effect of neurosteroid analogue, 3β-OH

We recently reported that a neurosteroid analogue with T-channel-blocking properties (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rat pups without triggering neuronal apoptosis. Furthermore, we found that the inhibition of the C

Differential effects of the novel neurosteroid hypnotic (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats

BACKGROUND: We recently showed that a neurosteroid analogue, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3β-OH further using electroencephalography. METHODS: We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3β-OH (30 and 60 mg kg RESULTS: We found dose-dependent sex differences in 3β-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3β-OH 30 mg kg CONCLUSIONS: Based on its behavioural effects and EEG signature, 3β-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats

Neurosteroids in Pain Management: A New Perspective on an Old Player

Since the discovery of the nervous system’s ability to produce steroid hormones, numerous studies have demonstrated their importance in modulating neuronal excitability. These central effects are mostly mediated through different ligand-gated receptor systems such as GABAA and NMDA, as well as voltage-dependent Ca2+ or K+ channels. Because these targets are also implicated in transmission of sensory information, it is not surprising that numerous studies have shown the analgesic properties of neurosteroids in various pain models. Physiological (nociceptive) pain has protective value for an organism by promoting survival in life-threatening conditions. However, more prolonged pain that results from dysfunction of nerves (neuropathic pain), and persists even after tissue injury has resolved, is one of the main reasons that patients seek medical attention. This review will focus mostly on the analgesic perspective of neurosteroids and their synthetic 5α and 5β analogs in nociceptive and neuropathic pain conditions

Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid

BACKGROUND: The novel synthetic neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABA METHODS: We used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the Ca RESULTS: Adult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABA CONCLUSIONS: The sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH

The T-type calcium channel isoform Ca v 3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile

BACKGROUND: The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown. METHODS: We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca RESULTS: Patch-clamp recordings showed that 3β-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3β-OH inhibited the spike firing mode more profoundly in WT than in Ca CONCLUSIONS: The C

Propofol-Induced Changes in Neurotrophic Signaling in the Developing Nervous System In Vivo

Several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules in the brain of 14-day-old (PND14) Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the protein levels of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors tropomyosin-related kinase (TrkA and TrkB) and downstream kinases Akt and the extracellular signal regulated kinase (ERK) were assessed by Western immunoblot analysis at different time points during the first 24 h after the treatment, as well as the expression of cleaved caspase-3 fragment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons. The obtained results show that the treatment caused marked alterations in levels of the examined neurotrophins, their receptors and downstream effector kinases. However, these changes were not associated with increased neurodegeneration in either the cortex or the thalamus. These results indicate that in the brain of PND14 rats, the interaction between Akt/ERK signaling might be one of important part of endogenous defense mechanisms, which the developing brain utilizes to protect itself from potential anesthesia-induced damage. Elucidation of the underlying molecular mechanisms will improve our understanding of the age-dependent component of anesthesia-induced neurotoxicity