Egor Nevsky

Endocannabinoid receptors of the CB1 subtype are the most abundant G-protein-coupled receptors in the central nervous system, where they strongly regulate neurotransmitter release. The effects of the activation of these receptors by exogenously applied agonists have also been described in the peripheral nervous system, particularly at neuromuscular junctions (NMJs). However, the physiological role of these receptors at NMJs has not been demonstrated. We have shown that blockade of CB1 receptors at the NMJs of newborn or young mice increases the quantal content of end-plate potentials, as well as their decay time constant. Neither effect of CB1 receptor blockade is observed if postsynaptic muscle acetylcholine receptors are partially blocked. Thus, CB1 receptors may be involved in maintaining synaptic homeostasis. Importantly, the effect of CB1 receptor blockade on quantal content is potentiated by blockade of the enzyme butyrylcholinesterase. Therefore, butyrylcholinesterase may be considered a component of the extracellular degradation system for endocannabinoids.

Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms.

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. However, GABA receptors, notably at the neuromuscular junction (NMJ), have also been identified in the peripheral nervous system. Here, we studied GABA_B receptor (GABA_B–R)-mediated regulation of acetylcholine (ACh) release in mouse NMJs during early postnatal development. The results revealed that, depending on the age of the mice, the activation of GABA_B–R had the opposite effect on ACh release. At the NMJ in mice on the second postnatal (P2) day, the GABA_B–R blocker CGP 55845 (5 μM) significantly increased the level of ACh release, whereas the GABA_B–R agonist baclofen (10 μM) decreased ACh release. In P14-aged mice, CGP 55845 decreased ACh release, while the application of baclofen significantly increased the release. At the NMJ of P14 mice, the mechanism of the ACh release-potentiating effect of GABA_B–R activation involves N-type calcium ion channels and small-conductance calcium ion-activated potassium ion channels.

Migraine is a widespread disorder which is defined by persistent and recurring headache attacks. Trigeminal-vascular system (TVS), including meningeal afferents of trigeminal ganglion, is considered to be a key structure in generating nociceptive signals in migraine, in which dopaminergic and trace amine-mediated effects remain unexplored. DAT-HET rats, heterozygous of DAT-KO line, provide a useful model for studying the role of moderate changes in DA homeostasis in migraine mechanisms. In this research, we investigated tyramine and dopamine (DA) effects in trigeminal peripheral afferents with elecrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicates that DA application exerts pro-nociceptive action in trigeminal meningeal afferents in both WT (wild type) and DAT-HET groups in similar manner. Tyramine application also exhibited pro-nociceptive action in peripheral afferents, but demonstrated prolonged pro-nociceptive effect in DAT-HET group. Our data contributes to understanding of dopaminergic signaling in TVS by functionally confirming interplay between dopaminergic system and trace amines in peripheral afferents; as well as by demonstrating of novel electrophysiological evidence of tyramine pro-nociceptive action in TVS.