ИСТИНА

Endocannabinoids (EC) are lipophilic compounds, which are produced by enzymatic cleavage of cell membrane lipids and then released into the synaptic cleft with following action on cells through their specific cannabinoid receptors (CB1 and CB2-type) (Mechoulam et al., 2014). Expression of all components of the EC system, including CB-receptors, has been shown in skeletal muscle (Crespillo et al., 2010). However, the role and selective involvement of CB1 and CB2-receptors in transmitter release regulation in mouse motor synapses remains unexplored. We investigated the effects of a common CB-receptor agonist anandamide (AEA) and two inverse agonists of CB-receptors with preferential selectivity either for CB1- or CB2-type on miniature end plate potentials (MEPPs). AEA (30 μM) caused (within 1.5-2 hours) a decrease in MEPP amplitude by 20.5%, with a parallel increase in MEPP frequency by 29.8%. Inverse agonist of CB2-receptors AM-630 (10 μM) caused an increase in MEPP frequency similar to AEA, but unlike AEA it had an inverse effect on MEPP amplitude, increasing it by 23.6%. This confirmed the involvement of CB2-type receptors in the regulation of MEPP parameters, but their contribution to AEA-mediated effects remained controversial. AM-251 (1 mkM), inverse agonist of CB1-receptors, did not change neuromuscular transmission, but prevented the effects of AEA. Apparently, AEA preferentially activates CB1-receptors in motor synapses, which leads to an increase in MEPP frequency and suppression of MEPP amplitude. This AEA action seems not to be accompanied by activation of CB2-receptors. Thus,comparative analysis of the effects of АЕА and inverse agonists of CB-receptors on MEPPs showed possible participation of both types of receptors in the regulation of MEPP parameters. Different types of CB-receptors appear to have a partially synergistic (judging by MEPP amplitude) and partly antagonistic (judging by MEPP frequency) action on quantal transmitter secretion, with selective involvement of only CB1-receptors in AEA-mediated effects on neuromuscular transmission in mouse motor synapses. Selective involvement of CB2-receptors in regulatory activity needs probably participation of some other endocannabinoids. This work is supported by RFBR grant №19-04-00616-а.