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The role of SGIP1 protein interaction with cannabinoid receptor 1 in nociception under pathological conditions.
Dresslerová, Denisa ; Špicarová, Diana (advisor) ; Zímová, Lucie (referee)
The cannabinoid receptor type 1 (CB1) is a component of the endocannabinoid system and is abundantly expressed in the central nervous system. CB1 receptor has been extensively studied primarily due to its inhibitory role in neurotransmitter release from presynaptic terminals, and this process subsequently modulates postsynaptic currents and postsynaptic neuron excitation. Its interaction with the Src homology domain 3 growth factor 2 receptor binding protein (SGIP1) has recently been investigated in the context of nociception modulation (Hájková et al., 2016b). However, the role of this CB1 regulatory protein, SGIP1, in pathological pain conditions has not yet been described. Clarification of the role of SGIP1 interaction with CB1 receptor may help future research based on the use of cannabinoids as potential therapeutics. The thesis is structured into two parts, theoretical and practical. In the theoretical part of the thesis, knowledge of the given topic is summarized. First, pain is described from an anatomical-physiological perspective, followed by a description of the endocannabinoid system, where a part is dedicated to the CB1 cannabinoid receptor itself, and then another part is dedicated to the SGIP1 protein and its interaction with the CB1 receptor. In the practical part, the role of SGIP1...
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The role of regulatory protein SGIP1 in nociceptive synaptic transmission at the spinal cord level.
Mužík, David ; Špicarová, Diana (advisor) ; Lindovský, Jiří (referee)
Cannabinoid receptor 1 (CB1), abundantly expressed in the CNS, is a promising target for the pharmacological treatment of pathological pain conditions due to its function as an inhibitor of neurotransmitter release from presynaptic neurons. Recently, the SGIP1 protein has been found to interact with the CB1 receptor and participates in the modulation of nociception. However, whether SGIP1 modulates spinal CB1 receptor signaling at the spinal cord level is unknown. To answer this question, we used the patch-clamp method in the superficial spinal cord dorsal horn neurons of wild-type (WT) and knockout (KO) SGIP1 mice to measure spontaneous (s) and miniature (m) excitatory postsynaptic currents (EPSCs). Results of naive mice and mice with carrageenan-induced peripheral inflammation were compared. The results show that the efficacy of the CB1 receptor agonist WIN 55,212-2 at the first spinal nociceptive synapse is identical in naive mice for both SGIP1 WT and KO phenotypes. The control frequencies of both groups of neurons did not differ in naïve conditions or the peripheral inflammation model. On the contrary, the WIN 55,212-2 application was more effective in SGIP1 KO mice during peripheral inflammation. This study further addressed how CB1 receptor activation affects spinal inhibitory synaptic...
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Modulation of spinal nociceptive mechanisms under pathological conditions
Mužík, David ; Špicarová, Diana (advisor) ; Smejkalová, Terézia (referee)
Pain is a crucial component of the body's innate defenses, which helps us to respond to the damage that is threatening or imminent. If the pain persists even after the injury has healed, or arises for no apparent reason, it itself becomes harmful. Nociception begins with the detection of a noxious stimulus that irritates free nerve endings on the peripheral projections of spinal ganglion neurons. If the stimulus induces depolarization of the cell and an action potential forms, information of the stimulus is conducted by thinly myelinated Aδ fibers, or unmyelinated C fibers to the spinal cord dorsal horn. Here, the first synapses of sensory pathways are located, which allow the transmission of nociception to secondary afferent neurons, and these further direct the information to the higher centers of the CNS. Synapses in the dorsal horn are key to modulating nociceptive signaling, in which the endocannabinoid system, including endogenous cannabinoids and their receptors, plays a significant role. However, under pathological conditions such as the development of neuropathic pain or neuroinflammation, changes in the expression and function of agonists and receptors of the endocannabinoid system occur. These changes are of great importance in the onset and persistence of pathological pain. The study of...
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