The study of features of pharmacodynamics of a new analgesic is an important and urgent task of modern pharmacology. These data allow us to clarify the nosology for application of an analgesic and to ...create a theoretical background to optimize its use. An effect mediated by the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) activation can also be an effective mechanism of the analgesic action. We evaluated the possibility of TRPV1 participation in implementation of the analgesic effect with the antiviral action of amizonum during the experiment. It is known that amino acids Tyr511 and Ser512 are the main components of the active site of TRPV1. In this connection, dipeptide Tyr-Ser has been completely synthesized as a model of the active site of TRPV1. In the experiment model this was shown, using the spectrophotometric method, with the formation of the “capsaicin - Tyr- Ser” intermolecular complex at the level of the stability constant Kkor=0.998 and Kr=0.3•10-4 L/mol and the “amizonum - Tyr-Ser” weak intermolecular complex Kr=0.05•104 L/mol; Kkor= 0.995, respectively. The data verification was carried out in experiments in vitro (isolated ratportal vein) and in vivo (Tail-flick model), with the TRPV1 agonist. It was shown that the amplitude of smooth muscle (SM) contraction of the portal vein at a capsaicin concentration 0.1 μmol/L, 0.5 μmol/L capsazepine, and 1.0 μmol/L amizonum was +30.3±5.3%, -3.2± 2.7% and +7.1±3.2% from initial level, respectivelly. In a combined application of amizonum with capsaicin or capsazepine, the amplitude of contraction of the SM portal vein was 20.1± 1.3% and -3.0±1.4%, respectively. This indicates the absence of action of amizonum under combined use of capsaicinoids. The Tail-flick model showed atypical potentiation of the amizonum antinociception with the use of capsaicin. The obtained data suggest the low probability of the participation of TRPV1 in the implementation of the antinociceptive action of amizonum.
Studija karakteristika farmakodinamike novog analgetika je važan i neodložan zadatak savremene farmakologije. Ovakvi podaci omogućavaju razjašnjenje nozologije primene analgetika i stvaranje teorijske pozadine kako bi njegova primena bila optimalna. Efekat posredovan aktivacijom katjonskog kanala tranzitornog receptorskog potencijala, podfamilija V, član 1 (TRPV1), takođe može biti efektivan mehanizam analgetskog dejstva. Procenjivali smo mogućnost učestvovanja TRPV1 u primeni analgetskog efekta uz protiv virusno dejstvo amizonuma u toku eksperimenta. Poznato je da su amino kiseline Tyr511 i Ser512 glavne komponente aktivnog domena TRPV1. U ovoj vezi dipeptid Tyr-Ser se potpuno sintetiše kao model aktivnog domena TRPV1. Ovo je u eksperimentalnom modelu i pokazano primenom spektrofometrijske metode, formiranjem ‘’kapsaicin-Tyr-Ser’’ intermolekularnog kompleksa na nivou konstante stabilnosti Kkor= 0.998 i Kr=0.3•10-4 L/mol i ‘’amizonum - Tyr-Ser’’ slabog intermolekularnog kompleksa Kr=0.05•104 L/mol; Kkor=0.995, redom. Provera podataka je u eksperimentu urađena in vitro (izolovana portalna vena pacova) i in vivo (Tail-flick model) pomoću TRPV1 agonista. Pokazano je da je amplituda kontrakcije portalne vene glatkog mišića (GM) pri koncentraciji kapsaicina od 0.1 μmol/L, 0.5 μmol/L capsazepina i 1.0 μmol/L amizonuma bila +30.3±5.3%, -3.2±2.7% and +7.1±3.2% od početnog nivoa, redom. U kombinovanoj primeni amizonuma sa kapsaicinom ili kapsazepinom amplituda kontrakcije portalne vene glatkog mišića bila je 20.1±1.3% i -3.0±1.4%, redom. Ovo ukazuje na odsustvo dejstva amizonuma usled kombinovane primene kapsaicinoida. Tail-flick model je pokazao atipični potencijal antinocicepcije amizonuma upotrebom kapsaicina. Dobijeni podaci ukazuju na malu mogućnost učešća TRPV1 u primeni antinociceptivnog dejstva amizonuma.
Autoradiographic and membrane binding studies with 3H(R,S)- or 3H(S)-zacopride were performed in combination with lesions using various neurotoxins in an attempt to identify which neuronal cell types ...are endowed with 5-HT3 receptors in the rat central nervous system. Lesions of noradrenergic (by DSP-4), dopaminergic (by 6-hydroxydopamine) and serotonergic (by 5,7-dihydroxytryptamine) systems had little effect generally on the density of 5-HT3 receptors labelled with 3H(R,S)- or 3H(S)-zacopride in various regions of the brain and the spinal cord. The only exception was the amygdala where a significant loss (approximately -20%) of 5-HT3 receptors labelled by 3H(R,S)-zacopride was associated with the selective lesion of serotonergic fibres by 5,7-dihydroxytryptamine. Microinjection of kainic or ibotenic acid into the dorsal and ventral hippocampus reduced the density of 5-HT1A receptors labelled with 3H8-OH-DPAT (approximately -45%) as expected from their known location on intrinsic neuronal cell bodies and/or dendrites. In contrast, the same lesion did not affect 5-HT3 receptors, suggesting their location on fibres 'en passage'. At the spinal level, 5-HT3 receptors were found to exist on primary afferent fibres terminating within the superficial layers of the dorsal horn, as shown by the marked reduction in the local autoradiographic labelling by 3H(S)-zacopride after either dorsal rhizotomy (-81%) or neonatal capsaicin treatment (-72%). These data suggest that 5-HT3 receptors in the central nervous system are generally located presynaptically on nerve terminals or fibres of non-monoaminergic neurones.
Istraženi su učinci kapsaicina, jetkog i glavnog sastojka crvenoga papra, na sjemenike miševa. Kapsaicin je bio primijenjen miševima u dobi od 21, 35 i 50 dana supkutano u dozi od 1 mg/kg tjelesne ...mase svakoga dana u tjednu. Prosječna tjelesna masa i masa sjemenika u miševa pokusnih skupina bila je veća nego u kontrolnih skupina. Intertubularni odjeljci sjemenika obiju skupina miševa pokazivali su ++ pozitivnu reakciju bojenjem uljnim crvenilom. Spermatogene stanice oblikovale su se ranije u pokusnoj skupini u odnosu na kontrolnu. Rezultati pokazuju da je kapsaicin relativno netoksičan u miševa u dozi od 1 mg/kg tjelesne mase. Tijekom istraživanja uginuća nisu bila zabilježena. Životinje pokusne skupine bile su hiperaktivne s ranije razvijenim spermatogenim stanicama.
