Élvezeti szerekhez történő hozzászokás in vivo és in vitro vizsgálata = In vivo and in vitro study of drugs with abuse potential

A pályázat az élvezeti szerekhez történő hozzászokás in vivo és in vitro vizsgálatát tűzte ki célul. Tanulmányoztuk a központi idegrendszerben előforuló idegi növekedési faktor és számos neuropeptid (PACAP, ghrelin, endomorfin) hatását in vivo a morfin és nikotin hozzászokáshoz, valamint in vitro körülmények között a sejtmámbránból felszabaduló eikonazoidokra. A vizsgált peptidek hatásosan módosítják az élvezeti szerekhez való hozzászokás általunk vizsgált paraméterit. Figyelmet érdemel az a tény, hogy az endogén módon előforduló endomorfin módosult származéka az anyavegyületnél biológiailag hatásosabb és mint ilyen további fejlesztés céljából potenciális vegyületként jöhet szóba. | This project is aimed at investigating the effects of drugs of abuse in vivo and in vitro. The effects of brain-derived neurotrophic factor and several neuropeptides (PACAP, ghrelin and endomorphine) were investigated on the behavioral effects of morphine and nicotine in vivo and on membrane-derived eicosanoid products in vitro. The peptides investigated can modify the behavioral response to drugs of abuse effectively under our experimental conditions. It should be emphasized that an endomorphine analogue is more efficient in biological response, than the parent molecule and it may serve as a potential candidate for future development

Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonist

Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity