EVALUATION OF THE TOLERANCE TO THE ANALGESIC ACTION OF MORPHINE DRUGS, BUTORPHANOL AND KAPPA-OPIOID RECEPTORS OF RU-1205 AGONISTS

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Purpose of the work: the estimation of analgesic tolerance of opioid agonists of morphine, butorphanol and a new derivative of benzimidazole with kappa-opioid activity - RU-1205 compound. Materials and methods of the study: the studies were carried out by using morphine drugs (OAO Moscow Pharmaceutical Factory, Russia), butorphanol (OAO Moscow Pharmaceutical Factory, Russia), and RU-1205 compound (synthesized by V.A. Anisimova at the Scientific and Research Institute of Physical and Organic Chemistry of Southern Federal University, Rostov on Don, Russia). The work was carried out using 64 white outbred male mice weighed 20-25 g. The animals were kept in the conditions of a standard vivarium at the natural illumination and nutrition ad libitum (GOST R 50258-92). We carried out manipulations with the animals in accordance with legal and ethical norms after the expert evaluation of the regional ethical committee (17.12.2011, protocol no. 149-2012). The formation of analgesic tolerance was carried out by means of subchronical injection of the substances under study to the rodents during 2 weeks two times a day (28 injections). Analgesic effect was registered in the hotplate analgesic assay. We fixed a latent period of nociceptive reaction (LP) (time from the placement of an animal into the hotplate up to the licking of its hind feet, maximum time registered - 30 se-conds). Substance dosage regime: RU-1205 compound - 1 and 10 mg/kg percutaneously, and 5 and 50 mg/kg per os. Statistically significant reduction of LP in the group which chronically received the substance in terms of the results of one-time injection was the criterion of the tolerance improvement. The data were processed statistically with the use of GraphPad Prism 5.0 program package using a Mann-Whitney test. Results: in a control group which received the solvent percutaneously LP amounted to 10.1±0.9 seconds. RU-1205 sub-stance at the doses 1 and 10 mg/kg with one-time percutaneous injection statistically significantly rose this rate in comparison with the control in 2.2 and 2.3 times respectively, while butorphanol in the pointed out doses rose LP in 1.8 times at average. RU-1205 substance did not lead to the reduction of nociceptive reaction time with the 14 day injection (1 and 10 mg/kg percutaneously) concerning one-time value of the rate. At the same time the analgesic activity of butorphanol after 14 day injection reduced significantly by 58% and 61% at doses 1 and 10 mg/kg respectively (Mann-Whitney, p<0.05). After the abdominal injection of the solvent, LP in the control group amounted to 10.5±1.3 seconds. RU-1205 compound at one-time injection at doses 5 and 50 mg/kg provoked statistically significant 2.2 and 1.7 times increase of nociceptive reaction threshold considering the control, and 2 and 1.6 times at 14-days injection. Morphine provoked statistically significant 1.9 and 2.0 times rise of the LP rate concerning the control at one-time administra-tion per os for doses 5 and 50 mg/kg. At that, analgesic activity of the drug significantly re-duced by 59% and 96% at doses 5 and 50 mg/kg respectively. Conclusions: RU-1205 compound did not lead to the tolerance improvement to the an-algesic effect at percutaneous and peroral 2-weeks administration. After 14-day peroral administration morphine provoked the reduction of sensitivity to analgesic effect by 59% and 96% for doses 5 and 50 mg/kg; butorphanol with 2-week percutaneous injection reduced anti-nociceptive action by 58% and 61% at doses 1 and 10 mg/kg respectively.