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AbstractWe have recently identified several aroylhydrazone-based molecular hybrids with antiseizure activity. We aimed to investigate the analgesic activity of these molecules further. Male ICR mice were injected intraperitoneally with the tested substances or with the vehicle only (controls). We performed hot plate tests, formalin test and maximal electroshock (MES) test and further studied the cytokine proteome in the brain. In silicoanalysis was performed for prediction of the physicochemical parameters and activity. The furan-substituted aroylhydrazone-based 2H-chromene hybrid showed a significant increase of the latent time as compared with the baseline values (p< .05). Both the chlorine-substituted and the methyl-substituted aroylhydrazone-based coumarin derivatives significantly decreased the first phase of the formalin test (p< .05). We also found suppression of all the cytokines which were overexpressed in the model of acute seizures (MES test) and in the formalin paw test. The in silicomodel predicted hydroxymethylglutaryl coenzyme A synthetase 2 (HMGCS2) enhancer activity. Further testing is needed to confirm the mechanism of the potentially beneficial effects of the tested substances and to evaluate the toxicity and efficacy of the proposed molecules.

Opioid and non-opioid effects of acute and chronic morphine administration on behaviour, cardiovascular responses, cell proliferation and apoptosis and nitric-oxide synthase (NOS) activity were studied in rats. A novel score-point scale was introduced to quantify the signs of opioid withdrawal syndrome. NOS inhibitor L-NAME (NG-nitro-L-arginine methyl ester) was applied to reveal the role of NOS/NO pathway in the modulation of morphine-induced in vivoand in vitroresponses. The obtained data showed that chronic co-administration of L-NAME drastically attenuated naloxone-precipitated withdrawal syndrome and prevented the development of morphine tolerance to cardiovascular action of morphine. The apoptotic process was very much restricted by L-NAME supplementation of chronic morphine treatment, which resulted in few apoptotic cells, less low molecular weight genomic DNA and preservation of high molecular weight non-fragmented genomic DNA. The study provides new data for nitroxidergic modulation of opioid tolerance and dependence.

ABSTRACTPelvic pain is a complex painful sensation caused by spasm/distension/inflammation in hollow organs, with still unclear mechanisms. The aim of this study was to develop and validate an en block—ex situ mouse model resembling the conditions of painful distension of the urinary system and an in vitro rat model resembling uterine contractions in conditions of hormonal simulation of dysmenorrhea. The effects of Metamizol (Analgin) were studied in test experiments in order to validate the experimental potential of the novel en block—ex situ and in vitro models. Mature male mice (27.8 g ± 0.4 g b.m.) and female Wistar rats (180 g ± 5 g b.m.) were used. (i) The lumbar-sacral portion of spine and pelvis with whole urinary system (kidneys, ureters, urinary bladder, urethra) and surrounding tissues were dissected en block, placed in an organ chamber and bathed with tissue medium. The effect of Metamizol (0.25 mmol/L) on sensory nerve firing during rapid distension of urinary bladder was studied. (ii) Anesthetized rats were ovariectomized via ventral approach. Postoperatively, the animals were implanted with matrix-driven delivery system (MDDS) containing Levonorgestrel (1.05 mg) or placebo. MDDS was removed after 4 days (hormone withdrawal) or 7 days (placebo application). The middle part of the uterine horns was excised and placed between two platinum ring electrodes near the outlet of a 1 mL plastic double-jacketed horizontal tissue chamber. The preparation was tied to a force-displacement transducer for registration of isometric changes of tension. Electric stimulation was applied to elicit myogenic motor responses. Metamizol (0.5 mmol/L) was applied in vitro. The in vitro results showed that Metamizol suppressed the spontaneous, as well as the electrical field stimulation evoked and PGF2α- induced contractions of isolated uterine horn. Metamizol alleviated the firing of pelvic nerve afferents due to bladder distension and/or intravesical application of ATP, but did not change the distension induced release of ATP. The results revealed a therapeutic potential of Metamizol in alleviation of pain in painful pelvic syndromes in humans.