Aminergic status in the brain of urokinase gene-deficient mice with malignant tumors growing in presence of chronic neurogenic pain.

Abstract

e21582 Background: The fibrinolytic system of the brain is important for its normal functioning and participation in processes that are significant in various stressful influences, including tumor growth and chronic neurogenic pain (CNP). These pathological conditions change the activity of the brain neurotransmitter system. On the other hand, urokinase deficiency is associated with significant inhibition of tumor growth, while CNP – with its stimulation. The purpose of the study was to analyze the effect of CNP on the levels of biogenic amines in the brain of mice with urokinase deficiency (uPA-/-) with transplanted B16/F10 melanoma. Methods: The study included male and female mice: С57ВL/6 (uPA+/+, n = 48) and C57BL/6-Plautm1.1Bug-ThisPlauGFDhu/GFDhu (urokinase gene-knockout - uPA-/-, n = 48). Mouse strains were divided into subgroups (each n = 6): intact; with CNP (bilateral sciatic nerve ligation); 21 days after subcutaneous transplantation of B16/F10 melanoma; 21 days of B16/F10 melanoma growth in presence of CNP (B16/F10+CNP), with tumor transplantation 2 weeks after the sciatic nerve ligation. Levels of adrenaline (A), noradrenaline (NA), dopamine (DA), histamine, serotonin (5HT), and 5-hydroxyindoleacetic acid (5OHIA) were determined in the brain by ELISA (Cusabio, China). Statistical processing - Statistica 10.0. Results: Levels of NA, DA and 5HT in the brain of intact uPA-/- mice were 3.5, 2.1 and 1.9 times higher (p < 0.05), respectively, than in intact uPA+/+ animals, while histamine and 5OHIA were on average 2.0 times lower. The dynamics of cerebral levels of biogenic amines in uPA-/- mice with pathological factors, alone or combined, had practically no gender specificity, with rare exceptions. So, 5HT levels increased up to 4.5 times in uPA-/- mice of both sexes in response to CNP or B16/F10 growth. Melanoma growth in presence of CNP, on the contrary, decreased 5HT by 3-10 times and DA by 1.6 times (p < 0.05) both in males and females, and decreased NA by 1.6 times (p < 0.05) in females. Conclusions: CNP together with melanoma inhibits the initial activation of the HA-, DA- and 5HT-ergic systems in the brain of uPA-/- mice, which may be an important pathogenetic mechanism of the cancellation of genetically determined inhibition of subcutaneous B16/F10 melanoma growth in urokinase deficiency.