The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2006-02, Vol.84 (2), p.159-167
• Main Authors: ORSAL, Arif Suphi, BLOIS, Sandra, LABUZ, Dominika, PETERS, Eva M. J, SCHAEFER, Martin, ARCK, Petra C
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Cytokines - biosynthesis; Down-Regulation - drug effects; Dydrogesterone - pharmacology; Female; General aspects; Inflammation; Lymphocytes - drug effects; Lymphocytes - immunology; Mast Cells - cytology; Mast Cells - drug effects; Mast Cells - metabolism; Medical sciences; Mice; Mice, Inbred CBA; Neurotransmitter Agents - metabolism; Pain Threshold - drug effects; Receptors, Neurokinin-1 - drug effects; Receptors, Neurokinin-1 - metabolism; Substance P - metabolism; Th2 Cells - drug effects; Th2 Cells - immunology; Uterus - cytology; Uterus - immunology
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-005-0005-5

Accumulating evidence indicates that the neuropeptide substance P (SP) is predominantly involved in neurogenic inflammation and pain perception via its high-affinity neurokinin 1 receptor (NK-1R). Intriguingly, decreased pain sensitivity is found to be associated with high plasma progesterone levels. We hypothesize that progesterone may attenuate nociception and associated inflammatory response via NK-1R-dependent pathways. To address our hypothesis, we incubated splenic lymphocytes from CBA/J female mice with different concentrations of the progesterone derivative dydrogesterone. Subsequently, the expressions of NK-1R and T helper (Th1)-type cytokines were analyzed by flow cytometry. Next, we subcutaneously injected CBA/J mice with 1.25 mg of dydrogesterone in 200-microl sesame oil; control mice were sham-injected. Tail flick test to detect the nociceptive threshold was performed in 30-min intervals upon injection. Lymphocytes were isolated from blood and uterus and analyzed for NK-1R surface expression. Immunohistochemical analyses were performed to investigate the uterine tissue distribution of NK-1R. Dydrogesterone induced a decrease in the percentage of NK-1R+ lymphocytes in vitro and in vivo. Additionally, an increase in Th2-type and a decrease in Th1-type cytokines could be detected in vitro after incubation with dydrogesterone. An increased tail flick latency following dydrogesterone injection supported the concept that decreased expression of the NK-1R on lymphocytes is associated with an increased pain threshold. Taken together, these results clearly reveal a pathway by which dydrogesterone or progesterone respectively modulates the cross talk of the nervous, endocrine and immune systems in inflammation and pain.