title: The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice.
abstract: 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.
authors.affiliation: Department of Biomedical Research, Charité, University Medicine, Berlin, Germany.
authors.forename: Arif Suphi
authors.initials: AS
authors.lastname: Orsal
authors.forename: Sandra
authors.initials: S
authors.lastname: Blois
authors.forename: Dominika
authors.initials: D
authors.lastname: Labuz
authors.forename: Eva M J
authors.initials: EM
authors.lastname: Peters
authors.forename: Martin
authors.initials: M
authors.lastname: Schaefer
authors.forename: Petra C
authors.initials: PC
authors.lastname: Arck
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D004394:Dydrogesterone / Q000494:pharmacology*; D005260:Female; D007249:Inflammation; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D018377:Neurotransmitter Agents / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D014599:Uterus / Q000166:cytology / Q000276:immunology
chemical_list: D016207:Cytokines; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; D004394:Dydrogesterone