The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice.
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.
Orsal
Arif Suphi
AS
Department of Biomedical Research, Charité, University Medicine, Berlin, Germany.
Blois
Sandra
S
Labuz
Dominika
D
Peters
Eva M J
EM
Schaefer
Martin
M
Arck
Petra C
PC
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
D016207:Cytokines; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; D004394:Dydrogesterone