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

TY - JOUR

T1 - The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice

AU - Orsal, Arif Suphi

AU - Blois, Sandra

AU - Labuz, Dominika

AU - Peters, Eva M J

AU - Schaefer, Martin

AU - Arck, Petra C

PY - 2006/2

Y1 - 2006/2

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Cytokines/biosynthesis

KW - Down-Regulation/drug effects

KW - Dydrogesterone/pharmacology

KW - Female

KW - Inflammation

KW - Lymphocytes/drug effects

KW - Mast Cells/cytology

KW - Mice

KW - Mice, Inbred CBA

KW - Neurotransmitter Agents/metabolism

KW - Pain Threshold/drug effects

KW - Receptors, Neurokinin-1/drug effects

KW - Substance P/metabolism

KW - Th2 Cells/drug effects

KW - Uterus/cytology

U2 - 10.1007/s00109-005-0005-5

DO - 10.1007/s00109-005-0005-5

M3 - SCORING: Journal article

C2 - 16389545

VL - 84

SP - 159

EP - 167

JO - J MOL MED

JF - J MOL MED

SN - 0946-2716

IS - 2

ER -