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-μl 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.

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Abbreviations

Th:

(T helper)

IL:

Interleukin

SP:

Substance P

NK-1R:

Neurokinin 1 receptor

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Acknowledgements

The authors would like to thank Evi Hagen, Petra Moschansky, Petra Busse and Bori Handjinski for their excellent technical assistance and continuous support in generating this work. Sandra Blois and Petra Arck are part of the EMBIC Network of Excellence, co-financed by the European Commission throughout the FP6 framework program ‘Life Science, Genomics and Biotechnology for Health’. Arif Orsal is supported by fellowships of Turkish Higher Education Council. Sandra Blois is a fellow of the Ernst Schering Foundation. This work was further made possible by research grants from the Charité to Arif Orsal and Petra Arck.

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Correspondence to Petra C. Arck.

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Orsal, A.S., Blois, S., Labuz, D. et al. The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice. J Mol Med 84, 159–167 (2006). https://doi.org/10.1007/s00109-005-0005-5

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Keywords

  • Neurogenic inflammation
  • Neurokinin-1 receptor
  • Progesterone
  • Dydrogesterone
  • Nociception
  • Cytokines