The Novel Roles of Neutrophils Via Opioid Peptides: Regulation of the Estrous Cycle and Pain

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The Novel Roles of Neutrophils Via Opioid Peptides: Regulation of the Estrous Cycle and Pain Yoshiro Kobayashi

Received: 21 August 2012 / Accepted: 1 February 2013 / Published online: 12 February 2013 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013

Abstract Neutrophils are excreted into the vaginal vault at metestrus during the estrous cycle, and this phenomenon has long been used to determine the phase of the estrous cycle. A much smaller number of neutrophils are also detected in the uterus and the ovary. Recently, we provided several lines of evidence supporting the notion that neutrophils infiltrate into the ovary to regulate the estrous cycle by opioid peptides. Upon inflammation, on the other hand, neutrophils infiltrate into the site of infection to suppress pain by opioid peptides. Thus, opioid peptides are key molecules by which neutrophils play a novel role in regulation of the pain and estrous cycle. In both cases, opioid peptides appear to be secreted by neutrophils stimulated with chemokines, such as MIP-2 and KC in mouse, corticotropin-releasing hormone and IL-1. Keywords Pain

Neutrophils  Opioid peptides  Estrous cycle 

Introduction Neutrophils comprise approximately 60 and 10 % of human and mouse peripheral blood leukocytes, respectively, and they circulate in the blood stream under physiological conditions. It is generally believed that neutrophils enter sites of infection or ischemia–reperfusion, where they execute a bacteria-killing function or cause tissue damage, respectively. However, even under

Y. Kobayashi (&) Division of Molecular Medicine, Department of Biomolecular Science, Faculty of Science, Toho University, Chiba, Funabashi, Japan e-mail: [email protected]

physiological conditions, neutrophils are excreted into the vaginal vault at metestrus during the estrous cycle. This phenomenon has long been known since Stockard and Papanicolaou found in 1917 that in guinea pigs, the morphology of epithelial cells in the vagina changes in association with the estrous cycle, and subsequently in 1922, Long and Evans published a method for determining the stage of the estrous cycle by means of vaginal smears (Goldman et al. 2007). It should be noted here that in rats and mice, the estrous cycle is driven by a light/dark cycle. The cycle comprises four stages, namely proestrus, estrus, metestrus and diestrus, and the cycle is repeated every 4–5 days. Excretion of neutrophils into the vaginal vault is reportedly mediated by MIP-2, one of the neutrophilselective chemokines in mice, which is expressed on epithelial cells in the vaginal vault (Sonoda et al. 1998). The role of neutrophils excreted into the vaginal vault, however, has been a matter of dispute, although it has been hypothesized that they may phagocytose and kill commensal bacteria. We thus initiated research to elucidate their role about seven years ago. Because it is well known that the administration of an anti-Gr-1 monoclonal antibody (anti-Gr-1 mAb) to mice causes depleti