Expression of aromatase in the rostral ventromedial medulla and its role in the regulation of visceral pain.

Abstract

Estrogens are known to exert a wide spectrum of actions on brain functions including modulation of pain. Besides the circulating estrogens produced mainly by the ovaries, many brain regions are also capable of de novo synthesizing estrogens, which may exert important modulatory effects on neuronal functions. This study was aimed to test the hypothesis that aromatase, the enzyme that catalyzes the conversion of testosterone to estradiols, may be distributed in the rostral ventromedial medulla (RVM), where it may impact on visceral pain. Adult female rats were treated with cyclophosphamide (CPM, 50mg/kg, ip, once every 3days) or saline. At approximately day 10 following the 3rd injection, CPM-treated rats exhibited colorectal hyperalgesia as they showed significantly greater abdominal withdrawal responses (AWR) to graded colorectal distension (CRD, 0-100mm Hg) than the saline group. Immunofluorescent staining and Western blot assay revealed that CPM-induced colorectal hyperalgesia was associated with significantly increased expression of aromatase and phosphorylated μ-type opioid receptor (pMOR) and decreased expression of total MOR in the RVM. Intracisternal application of aromatase inhibitors, fadrozole, and letrozole reversed CPM-induced colorectal hyperalgesia and restored pMOR and MOR expression in the RVM. Our observations confirmed the expression of aromatase in the RVM, a pivotal brain region in descending modulation of pain and opioid analgesia. The results support the hypothesis that locally produced estrogens in the RVM may be involved in the maintenance of chronic visceral hyperalgesia and the downstream signaling may involve phosphorylation of MOR.