title: Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.
abstract: Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A.
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ono
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kanemasa
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: shunji.shinohara@shionogi.co.jp.
authors.forename: Shunji
authors.initials: S
authors.lastname: Shinohara
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D045744:Cell Line, Tumor; D004399:Dynorphins / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology*; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005269:Femur / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D010052:Ovariectomy; D010098:Oxycodone / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology
chemical_list: D000700:Analgesics; D004967:Estrogens; D004399:Dynorphins; D009020:Morphine; D010098:Oxycodone
keywords: Dynorphin; Estrogen; Femur bone cancer pain; Morphine; Oxycodone