title: The cAMP response element-binding protein in the bed nucleus of the stria terminalis modulates the formalin-induced pain behavior in the female rat.
abstract: Abstract Differences in male and female responses to pain are widely recognized in many species, including humans, but the cerebral mechanisms that generate these responses are unknown. Using the formalin test, we confirmed that proestrus female rats showed nociceptive behavior, modulated by estrogen that was distinct from male rats, particularly during the interphase period. We then explored the brain areas, which were involved in the female pattern of nociceptive behavior. We found that, after a formalin injection and at the time corresponding to the behavioral interphase, the number of phosphorylated cAMP response element-binding protein (pCREB)-immunoreactive neurons observed by immunocytochemistry increased in the dorsolateral division of the bed nucleus of the stria terminalis (BSTLD) in female but not male rats. There were no significant sex differences in pCREB expression following formalin in any region other than the BSTLD. The increased pCREB in female rats was eliminated after an ovariectomy and restored with 17beta-estradiol treatment. Neither an orchidectomy nor 17beta-estradiol treatment affected the pCREB response in male rats. The increase in pCREB expression in the BSTLD in female rats after formalin injection was confirmed with immunoblotting. To determine the role of CREB in the BSTLD, adenovirus-mediated expression of a dominant-negative form of CREB (mCREB) was carried out. The nociceptive behavior during interphase was significantly attenuated by injection of virus carrying mCREB into the BSTLD in female rats but not in male rats. These results suggest a novel role for CREB in the BSTLD as a modulator of the pain response in a female-specific, estrogen-dependent manner.
authors.affiliation: Department of Physiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hagiwara
authors.forename: Maho
authors.initials: M
authors.lastname: Ishida
authors.forename: Jun
authors.initials: J
authors.lastname: Arita
authors.forename: Dai
authors.initials: D
authors.lastname: Mitsushima
authors.forename: Takuya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Fukuko
authors.initials: F
authors.lastname: Kimura
authors.forename: Toshiya
authors.initials: T
authors.lastname: Funabashi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D059408:Pain Management; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012686:Septal Nuclei / Q000187:drug effects / Q000503:physiopathology*; D012727:Sex Characteristics; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004967:Estrogens; D005557:Formaldehyde; D004958:Estradiol