Estrogen rapidly modulates mustard oil-induced visceral hypersensitivity in conscious female rats: a role of CREB phosphorylation in spinal dorsal horn neurons

Abstract

rapidly modulates mustard oil-induced visceral hypersensitivity in conscious female rats: a role of CREB phosphorylation in spinal dorsal horn neurons. Am J Physiol Gastrointest Liver Physiol 292: G438 -G446, 2007. First published September 14, 2006; doi:10.1152/ajpgi.00210.2006.-This study investigated the effect of sex hormones on mustard oil (MO)-induced visceral hypersensitivity in female rats and analyzed possible involved signaling pathways. Female rats, either intact or ovariectomized (OVX), were prepared for abdominal muscle electromyography in response to colorectal distension after intracolonic instillation of MO. The effect of MO intracolonic sensitization was evaluated in intact rats, OVX rats, and OVX rats pretreated with a single injection of 17␤-estradiol (E), progesterone (P), EϩP, or vehicle. cAMPresponsive element-binding protein (CREB) and phosphorylated CREB (pCREB) were detected in the superficial dorsal horn of L6 and S1 in MO or mineral oil-treated OVX rats with/without colorectal distension and estrogen replacement. The distal colorectum was removed for histological evaluation of inflammatory severity in MOtreated intact or OVX rats. The MO-treated rats had significantly higher visceromotor reflex than controls (enhanced visceral hypersensitivity), whereas OVX eliminated this hypersensitivity. After a single injection of E or EϩP, the rats rapidly restored MO-induced visceral hypersensitivity within 2 h. Estrogen also rapidly induced a dosedependent increase in pCREB expression in the superficial dorsal horn neurons in MO-treated, but not mineral oil-treated, OVX rats. The present study suggests that estrogen can rapidly modulate visceral hypersensitivity induced by MO intracolonic instillation in conscious female rats, which may involve spinal activation of the cAMP response element-mediated gene induction pathway.irritable bowel syndrome; spinal cord; cAMP-response element binding protein; gender VISCERAL PAIN IS A COMMON complaint frequently encountered in the daily practice of gastrointestinal clinics. Studies have shown women are more likely than men to report pain, have lower pain thresholds, and feel pain with greater intensity (6, 43). Some chronic visceral or musculoskeletal pain syndromes, such as irritable bowel syndrome (IBS), fibromyalgia, and temporomandibular disorders, are also female predominant (11,21,44). Even in Eastern society, gender differences in IBS have been reported (28). Similarly, female rats exhibit larger pain reactions than males to thermal stimuli or formalin testing (4, 38).Both human and animal studies suggest gender differences in pain processing; however, the roles of sex hormones in visceral pain modulation are conflicting. For example, ovariectomized (OVX) rats exhibit similar or reduced visceromotor reflex (VMR) to colorectal distension (CRD) compared with controls (7, 23), whereas visceral pain behaviors are greatly increased in OVX mice upon intracolonic capsaicin stimulation (41). Estrogen did not affect the VMR by uterine cervical distension in ...

Visceral hypersensitivity in female but not in male serotonin transporter knockout rats

“…An interaction between female gonadal hormones and increased extracellular serotonin could be the key factor responsible for visceral hypersensitivity in female SERT KO rats. In a rat model of colonic inflammation‐induced visceral hypersensitivity, ovariectomy reduces, while estrogen treatment of ovariectomized rats restores visceral hypersensitivity . This effect occurred within 2 h of estrogen treatment, suggesting that it was mediated by non‐genomic mechanisms.…”

Estrogen Rapidly Modulates 5-Hydroxytrytophan-Induced Visceral Hypersensitivity via GPR30 in Rats

“…S ex hormones are reported to be important in animal models in the modulation of "visceral hypersensitivity" (VH), a defining factor in pathogenesis of irritable bowel syndrome (IBS). However, the VH models in these reports were mainly secondary to severe colonic mucosal inflammation, 1,2 which is not observed in IBS patients. Therefore, the role of estrogen in the VH model in the absence of mucosal inflammation should be examined.…”

“…7 For example, we have shown that estrogen can restore mustard oil-induced VH in ovariectomized (OVX) rats in 90 minutes. 2 Others have demonstrated that a single injection of estrogen can rapidly phosphorylate CREB in gonadotropin-releasing neurons in OVX mice within only 15 minutes, and this effect can persist for 4 hours. 9 A G-protein-coupled receptor, GPR30 (an alternative to the classical ERs), has recently been identified to be involved in the rapid action of estrogen through its direct association with estrogen.…”

Sex differences and hormonal modulation of deep tissue pain

“…There are several models that induce colonic or bladder hypersensitivity lasting from hours to weeks in the absence or presence of inflammation. Female hypersensitivity to colorectal distention was reported following mustard oil irritation of the colon and the magnitude of the increase was greater in females compared to males (Ji et al, 2012b; Lu et al, 2007). Similarly, hypersensitivity that persisted several weeks in the absence of colonic inflammation was greater in female rats (Bourdu et al, 2005).…”

“…Similar to noninflamed animals, estrogen modulated the magnitude of response in females. Ovariectomy reduced the visceromotor response to intracolonic mustard oil which was restored by E2 replacement (Ji et al, 2005; Lu et al, 2007). Intracolonic 5HTP, a serotonin precursor, induced colonic hypersensitivity without noticeable inflammation that was attenuated by ovariectomy and facilitated by E2 (Lu et al, 2009).…”