Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat

We previously reported that 17 beta-estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared with met/diestrous rats. The site of action, the type of estrogen receptors activated, and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting that spinal estrogen receptors are involved. This is further supported by the observations that the antiestrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx, and colonic afferents did not label for estrogen receptor alpha (ER alpha). The ER alpha selective agonist, 4,4',4 ''-[4-propyl-(1H)-pyrazole-1,3,5-triyl] tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ER alpha activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ER alpha mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.