Role of the Oestrogen Receptors GPR30 and ERα in Peripheral Sensitization: Relevance to Trigeminal Pain Disorders in Women

Estrogen increases facial allodynia through its actions on activation of the MAP kinase ERK in trigeminal ganglion neurons. This goal of study was to determine which estrogen receptor is required for behavioral sensitization. Immunohistochemical studies demonstrated the presence of estrogen receptor alpha (ERα) in nuclei of larger neurons and cytoplasm of smaller neurons, and the novel estrogen receptor G-protein coupled receptor 30 (GPR30) in small diameter neurons that also contained peripherin, a marker of unmyelinated C-fibers. Specific agonists for ERα (PPT) and GPR30 (G-1), but not ERβ (DPN), activated ERK in trigeminal ganglion neurons in vitro. Both G-1 and PPT treatment increased allodynia after CFA injections in to the masseter of ovariectomized Sprague-Dawley rats. Treatment with estrogen increased expression of ERα but not GPR30, while masseter inflammation increased GRP30 but not ERα. Differential modulation of these ERK-coupled receptors by estrogen and inflammation may play a role in painful episodes of TMD and migraine.