GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat

Abstract

We evaluated the signalling pathway by which estrogen acts in peripheral tissue to produce protein kinase Cepsilon (PKCepsilon)-dependent mechanical hyperalgesia. Specific agonists for the classical estrogen receptors (ER), ERalpha and ERbeta, did not result in activation of PKCepsilon in neurons of dissociated rat dorsal root ganglia. In contrast, G-1, a specific agonist of the recently identified G-protein-coupled estrogen receptor, GPR30, induced PKCepsilon translocation. Involvement of GPR30 and independence of ERalpha and ERbeta was confirmed using the GPR30 agonist and simultaneous ERalpha and ERbeta antagonist ICI 182,780 (fulvestrant). The GPR30 transcript could be amplified from dorsal root ganglia tissue. We found estrogen-induced as well as GPR30-agonist-induced PKCepsilon translocation to be restricted to the subgroup of nociceptive neurons positive for isolectin IB4 from Bandeiraea simplicifolia. Corroborating the cellular results, both GPR30 agonists, G-1 as well as ICI 182,780, resulted in the onset of PKCepsilon-dependent mechanical hyperalgesia if injected into paws of adult rats. We therefore suggest that estrogen acts acutely at GPR30 in nociceptors to produce mechanical hyperalgesia.

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

“…Indeed, in both rodent and human females pain threshold and pain tolerance vary in relationship to the stage of the estrous cycle with increased mechanosensation, presumably acting by way of low-threshold myelinated afferents, being implicated as a potential underlying mechanism. (56) These data are consistent with recent observations that GPR30 ER agonists can induce mechanical hyperalgesia and visceral hypersensitivity in the rat (27,34). Collectively, these reports are consistent with our previous demonstration (30) that lowthreshold myelinated Ah-type VGN can be sensitized through agonist activation of purinergic (P 2x ) receptors that have long been associated with afferent signaling of pain and inflammatory responses (51).…”

The GPER1 Agonist G-1 Attenuates Endothelial Cell Proliferation by Inhibiting DNA Synthesis and Accumulating Cells in the S and G2 Phases of the Cell Cycle

“…The low GPER1 expression level in COS-7 cells is probably not sufficient to evoke antiproliferation upon stimulation by G-1. Another support for the involvement of GPER1 is that the ER antagonist ICI182780, reported to act as a GPER1 agonist [22,39], reduces endothelial cell DNA synthesis with similar potency as G-1. GPER1 siRNA abolished the G-1-induced attenuation of DNA synthesis, providing direct evidence for the involvement of GPER1.…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…The activation of ERK1/2 in trigeminal ganglion neurons and the increased allodynia induced by PPT [4,49,-pyrazole-1,3,5-triyl) trisphenol] and G-1 has led to the conclusion of roles for both ERa and GPER in peripheral sensitization (Liverman et al, 2009); however, with the recent demonstration that PPT can also function as a GPER agonist (Petrie et al, 2013), it is possible that both responses, in fact, were mediated by GPER, because independent methods to assess receptor involvement were not employed. G-1 also depolarizes spinal cord neurons , stimulates mechanical hyperalgesia via protein kinase C« activation (Kuhn et al, 2008), and mediates visceral hypersensitivity in the absence of inflammation (Lu et al, 2009).…”