Estradiol attenuates the adenosine triphosphate‐induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat dorsal root ganglion neurons

Abstract

Estradiol attenuates the ATP-induced increase of intracellular calcium concentration ([Ca2+]i) in rat dorsal root ganglion (DRG) neurons by blocking the L-type voltage gated calcium channel (VGCC). Since ATP is a putative nociceptive signal, this action may indicate a site of estradiol regulation of pain. In other neurons, 17β-estradiol (E2) has been shown to modulate L-type VGCC through a membrane estrogen receptor-group II metabotropic glutamate receptor (mGluR2/3). The present study investigated whether the rapid estradiol attenuation of ATP-induced increase [Ca2+]i requires the mGluR2/3. Previously we showed that DRG (L1-S3) express ERα, P2X3 and mGluR2/3 receptors. DRG were acutely dissociated by enzyme digestion and grown in short-term culture for imaging analysis. DRG neurons were stimulated twice, once with ATP (50 μM) for 5 seconds, and then again in the presence of E2 (100 nM) or E2 (100 nM) + LY341495 (100nM), an mGluR2/3 inhibitor. ATP induced transient increase in [Ca2+]i (216.3 ± 41.2 nM). This transient could be evoked several times in the same DRG neurons if separated by a 5 min washout. Treatment with estradiol significantly attenuated the ATP-induced [Ca2+]i in 60% of the DRG neurons, to 163.3±20.9 nM (p<0.001). Co-application of E2 and the mGluR2/3 inhibitor LY341495 blocked the 17β-estradiol-attenuation of the ATP-induced [Ca2+]i transient (209.1±32.2 nM, p>0.05). These data indicate that the rapid action of E2 in DRG neurons is dependent on the mGluR2/3, and demonstrate that membrane estrogen receptor-α initiated signaling involves tan interaction with mGluRs.

Estrogenic influences in pain processing

“…ER and ER are expressed in cells in the rat trigeminal ganglion (Bereiter et al, 2005) and dorsal root ganglia (DRG) and regulate sensory neuron survival during the development of the DRG in this species (Patrone et al, 1999). Estrogens profoundly increase the size of the receptive field of primary afferent nerve fibers in female rats (Bereiter and Barker, 1975;Kow and Pfaff, 1973) and rapidly attenuate nociceptive signaling in female mouse primary afferent neurons by an ER-dependent mechanism that is most likely non-genomic (Chaban et al, 2011;Chaban and Micevych, 2005). Prolonged exposure to estradiol in neuronal cultures from DRGs of female rats inhibits activation of the ion channel TRPV1, which is central to nociceptive transmission in the DRG (Xu et al, 2008) and cultured trigeminal ganglion cells from ovariectomized rats exhibit increased sensitivity to capsaicin (Diogenes et al, 2006).…”

Irritable Bowel Syndrome: Functional Gastrointestinal Disease Regulated by Nervous System

“…In vitro, ATP-sensitive DRG neurons respondtoE2 [6,7],whichcorrelatedwellwiththeideathatvisceralaferentsareE2sensitive: (i)visceralpainisafectedbyhormonallevelincyclingfemales;(ii)therearesexdiferences intheprevalenceoffunctionaldisordersinvolvingtheviscera;and(iii)putativevisceralaferentsitintothepopulationofDRGneuronsthataresensitivetoE2 [7]. These data suggest thatinadditiontotheCNSactions,E2canactintheperipherytomodulatenociception [6,7]. E2modulatescellularactivitybyalteringionchannelopening,G-proteinsignaling,andactivationoftrophicfactor-likesignaltransductionpathways.Theseefectshavebeenascribed to membrane-associated receptors [8].…”

“…E2modulatescellularactivitybyalteringionchannelopening,G-proteinsignaling,andactivationoftrophicfactor-likesignaltransductionpathways.Theseefectshavebeenascribed to membrane-associated receptors [8]. The results from our laboratory and others indicate thatE2actsinDRGneuronstomodulateL-typeVGCCandthroughgroupIImetabotropic glutamatereceptors [6].…”

“…E2(bothshort-termandlong-termexposure)signiicantlydecreasedthenociceptivesignalinginviscerallylabeledDRGneurons [6,7]. Thus, in addition to central regulation, estrogen mayafectnociceptionassociatedwithIBSperipherally.…”

“…Several lines ofevidenceindicatethat17β-estradiol(E2)directlyinluencethefunctionsofprimaryaferentneurons.Bothsubtypesofestrogenreceptors(ERαandERβ)arepresentinDRGneurons includingthesmall-diameterputativenociceptors [4]. In vitro, ATP-sensitive DRG neurons respondtoE2 [6,7],whichcorrelatedwellwiththeideathatvisceralaferentsareE2sensitive: (i)visceralpainisafectedbyhormonallevelincyclingfemales;(ii)therearesexdiferences intheprevalenceoffunctionaldisordersinvolvingtheviscera;and(iii)putativevisceralaferentsitintothepopulationofDRGneuronsthataresensitivetoE2 [7]. These data suggest thatinadditiontotheCNSactions,E2canactintheperipherytomodulatenociception [6,7].…”