title: Sex-dependent differences in the activity and modulation of N-methyl-d-aspartic acid receptors in rat dorsal root ganglia neurons.
abstract: Women have greater temporal summation of experimental pain stimuli and also have a higher propensity for developing chronic visceral pain conditions. Sex hormone-mediated regulation of N-methyl-d-aspartic acid receptors (NMDARs) in nociceptive pathways is a plausible mechanism that may underlie these phenomena. The aim of this study was to compare the effect of 17-beta-estradiol (E2) in modulation of NMDAR activity in adult male and female rat dorsal root ganglia (DRG) neurons. DRG neurons were collected from adult male or female rats and grown in short-term culture in steroid-free media. NMDAR currents were recorded on small to medium size neurons by whole cell patch clamp using rapid perfusion with saturating concentrations of N-methyl-d-aspartic acid and glycine in the absence of extracellular Mg(2+). We found that the average density of NMDAR currents was 2.8-fold larger in DRG neurons from female rats compared with male rats (P<0.0001). Addition of 100 nM E2 increased NMDAR currents 55+/-15% in female neurons, but only 19+/-7% in male neurons. Potentiation was maximal after 20-40 min and dose dependent with an apparent 50% excitatory concentration of 17-23 nM. This effect was mimicked by E2 conjugated to BSA and attenuated by pretreatment with the protein tyrosine kinase inhibitor lavendustin A (1 microM) or the estrogen receptor (ER) antagonist, ICI 182,780 (1 microM), strongly suggesting activation of a cell surface ER acting through a non-genomic mechanism involving protein tyrosine kinases to increase NMDAR currents. These results identify sex-based differences in both the basal expression and the regulation of the NMDARs in DRG neurons.
authors: Center for Neurovisceral Sciences and Women's Health, David Geffen School of Medicine at UCLA, Warren Hall, Room 14-103, 900 Veteran Avenue, Los Angeles, CA 90095, USA. mcrobert@ucla.edu
authors: J A
authors: JA
authors: McRoberts
authors: J
authors: J
authors: Li
authors: H S
authors: HS
authors: Ennes
authors: E A
authors: EA
authors: Mayer
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D005727:Ganglia, Spinal / Q000166:cytology*; D005998:Glycine / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012727:Sex Characteristics
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; D018683:Excitatory Amino Acid Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000077267:Fulvestrant; D004958:Estradiol; D016202:N-Methylaspartate; D005998:Glycine
references: Pain. 2003 Mar;102(1-2):87-95
references: 12620600
references: Am J Physiol Gastrointest Liver Physiol. 2006 Aug;291(2):G219-28
references: 16565418
references: Clin J Pain. 2003 May-Jun;19(3):168-74
references: 12792555
references: Auton Neurosci. 2003 May 30;105(2):90-100
references: 12798205
references: Biol Res Nurs. 2003 Jul;5(1):56-65
references: 12886671
references: J Neurophysiol. 2003 Oct;90(4):2098-105
references: 12815021
references: J Orofac Pain. 2003 Fall;17(4):317-25
references: 14737876
references: Prog Neurobiol. 2000 Jun;61(2):169-203
references: 10704997
references: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3602-7
references: 10725383
references: Eur J Pain. 2000;4(2):157-72
references: 10957697
references: In Vitro Cell Dev Biol Anim. 2000 Jul-Aug;36(7):447-64
references: 11039495
references: Brain Res. 2000 Nov 3;882(1-2):236-40
references: 11056207
references: Eur J Pharmacol. 2001 Mar 30;416(3):203-12
references: 11290370
references: Gastroenterology. 2001 Jun;120(7):1737-48
references: 11375955
references: Brain Res Brain Res Rev. 2001 Nov;37(1-3):153-61
references: 11744083
references: Neurosci Lett. 2002 Feb 15;319(2):71-4
references: 11825673
references: J Comp Neurol. 2002 May 13;446(4):325-41
references: 11954032
references: Recent Prog Horm Res. 2002;57:357-84
references: 12017552
references: Gastroenterology. 2002 Nov;123(5):1686-701
references: 12404243
references: Pain. 2003 Feb;101(3):221-7
references: 12583864
references: J Pain. 2004 Mar;5(2):77-82
references: 15042515
references: Pain. 2004 May;109(1-2):115-23
references: 15082133
references: Pain. 2004 Jun;109(3):274-83
references: 15157688
references: Pain. 2004 Jun;109(3):443-52
references: 15157705
references: Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496-500
references: 3458212
references: Neurosci Lett. 1995 Sep 1;197(1):25-8
references: 8545047
references: Neuroreport. 1996 Mar 22;7(4):895-900
references: 8724668
references: J Neurosci. 1996 Nov 1;16(21):6830-8
references: 8824322
references: Physiol Res. 1996;45(1):1-9
references: 8884918
references: J Neurosci. 1997 Mar 1;17(5):1848-59
references: 9030643
references: Nature. 1997 Apr 17;386(6626):721-4
references: 9109489
references: J Neurosci. 1997 Nov 1;17(21):8129-36
references: 9334388
references: Pharmacol Toxicol. 1998 Jan;82(1):34-9
references: 9527645
references: Horm Behav. 1998 Oct;34(2):140-8
references: 9799624
references: Br J Pharmacol. 1998 Dec;125(8):1625-6
references: 9886751
references: Pain. 1999 Jan;79(1):67-73
references: 9928778
references: Endocrinology. 2005 Apr;146(4):1650-73
references: 15618360
references: J Neurosci Res. 2005 Jul 1;81(1):31-7
references: 15952176
references: Spine (Phila Pa 1976). 2005 Aug 15;30(16):1821-7
references: 16103850
references: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12938-43
references: 16118273
references: Pain. 2005 Oct;117(3):433-42
references: 16154701
references: Exp Brain Res. 2006 Mar;169(4):467-72
references: 16292641
references: Mol Cell Neurosci. 2006 Mar;31(3):539-48
references: 16413788
references: Neuroscience. 2003;118(2):547-62
references: 12699789