17beta-estradiol rapidly enhances bradykinin signaling in primary sensory neurons in vitro and in vivo.
Many studies have demonstrated that premenopausal women are at increased risk for various pain disorders. Pain-sensing neurons, termed "nociceptors," in the trigeminal ganglia (TG) and dorsal root ganglia (DRG) express receptors for inflammatory mediators and noxious physical stimuli and transmit signals for central processing of pain sensation. Estrogen receptors (ERs) are also expressed on nociceptors in the TG and DRG, and there is ample literature to suggest that activation of ERs can influence pain mechanisms. However, the mechanism for ER modulation of nociceptor activity is incompletely understood. The aim of this study was to characterize the effect of 17β-estradiol (17β-E(2)) on signaling of the inflammatory mediator bradykinin (BK) in primary cultures of rat sensory neurons and a behavioral model of thermal allodynia in rats. Here, we show that exposure to 17β-E(2) rapidly (within 15 min) enhanced responses to BK in vitro and in vivo. The 17β-E(2)-mediated enhancement of BK signaling was not blocked by the transcription inhibitor anisomycin and was mediated by a membrane-associated ER. The effect of 17β-E(2) to enhance BK responses required activation of β1-containing, RGD-binding integrins. These data show that 17β-E(2) rapidly enhances inflammatory mediator responses both in vitro and in vivo and suggest that 17β-E(2) acting at primary sensory pain neurons may participate in regulating the sensitivity of women to painful stimuli.
Rowan
Matthew P
MP
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Berg
Kelly A
KA
Milam
Stephen B
SB
Jeske
Nathan A
NA
Roberts
James L
JL
Hargreaves
Kenneth M
KM
Clarke
William P
WP
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001920:Bradykinin / Q000502:physiology*; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009411:Nerve Endings / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010146:Pain / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism
D007295:Inositol Phosphates; D016023:Integrins; D019384:Nucleic Acid Synthesis Inhibitors; D004958:Estradiol; D000841:Anisomycin; D010738:Type C Phospholipases; D001920:Bradykinin