Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons.
Protein kinase C epsilon (PKCepsilon) is an important intracellular signaling molecule in primary afferent nociceptors, implicated in acute and chronic inflammatory as well as neuropathic pain. In behavioral experiments inflammatory mediators produce PKCepsilon-dependent hyperalgesia only in male rats. The mechanism underlying this sexual dimorphism is unknown. We show that the hormone environment of female rats changes the nociceptive signaling in the peripheral sensory neuron. This change is maintained in culture also in the absence of a gender-simulating environment. Stimulation of beta(2)-adrenergic receptors (beta(2)-AR) leads to PKCepsilon activation in cultured dorsal root ganglia (DRG) neurons derived from male but not from female rats. Addition of estrogen to male DRG neurons produces a switch to the female phenotype, namely abrogation of beta(2)-AR-initiated activation of PKCepsilon. Estrogen interferes downstream of the beta(2)-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKCepsilon. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKCepsilon. If applied before beta(2)-AR or Epac stimulation, estrogen abrogates the activation of PKCepsilon. In contrast, estrogen applied alone leads to a brief translocation of PKCepsilon. Also in vivo the activity of estrogen depends on the stimulation context. In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCepsilon-dependent mechanism. In contrast, injection of estrogen preceding the activation of Epac completely abrogates the Epac-induced mechanical hyperalgesia. Our results suggest that gender differences in nociception do not reflect the use of generally different mechanisms. Instead, a common set of signaling pathways can be modulated by hormones.
Hucho
Tim B
TB
NIH Pain Center, UCSF, University of California, San Francisco, 521 Parnassus Avenue, PO-Box 0440, 94143, USA. hucho@molgen.mpg.de
Dina
Olayinka A
OA
Kuhn
Julia
J
Levine
Jon D
JD
D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D058666:Adrenergic beta-2 Receptor Agonists; C482601:Epac protein, mouse; D004967:Estrogens; D020662:Guanine Nucleotide Exchange Factors; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D051744:Protein Kinase C-epsilon