Sexual dimorphism for protein kinase c epsilon signaling in a rat model of vincristine-induced painful peripheral neuropathy.
Painful peripheral neuropathy is a major dose-limiting adverse effect of many cancer chemotherapeutic agents, such as the vinca alkaloids and taxanes. Recent studies demonstrate sexual dimorphism in second-messenger signaling for primary afferent nociceptor sensitization, and a role of second messengers in the models of metabolic and toxic painful peripheral neuropathies. This study tested the hypothesis that sexual dimorphism alters the severity and second-messenger signaling pathways for enhanced nociception in an animal model of vincristine-induced painful peripheral neuropathy.I.V. injection of vincristine induced mechanical hyperalgesia that was greater in female rats. Gonadectomy in the females but not the males abolished the sex-dependent difference in mechanical hyperalgesia; this effect of gonadectomy in females was reversed by estrogen replacement. Inhibition of protein kinase C epsilon (PKC epsilon ) attenuated vincristine-induced hyperalgesia in males and ovariectomized females, but not in normal females or in estrogen-replaced ovariectomized females. Inhibitors of protein kinase A, protein kinase G, p42 / p44-mitogen activated protein kinase and nitric oxide synthase also attenuated vincristine-induced hyperalgesia, but to a similar degree in both sexes. These data demonstrate an estrogen-dependent sexual dimorphism in vincristine-induced hyperalgesia (female>male) and an unexpected opposite sexual dimorphism in the contribution of PKC epsilon to the severity of this hyperalgesia (male>female).
Joseph
E K
EK
Department of Oral and Maxillofacial Surgery, University of California, 521 Parnassus Avenue, San Francisco, CA, 94143-0440, USA. aley@itsa.ucsf.edu
Levine
J D
JD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency* / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009919:Orchiectomy; D010052:Ovariectomy; D010525:Peripheral Nerves / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014750:Vincristine / Q000009:adverse effects*
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D004967:Estrogens; D014750:Vincristine; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon