Sexual dimorphism for protein kinase cε signaling in a rat model of vincristine-induced painful peripheral neuropathy

doi:10.1016/S0306-4522(03)00203-3

Neuroscience

Volume 119, Issue 3, 4 July 2003, Pages 831-838

https://doi.org/10.1016/S0306-4522(03)00203-3 Get rights and content

Abstract

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 Cε (PKCε) 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 PKCε to the severity of this hyperalgesia (male>female).

Section snippets

Animals

Experiments were performed on male and female Sprague–Dawley rats (220–250 g, Bantin and Kingman, Fremont, CA, USA). Rats were housed in groups of two under a 12-h light/dark cycle. Food and water were available ad libitum. Experiments were carried out in accordance with NIH regulations for animal care and with the approval of the Institutional Animal Care and Use Committee of the University of California, San Francisco. All efforts were made to minimize the number of animals used and their

Vcr-induced mechanical hyperalgesia

A single i.v. injection of VCR, 50, 100 and 200 μg/kg, to male and female rats produced a dose-dependent decrease in nociceptive threshold that persisted for a period of at least 15 days. The magnitude of this mechanical hyperalgesia was greater in female rats at all doses and time points (Fig. 1A–C, n=8/group; Table 1).

Vcr-induced mechanical allodynia

Both male and female rats demonstrated a significant increase in paw-withdrawal frequency in response to 1.3-, 3.6-, 10- and 27.5-mN von Frey stimulation, tested 5 days after a

Discussion

Vinca alkaloids such as VCR, are widely used alone or in combination with other chemotherapeutic agents in the treatment of many different malignancies including breast cancer, leukemias, lymphomas, and primary brain tumors Di Cataldo et al., 2002, Ito et al., 2002, Kochi and Ushio, 2002, Robak et al., 2002. VCR kills mitotically active cells by binding tubulin and preventing microtubule formation in mitotic spindles Mahboobi et al., 2001, Blajeski et al., 2002. Tumor cells are most effectively

Acknowledgements

Funded by NIH grant DE08973. We thank Dr. Robert Gear for his helpful suggestions and assistance in the statistical analysis of the data.

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Sexual dimorphism for protein kinase cε signaling in a rat model of vincristine-induced painful peripheral neuropathy

Abstract

Section snippets

Animals

Vcr-induced mechanical hyperalgesia

Vcr-induced mechanical allodynia

Discussion

Acknowledgements

Neuroscience

Neuroscience

Brain Res

Curr Opin Pharmacol

Pain

Pain

J Neurosci Methods

Neurosci Lett

Neurosci Lett

Pain

Neurosci Lett

Lancet

Toxicology

Brain Res

Life Sci

Am J Med

Neuroscience

Pain

Brain Res

Biochem Biophys Res Commun

Oral Surg Oral Med Oral Pathol

Pain

Pain

Neuroscience

Neurosci Lett

J Steroid Biochem Mol Biol

Pharmacol Biochem Behav

Prog Neurobiol

Neuroscience

Role of protein kinase A in the maintenance of inflammatory pain

J Neurosci

Nociceptor sensitization by extracellular signal-regulated kinases

J Neurosci

Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C

J Neurosci

Sex differences in pain

Behav Brain Sci

Changes in tactile stimuli-induced behavior and c-Fos expression in the superficial dorsal horn and in parabrachial nuclei after sciatic nerve crush

J Comp Neurol