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. 2007 Mar 2;145(1):350-6.
doi: 10.1016/j.neuroscience.2006.11.053. Epub 2007 Jan 3.

Severity of alcohol-induced painful peripheral neuropathy in female rats: role of estrogen and protein kinase (A and Cepsilon)

O A Dina  1 , R W Gear, R O Messing, J D Levine
Affiliations

Severity of alcohol-induced painful peripheral neuropathy in female rats: role of estrogen and protein kinase (A and Cepsilon)

O A Dina et al. Neuroscience. .

Abstract

Small-fiber painful peripheral neuropathy, a complication of chronic ethanol ingestion, is more severe in women. In the present study, we have replicated this clinical finding in the rat and evaluated for a role of estrogen and second messenger signaling pathways. The alcohol diet (6.5% ethanol volume:volume in Lieber-DeCarli formula) induced hyperalgesia with more rapid onset and severity in females. Following ovariectomy, alcohol failed to induce hyperalgesia in female rats, well past its time to onset in gonad intact males and females. Estrogen replacement reinstated alcohol neuropathy in the female rat. The protein kinase A (PKA) inhibitor (Walsh inhibitor peptide, WIPTIDE) only attenuated alcohol-induced hyperalgesia in female rats. Inhibitors of protein kinase Cepsilon (PKCepsilon-I) and extracellular-signal related kinase (ERK) 1/2 (2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (U0126)) attenuated hyperalgesia in males and females, however the degree of attenuation produced by PKCepsilon-I was much greater in females. In conclusion, estrogen plays an important role in the expression of pain associated with alcohol neuropathy in the female rat. In contrast to inflammatory hyperalgesia, in which only the contribution of PKCepsilon signaling is sexually dimorphic, in alcohol neuropathy PKA as well as PKCepsilon signaling is highly sexually dimorphic.

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Figures

Figure 1
Figure 1. Nociceptive effects of ethanol diet
(A) Ethanol diet (ED) reduces the mechanical nociceptive threshold in male and female rats. Males and females receiving the control diet (CD) did not differ significantly. In this and subsequent figures data are plotted as mean ± standard error of the mean (s.e.m.). (B) Ovariectomy (Ovx) prevents ethanol diet-induced hyperalgesia in females. Scheffé post hoc analysis indicated that the ovariectomized group was significantly different from the intact females and the ovariectomized group that received estrogen supplement (OvxE) (p<0.001, in both cases), but the intact group was not significantly different from the OvxE group.
Figure 2
Figure 2. Protein kinase inhibitors differentially modulate alcohol-induced hyperalgesia
Baseline responses were measured in intact males (IM), intact females (IF) and ovariectomized females with estrogen implants (OvxE) prior to commencement of the ethanol diet; pre-inhibitor and post-inhibitor responses are plotted as percentage change from the baseline scores. Data were analyzed by two-way repeated measures ANOVA with one within-subjects factor (treatment with two levels, pre-inhibitor and post-inhibitor) and sex with three levels (males, females, and ovariectomized females plus estrogen). If there was a significant treatment × sex interaction, separate one-way repeated measures were performed for each sex to determine the basis of the significant differences. Effect of the inhibitors, namely; PKCε, WIPTIDE, PD98059 and U0126 are shown in Figures 2a, 2b, 2c and 2d, respectively. Statistical analysis and data are described in the results, as appropriate.
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