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

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 Cε (PKCε-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 PKCε-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 PKCε signaling is sexually dimorphic, in alcohol neuropathy PKA as well as PKCε signaling is highly sexually dimorphic.