Symptoms of ethanol withdrawal include heightened responses to sensory stimuli, as well as tremors and convulsions. We tested the hypothesis that repeated episodes of ethanol intake and withdrawal exacerbate the symptoms of alcohol-induced peripheral neuropathy. In contrast to the hyperalgesia produced when an alcohol (6.5%)-containing diet was fed continuously to male rats which took 4 weeks to develop (Dina et al., 2000), feeding alcohol (6.5%) in repeated cycles of 4 days of alcohol followed by 3 days without alcohol resulted in a withdrawal-induced hyperalgesia that began at the end of one weekly cycle and reached a maximum during the fourth cycle. For ethanol withdrawal to produce hyperalgesia, ethanol consumption needed to be terminated for a period of 2 days. Paradoxically, as the amount of alcohol consumed decreased, the hyperalgesia induced by withdrawal developed more rapidly, being maximal between 1.4 and 1.6% ethanol. These results suggest that continued exposure to ethanol also has a neuroprotective effect. Withdrawal-induced hyperalgesia, similar to the hyperalgesia induced by continuous, chronic alcohol intake, was inhibited reversibly by intrathecal administration of an antisense oligodeoxynucleotide to protein kinase C (PKC)epsilon.