Key role for the epsilon isoform of protein kinase C in painful alcoholic neuropathy in the rat

Chronic alcohol consumption produces a painful peripheral neuropathy for wh ich there is no reliably successful therapy, attributable to, in great part , a lack of understanding of the underlying mechanisms. We tested the hypot hesis that neuropathic pain associated with chronic alcohol consumption is a result of abnormal peripheral nociceptor function. In rats maintained on a diet to simulate chronic alcohol consumption in humans, mechanical hypera lgesia was present by the fourth week and maximal at 10 weeks. Thermal hype ralgesia and mechanical allodynia were also present. Mechanical threshold o f C-fibers in ethanol fed rats was lowered, and the number of action potent ials during sustained stimulation increased. The hyperalgesia was acutely a ttenuated by intradermal injection of nonselective protein kinase C (PKC) o r selective PKC epsilon inhibitors injected at the site of nociceptive test ing. Western immunoblot analysis indicated a higher level of PKC epsilon in dorsal root ganglia from alcohol-fed rats, supporting a role for enhanced PKC epsilon second-messenger signaling in nociceptors contributing to alcoh ol-induced hyperalgesia.