Key Role for the Epsilon Isoform of Protein Kinase C in Painful Alcoholic Neuropathy in the Rat

Abstract

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliably successful therapy, attributable to, in great part, a lack of understanding of the underlying mechanisms. We tested the hypothesis 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 hyperalgesia was present by the fourth week and maximal at 10 weeks. Thermal hyperalgesia and mechanical allodynia were also present. Mechanical threshold of C-fibers in ethanol fed rats was lowered, and the number of action potentials during sustained stimulation increased. The hyperalgesia was acutely attenuated by intradermal injection of nonselective protein kinase C (PKC) or selective PKC⑀ inhibitors injected at the site of nociceptive testing. Western immunoblot analysis indicated a higher level of PKC⑀ in dorsal root ganglia from alcohol-fed rats, supporting a role for enhanced PKC⑀ secondmessenger signaling in nociceptors contributing to alcohol-induced hyperalgesia.Key words: protein kinase C ⑀; alcoholic peripheral neuropathy; pain; hyperalgesia; allodynia; primary afferent nociceptor Ethanol consumption is the most common cause of peripheral nervous system, as well as CNS, neurotoxicity. Ethanol is thought to exert a direct neurotoxic action on the peripheral nervous system, resulting in a neuropathy that mostly involves smalldiameter fibers (Diamond and Messing, 1994;Monforte et al., 1995;Kielhorn, 1996;Ortiz-Plata et al., 1998;Tredici et al., 1999). The peripheral neuropathy is a potentially incapacitating complication of chronic consumption of ethanol, characterized by pain and dysesthesias, primarily in the lower extremities, and is poorly relieved by available therapies (Ratcliff, 1979;Monforte et al., 1995;Ortiz-Plata et al., 1998).Whereas enhanced nociception and primary afferent nociceptor hypersensitivity have been demonstrated in animal models of other neuropathic pain states, such as those induced by diabetes (Ahlgren and Levine, 1994), chemotherapy (Tanner et al., 1998; Authier et al., 1999), or trauma (Bennett andXie, 1988;Campbell et al., 1988;Seltzer et al., 1990;Xie and Xiao, 1990;Kim and Chung, 1992;Kim et al., 1993;Sheen and Chung, 1993;Yoon et al., 1996;Pedersen and Kehlet, 1998;Zahn and Brennan, 1999), an animal model for alcohol-induced neuropathy does not exist, nor has it even been demonstrated that primary afferent nociceptor function is altered by chronic exposure to alcohol.In animal models of other painful peripheral neuropathies, enhanced nociception involves alterations in intracellular signaling. Specifically, protein kinase C (PKC) (Ahlgren and Levine, 1994) [particularly the epsilon (⑀) isoform (Gerstin et al., 1998; Khasar et al., 1999] and protein kinase A (PKA) (Ahlgren and Levine, 1994) signaling pathways have been implicated in enhancing nociceptor function. Because alcohol has been shown to activate PKC and PKA (Coe et al., 1...

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

“…A significant increase was also observed in thalamus for both isoforms and in striatum only for PKCc. Both c and e isoforms of PKC have been previously shown to be implicated in hyperalgesia [1,7]. A number of studies over the last several years indicate that brainstem descending pathways linking the PAG, the rostral ventromedial medulla (RVM) and the spinal cord constitute a major mechanism in the modulation of pain transmission [8].…”

Epac Mediates a cAMP-to-PKC Signaling in Inflammatory Pain: An Isolectin B4(+) Neuron-Specific Mechanism

“…The understanding of the underlying intracellular signaling pathways, as well as the mechanoreceptors involved, remains fragmentary. Nevertheless, one signaling component, the ⑀ isoform of protein kinase C (PKC⑀), has turned out to be important in nociceptor sensitization caused by inflammation (Khasar et al, 1999b;Numazaki et al, 2002;Sweitzer et al, 2004), peripheral neuropathies such as diabetes , chronic alcoholism (Dina et al, 2000), and cancer chemotherapy (Dina et al, 2001;Joseph and Levine, 2003b), as well as the transition from acute to chronic pain (Aley et al, 2000;Parada et al, 2003a,b). However, a signaling pathway leading to activation of PKC⑀ remains still to be elucidated.…”

Acute Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

“…Numerous studies have suggested that the Ca 2ϩ -mediated cell signaling pathways are crucial to nociception (e.g., Saegusa et al, 2001;Kim et al, 2003). In particular, Ca 2ϩ activates protein kinase C, specific isoforms of which have been demonstrated to be important in studies employing various experimental neuropathic pain models (Malmberg et al, 1997;Hua et al, 1999;Dina et al, 2000).…”