Identifying the Role of Novel Protein Kinase C Isoforms in Mediating Paclitaxel-Induced Peripheral Neuropathy

A. L. Blaker, C. M. Mitchell, E. A. Semple
2015 Journal of Neuroscience  
Review of He and Wang Paclitaxel (Taxol) is a commonly prescribed chemotherapeutic drug that stabilizes microtubules and consequently prevents progression of mitosis in rapidly dividing tumor cells. Like many other chemotherapeutics, paclitaxel is not selective, and it can therefore produce many undesired side effects. One debilitating effect experienced by individuals receiving the drug is paclitaxelinduced peripheral neuropathy (PIPN). The neuropathy is characterized by spontaneous pain, as
more » ... ll as evoked hyperalgesia and allodynia. Due to a limited physiological understanding of PIPN, there are few treatments available for patients experiencing PIPN (Scripture et al., 2006). Multiple second messenger signaling molecules have been implicated in the pathophysiology of PIPN, including cAMP, protein kinase A, and protein kinase C (PKC) (Hucho and Levine, 2007). Although each is necessary for pain transmission, PKC plays a predominant role in the nociceptive pathway involved in chronic pain and PIPN. Specifically, inhibition of the PKC isoform in chronic pain models has been shown to block hyperalgesia, whereas inhibition of other second messengers, like cAMP, only partially block hyperalgesia. Many chronic pain studies have focused on the role of PKC in evoked pain, while neglecting its role in spontaneous pain. Furthermore, in attempts to understand chronic pain, most research has focused primarily on PKC; other isoforms of PKC (e.g., PKC␤II and PKC␦) have yet to be tested. In a recently article published in The Journal of Neuroscience, He and Wang (2015) set out to further investigate the unique roles of various PKC isoforms in both spontaneous and evoked adverse pain associated with rodent models of PIPN. Because the dorsal root ganglion (DRG) is an important site for excitatory nociceptive transmission, He and Wang (2015) focused their investigation in this region. Upon in vitro application of paclitaxel, PKC␤II and PKC␦, in addition to PKC, translocated to the plasma membrane that indicated an activated state. To determine the importance of PKC isoform activation in PIPN, He and Wang (2015) pharmacologically manipulated PKC by using specific PKC isoform inhibitors to block paclitaxel's effects on isolated DRG neurons. In normal pain transmission, calcitonin gene-related peptide (CGRP), an excitatory neuropeptide, is released from primary sensory afferents. CGRP was upregulated with paclitaxel exposure, and inhibiting any of the three PKC isoforms restored CGRP to basal concentrations, indicating that these PKC isoforms were involved in CGRP regulation. These results confirmed the previously established role for PKC in pain transmis-sion, and identified a novel role for PKC␤II and PKC␦ as two additional PKC isoforms activated by paclitaxel treatment that are necessary for CGRP release in the nociceptive pathway and thus possibly in pain transmission. The activation of multiple PKC isoforms after paclitaxel exposure raises the possibility that differential isoform activation is associated with functional differences in pain transmission. Pain transmission can be influenced by differential expression of specific molecules on the plasma membrane of nociceptors. Generally, DRG nociceptors can be divided into two categories depending on whether the cell binds isolectin B 4 (IB 4 ). Both IB 4 -negative and IB 4 -positive nociceptors are involved in pain transmission, but much speculation has been made regarding functional differences such as action potential threshold and duration, and response to different types of stimuli (Snider and McMahon, 1998; Stucky and Lewin, 1999). He and Wang (2015) revealed that paclitaxel treatment activated all three PKC isoforms in both IB 4 -positive and IB 4negative afferents, but PKC␤II was more prominently activated in IB 4 -negative neurons than in IB 4 -positive neurons. Unlike IB 4 -positive nociceptors, IB 4 -negative nociceptors contain CGRP. This fits nicely with data showing that inhibition of PKC␤II was most effective at blocking CGRP release. Based on these results, it is reasonable to speculate that PKC␤II may have a different role than other isoforms in mediating pain
doi:10.1523/jneurosci.1903-15.2015 pmid:26180187 fatcat:bn5alvuyfnci5jg6kpsp6gebze