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Review of He and WangPaclitaxel (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 well 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 transmission, 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 difference...

Cerebrovascular damage caused by either exposure to stress or the widely abused drug, methamphetamine (Meth) is known but stress and drug abuse frequently occur in tandem that may impact their individual cerebrovascular effects. This study examined their co-morbid cerebrovascular effects during abstinence from self-administered Meth after the exposure to chronic unpredictable stress (CUS). Exposure to CUS prior to unrestricted Meth self-administration had no effect on Meth intake in rats; however, the pro-inflammatory mediator cyclooxygenase-2 (COX-2) and the breakdown of cell-matrix adhesion protein β-dystroglycan in isolated cerebral cortical capillaries were increased after 3 days of abstinence and persisted for 7 days. These changes preceded decreases in occludin, a key structural protein component of the blood-brain barrier. The decrease in occludin was blocked by the COX-2 specific inhibitor nimesulide treatment during abstinence from Meth. The changes in COX-2, β-dystroglycan, and occludin were only evident following the serial exposure to stress and Meth but not after either one alone. These results suggest that stress and voluntary Meth intake can synergize and disrupt cerebrovasculature in a time-dependent manner during abstinence from chronic stress and Meth. Furthermore, COX-2 inhibition may be a viable pharmacological intervention to block vascular changes after Meth exposure.