Furthermore, the lower levels of 5-HT levels were shown in the peripheral and central nervous tissue of vincristine-treated 5-HTT−/− mice (Hansen et al., 2011). The requirement of PKC activity in supra-spinal brain regions for induction of chronic administration of oxaliplatin-induced mechanical hyperalgesia has been demonstrated by showing the attenuation of pain with supra-spinal administration of selective PKC inhibitor calphostin C. Oxaliplatin treatment induces specific up-regulation of gamma isoforms of PKC and increase phosphorylation of gamma/epsilon PKC isoforms within

thalamus and periaqueductal area (Norcini et al., 2009 and Galeotti et al., 2010). Furthermore, St. John’s Wort also attenuates oxaliplatin-induced IWR-1 cell line pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity (Galeotti et al., 2010). Very recently, it has been reported that paclitaxel-induced mechanical allodynia/hyperalgesia is associated with reduction in l-serine concentration in the DRG but not in the sciatic nerve or spinal cord. Paclitaxel was also shown to decrease expression of phosphoglycerate dehydrogenase (3PGDH, localized in satellite cells), a biosynthetic enzyme of l-serine, in the DRG. Furthermore, intraperitoneal administration of l-serine was reported to improve paclitaxel-induced

pain behavior. Therefore, it has been proposed that satellite cell-derived l-serine in the DRG plays an important role in Cell Cycle inhibitor paclitaxel-induced painful peripheral neuropathy (Kiya et al., 2011). The above explained mechanisms involved in neuropathic pain are not independent and all these pathways may actually be inter-related to one other (Fig. 1). It may be postulated that anticancer agents trigger the changes in the sodium channel expression/functional characteristics of DRG and dorsal horn sensory neurons to increase its opening frequency/duration to increase intracellular sodium ion levels which is in turn may cause increased opening of calcium channels. An increased expression of α2δ subunit of

calcium channels may also be responsible for increased entry of extracellular calcium. Furthermore, an enhanced entry of extracellular calcium may also be contributed via pronounced activation of NMDA Tangeritin receptors in response to increased pre-synaptic glutamate release. Increased cytosolic calcium acts as a trigger to release more calcium from intracellular stores particularly mitochondria. Increased calcium may trigger number of other secondary changes including activation of protein kinase C leading to phosphorylation and activation of TRPV that directly produce hyper-responsiveness changes in sensory neurons along with generation of nitric oxide and oxygen free radicals to produce cytotoxicity of axonal terminals and neuronal cell bodies.