Sensitization of TRPV1 receptors by TNF‑α orchestrates the development of vincristine‑induced pain

Abstract

Vincristine is one of the most common anticancer drugs clinically employed in the treatment of various malignancies. A major side effect associated with vincristine is the development of neuropathic pain, which is not readily relieved by available analgesics. Although efforts have been made to identify the pathogenesis of vincristine-induced neuropathic pain, the mechanisms underlying its pathogenesis have not been fully elucidated. In the present study, a neuropathic pain model was established in Sprague-Dawley rats by intraperitoneal injection of vincristine sulfate. The results demonstrated that vincristine administration induced the upregulation of transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression and current density in dorsal root ganglion (DRG) nociceptive neurons. Consistently, inhibition of TRPV1 with capsazepine alleviated vincristine-induced mechanical allodynia and thermal hyperalgesia in rats. Furthermore, vincristine administration induced the upregulation of tumor necrosis factor (TNF)-α production in DRGs, and inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression, as well as pain hypersensitivity induced by vincristine in rats. The present results suggested that TNF-α could sensitize TRPV1 by promoting its expression, thus leading to mechanical allodynia and thermal hyperalgesia in vincristine-treated rats. Taken together, these findings may enhance our understanding of the pathophysiological mechanisms underlying vincristine-induced pain.

Sensory Neurons of the Dorsal Root Ganglia Become Hyperexcitable in a T-Cell-Mediated MOG-EAE Model of Multiple Sclerosis

“…Inflammatory mediators, such as IL-1β (Binshtok et al, 2008; Stemkowski et al, 2015; Alles and Smith, 2018) and TNFα (Czeschik et al, 2008; Leung and Cahill, 2010; Wang et al, 2018), that are induced in EAE (Melanson et al, 2009; Rodrigues et al, 2016) can modulate ion channel expression and/or activity and induce neuronal hyperexcitability. The electrophysiological changes remaining into the chronic phase of MOG-EAE suggest that transient immune cell infiltration and activation in the DRG inherently alters neuronal properties into the chronic phase of MOG-EAE.…”

The Mystery of “Metal Mouth” in Chemotherapy

“…Chemotherapy-induced peripheral sensory neuropathy is linked to the sensitisation of TRPV1 (e.g., Wang et al, 2018b) and TRPV1 is also overexpressed following nerve damage in the oral cavity (e.g., Yilmaz et al, 2007). Finally, it has been suggested that metal mouth can be explained by the retronasal activation of olfactory epithelium (e.g., Omur-Ozbek et al, 2012), perhaps due to an intra-oral over-production of metallic volatiles, although a source for these metallic volatiles in chemotherapy has yet to be identified (e.g., Mirlohi et al, 2015), and it is not clear which congruent stimulus (Lim & Johnson, 2011;Lim & Johnson, 2012) 4.…”

“…Not only does oxidative stress sensitise TRPV1 (Chuang & Lim, 2009), but at least three chemotherapy drugs-oxaliplatin, paclitaxel, and vincristine-have been found to sensitise TRPV1, markedly heightening capsaicin responses in dorsal root ganglia (see Figure 7) (Anand, Otto, & Anand, 2010;Li et al, 2015;Wang et al, 2018b). There may be a link to inflammatory activation via interplay with TLR4 (Li et al, 2015) and TNF-α (Wang et al, 2018b). Researchers have notto the best of our knowledge-investigated whether TRPV1 sensitisation also occurs in the oral cavity during chemotherapy.…”

Synthesis and Characterization of ZnO-Ag Nanoparticles Supported on MCM-41 as Photocatalyst

“…The XRD patterns in Fig. 2d) also exhibited a small peak of metallic Ag at 38.8 and 44.9 2ϴ in its cubic and wurtzite phase; this indicate that ZnO-Ag nanopar ticles were completely formed 16,17 . Fig.…”