Expression profiles of TRPV1, TRPV4, TLR4 and ERK1/2 in the dorsal root ganglionic neurons of a cancer-induced neuropathy rat model (Publication with Expression of Concern)

Background: The spread of tumors through neural routes is common in several types of cancer in which patients suffer from a moderate-to-severe neuropathy, neural damage and a distorted quality of life. Here we aim to examine the expression profiles of transient receptor potential vanilloid 1 (TRPV1) and of transient receptor potential vanilloid 4 (TRPV4), toll-like receptor 4 (TLR4) and extracellular signal-regulated kinase (ERK1/2), arid to assess the possible therapeutic strategies through blockade of transient receptor potential (TRP) channels. Methods: Cancer was induced within the sciatic nerves of male Copenhagen rats, and tissues from dorsal root ganglia (DRG) were collected and used for measurements of innnunofluorescence and Western blotting. The TRPV1 antagonist capsazepine, the selective TRPV4 antagonist HC-067047 and the calcium ions inhibitor ruthenium red were used to treat. thermal and/or mechanical hyperalgesia. Results: Transient receptor potential vanilloid 1 showed a lower expression DRGs on days 7 and 14. The expression of TRPV4, TLR4 and ERK1/2 showed an increase on day 3 then a decrease on days 7 and 14. TRPV1 and TLR4 as well as TRPV4 and ERK1/2 co-existed on the same neuronal cells. The neuropathic pain was reversed in dose-dependent manners by using the TRP antagonists and the calcium ions inhibitor. Conclusion: The decreased expression of TRPV1 and TRPV4 is associated with high activation. The increased expression of TLR4 and ERK1/2 reveals earlier immune response and tumor progression, respectively, and their ultimate decrease is an indicator of nerve damage. We studied the possible role of TRPV1 and TRPV4 in transducing cancer-induced hyperalgesia. The possible treatment strategies of cancer-induced thermal and/or mechanical hyperalgesia using capsazepine, HC-067047 and ruthenium red are examined.