Abstract
BackgroundThe 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), and to assess the possible therapeutic strategies through blockade of transient receptor potential (TRP) channels.MethodsCancer was induced within the sciatic nerves of male Copenhagen rats, and tissues from dorsal root ganglia (DRG) were collected and used for measurements of immunofluorescence 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.ResultsTransient receptor potential vanilloid 1 showed a lower expression in 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.ConclusionThe 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.
Highlights
In a recent study, we established a cancer-induced neuropathy model and determined the thresholds of cold allodynia and thermal and mechanical hyperalgesia
To study the molecular mechanisms underlying the process of tumor infiltration of the peripheral nerves, we quantified two key transducers, transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential vanilloid 4 (TRPV4), within the neuronal cells by immunofluorescence and Western blotting
TRPV1 and toll-like receptor 4 (TLR4) Fluorescence images of the double-stained capsaicin (TRPV1) and the lipopolysaccharide toll-like (TLR4) receptors showed no changes in TRPV1 positive immunoreactive (+IR)
Summary
We established a cancer-induced neuropathy model and determined the thresholds of cold allodynia and thermal and mechanical hyperalgesia. The objective of our current study is to understand the underlying molecular mechanisms of the transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential vanilloid 4 (TRPV4), the innate immunity toll-like receptor 4 (TLR4) and the extracellular signal-regulated kinase (ERK1/2) through their expression profiles in the sensory neurons of this Copenhagen rat model. We aim to assess a strategy for treatment of cancer-induced neuropathic pain using selective and non-selective transient receptor potential (TRP) antagonists and a calcium ions inhibitor. The possible treatment strategies of cancer-induced thermal and/or mechanical hyperalgesia using capsazepine, HC-067047 and ruthenium red are examined
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