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Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1
Published on: February 13, 2018
Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat
Nicole Alessandri-Haber1, Olayinka A Dina, Jenny J Yeh
1Division of Neurosciences, University of California San Francisco, San Francisco, California 94143-0440, USA.
Abstract:
The development of treatments for neuropathic pain has been hindered by our limited understanding of the basic mechanisms underlying abnormalities in nociceptor hyperexcitability. We recently showed that the polymodal receptor transient receptor potential vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) family of ion channels, may play a role in inflammatory pain (Alessandri-Haber et al., 2003). The present study tested whether TRVP4 also contributes to neuropathic pain, using a rat model of Taxol-induced painful peripheral neuropathy. Taxol is the most widely used drug for the treatment of a variety of tumor types, but the dose of Taxol that can be tolerated is limited by the development of a small-fiber painful peripheral neuropathy. We found that Taxol treatment enhanced the nociceptive behavioral responses to both mechanical and hypotonic stimulation of the hind paw. Spinal administration of antisense oligodeoxynucleotides to TRPV4, which reduced the expression of TRPV4 in sensory nerve, abolished Taxol-induced mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%. The enhancement of osmotic nociception involves sensitization of osmotransduction in primary afferents because osmotransduction was enhanced in cultured sensory neurons isolated from Taxol-treated rats. Taxol-induced TRPV4-mediated hyperalgesia and the enhanced osmotransduction in cultured nociceptors were dependent on integrin/Src tyrosine kinase signaling. These results suggest that TRPV4 plays a crucial role in a painful peripheral neuropathy, making it a very promising target for the development of a novel class of analgesics.
Insights
Transient receptor potential vanilloid 4 (TRPV4) channels contribute to Taxol-induced neuropathic pain. Inhibiting TRPV4 in sensory nerves reduces pain hypersensitivity, suggesting TRPV4 as a novel analgesic target.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Neuropathic pain treatment is limited by poor understanding of nociceptor hyperexcitability.
- Transient receptor potential vanilloid 4 (TRPV4) channels are implicated in inflammatory pain.
- Taxol chemotherapy causes painful peripheral neuropathy, limiting its clinical use.
Purpose of the Study:
- To investigate the role of TRPV4 in Taxol-induced neuropathic pain.
- To determine if TRPV4 contributes to mechanical and osmotic hyperalgesia in a rat model.
Main Methods:
- A rat model of Taxol-induced painful peripheral neuropathy was used.
- Antisense oligodeoxynucleotides targeting TRPV4 were administered spinally.
- Nociceptive behavioral responses to mechanical and hypotonic stimuli were measured.
- Osmotransduction was assessed in cultured sensory neurons from Taxol-treated rats.
Main Results:
- Taxol treatment enhanced nociceptive responses to mechanical and hypotonic stimuli.
- Spinal TRPV4 inhibition abolished mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%.
- Taxol treatment enhanced osmotransduction in cultured sensory neurons, dependent on integrin/Src tyrosine kinase signaling.
Conclusions:
- TRPV4 plays a critical role in Taxol-induced neuropathic pain.
- TRPV4-mediated hyperalgesia involves enhanced osmotransduction and integrin/Src signaling.
- TRPV4 represents a promising therapeutic target for novel analgesics to treat chemotherapy-induced neuropathic pain.
