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Application of RNA Interference to Treat Conditions Associated with Dysregulation of Transient Receptor Potential Vanilloid 1 Channel

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RNA Technologies and Their Applications

Part of the book series: RNA Technologies ((RNATECHN))

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Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a member of the transient receptor potential (TRP) family of proteins and is most notably the target of capsaicin, the active ingredient of “hot” pepper such as jalapeño and habanero. The channel is expressed primarily in small diameter neurons (Aδ and C fibers) within sensory ganglia comprising the pain pathway but expression is observed in larger diameter neurons under conditions of inflammation. TRPV1 is a nonselective cation channel, which responds to heat (activation threshold ∼43°C) and transmits pain sensations in response to noxious heat. It is also expressed in nonneuronal tissue such as keratinocytes, bladder uroepithelium, knee joints, the gastrointestinal tract and the cochlea, suggesting additional physiological roles of channel activation. Several disease states associated with dysregulation of TRPV1 include visceral and peripheral inflammatory pain observed in irritable bowel disease, bone cancers, arthritis and bladder inflammation. Other conditions include diabetic peripheral neuropathy, obesity, and drug-induced hearing loss. Animal studies have shown beneficial effects of targeting TRPV1, using both agonist and antagonist drugs, in the treatment of some of these conditions. However, the propensity of TRPV1 antagonists to produce hyperthermia could limit their future application. Such problems might be resolved by the focal administration of short interfering (si) RNA to the affected organ in order to reduce TRPV1 expression. While demonstration of TRPV1 knockdown by RNA interference (RNAi) is widely used in vitro, results obtained from a limited number of in vivo studies suggest that RNAi could be applied to the treatment of diseases associated with TRPV1 hyperactivity. To date, RNAi has proven beneficial in reducing inflammatory pain and in treating hearing loss associated with cisplatin chemotherapy. This review will focus on the current progress of RNAi in the treatment of diseases associated with TRPV1 dysfunction, discuss potential future applications of this technology, and highlight factors that could affect its use clinically.

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Abbreviations

TRPV1:

Transient receptor potential vanilloid 1

CGRP:

Calcitonin gene-related peptide

BCTC:

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox amide

shRNA:

Short hairpin RNA

ROS:

Reactive oxygen species

siRNA:

Short interfering RNA

IL:

Interleukin

TNF-α:

Tumor necrosis factor-α

NK:

Neurokinin 1

NF-κB:

Nuclear factor κB

AP-1:

Activator protein 1

SB366791:

N-(3-Methoxyphenyl)-4-chlorocinnamide

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Acknowledgments

This work was supported by a grants from the National Institute of Health (DC02396) to LPR and (CA135494) to VR, a grant from the National Organization for Hearing Research and SIU School of Medicine Excellence in Academic Medicine Award to VR.

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Authors and Affiliations

  1. Department of Pharmacology, Southern Illinois University School of Medicine, 19629, Springfield, IL, 62794-9629, USA

    Vickram Ramkumar, Sarvesh Jajoo, Tejbeer Kaur & Leonard P. Rybak

  2. Department of Surgery, Southern Illinois University School of Medicine, 19629, Springfield, IL, 62794-9629, USA

    Debashree Mukherjea & Leonard P. Rybak

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  1. Vickram Ramkumar
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  2. Debashree Mukherjea
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  3. Sarvesh Jajoo
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  4. Tejbeer Kaur
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  5. Leonard P. Rybak
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Correspondence to Vickram Ramkumar .

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Editors and Affiliations

  1. Inst. Chemie und Biochemie, FU Berlin, Thielallee 63, Berlin, 14195, Germany

    Volker A. Erdmann

  2. Inst. Bioorganic Chemistry, PAN Poznan, ul. Z. Noskowskiego 12/14, Poznan, 61-704, Poland

    Jan Barciszewski

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Ramkumar, V., Mukherjea, D., Jajoo, S., Kaur, T., Rybak, L.P. (2010). Application of RNA Interference to Treat Conditions Associated with Dysregulation of Transient Receptor Potential Vanilloid 1 Channel. In: Erdmann, V., Barciszewski, J. (eds) RNA Technologies and Their Applications. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12168-5_9

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