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Vol. 51, Issue 2, 159-212, June 1999

Vanilloid (Capsaicin) Receptors and Mechanisms

Arpad Szallasi1 and Peter M. Blumberg

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland

I. Foreword: A Brief History of a Really "Hot" Aspect of Pharmacology
II. Introduction
    A. Overview
    B. Capsaicin: Targets and Actions
    C. Early, Indirect Evidence for and against a Vanilloid (Capsaicin) Receptor VR
III. Direct Evidence for a Vanilloid (Capsaicin) Receptor
    A. Specific Binding of resiniferatoxin (RTX), a Naturally Occurring Ultrapotent Agonist
    B. Development of Capsazepine, a Competitive Vanilloid Antagonist
    C. Cloning of the First VR, Termed VR1
IV. Anatomical Localization and Tissue Specificity of VRs
    A. VRs in Primary Sensory Neurons; Colocalization with Other Receptors, Neuropeptides, and the Isolectin B4
    B. VRs in Vagal (Nodose Ganglion) Neurons
    C. VRs in Brain
    D. Possible Presence of VRs in Nonneuronal Tissues Such as Mast Cells and Glia
V. Evidence for Multiple VRs
VI. Biochemical Pharmacology of VRs
    A. The Cloned VR Is a Nonselective Cation Channel with a Limited Selectivity for Calcium
    B. Role of Calcium in Modulating VR Functions
    C. Where Is the Vanilloid Binding Site on VRs?
    D. VR1 Is Activated by Noxious Heat and Low pH (Protons): the VR as an Integrator of Painful Chemical and Physical Stimuli
    E. Ruthenium Red Blocks VRs by an Unknown Mechanism
    F. VRs Are Sensitized by Inflammatory Mediators and Proinflammatory Cytokines
    G. Aspirin and Related Drugs May in Part Exert Their Analgesic Actions by Blocking VRs
    H. Proposed Role of Phosphorylation Sites in Modulating VR1 Activity
    I. Regulation of VR Expression
    J. VRs Are Thiol Proteins Displaying Positive Cooperativity
VII. Requirements for Ligand Recognition by VRs: Typical and Novel Vanilloids
    A. Structure-Activity Relations for Capsaicinoids
    B. Structure-Activity Relations for Resiniferanoids for Inducing Calcium Uptake by Sensory Neurons
    C. Differences in Structure-Activity Relationships of Vanilloids for Receptor Binding and Calcium Uptake
    D. Why Is RTX Ultrapotent as a Vanilloid?
    E. Novel Vanilloids Lacking 3-Hydroxy 4-methoxyphenyl (Vanillyl) Functionality
        1. Sesquiterpene Unsaturated 1,4-Dialdehydes and Related Bioactive Terpenoids.
        2. Triprenyl Phenols as Vanilloids.
        3. Implications of the Discovery of Novel Vanilloids Lacking a Vanillyl-Like Functionality.
VIII. Vanilloid Mechanisms
    A. Excitation by Vanilloids
        1. Stimulation of Vanilloid-Sensitive Neurons and Its Consequences.
        2. Hyperalgesia and Allodynia Following Vanilloid Administration.
    B. Desensitization to Vanilloids
        1. Desensitization.
        2. Tachyphylaxis.
        3. Is Lasting Tachyphylaxis Possible Without Prior Excitation?
        4. Impairment of Neuronal Functions after Vanilloid Treatment.
        4. Down-Regulation of VRs as a Mechanism of Long-Term Desensitization to Vanilloids.
        6. Messenger Plasticity by Vanilloids as a Novel Mechanism of Analgesia.
    C. Neurotoxicity by Vanilloids
IX. Diverse Biological Actions of Vanilloids; VR-Mediated and Independent Mechanism
X. Species-Related Differences in Vanilloid Actions
    A. Species-Related Differences in VR Expression
    B. Species-Related Differences in Expression of Sensory Neuropeptides and Their Receptors
    C. Human VRs
XI. Endogenous Vanilloids: Do They Exist?
XII. Vanilloids in Clinical Practice: Current Uses and Future Perspectives
    A. Counterirritation with Capsaicin
    B. Desensitization to Capsaicin
    C. Adverse Effects of Topical Capsaicin
    D. Novel, Innovative Clinical Uses
    E. RTX, an Improved Vanilloid Drug Undergoing Clinical Trials
XIII. Vanilloids: Carcinogens, Anticarcinogens, or Neither?
    A. Capsaicin
        1. Mutagenesis by Capsaicin.
        2. Carcinogenesis by Capsaicin: Animal Experiments.
        3. May Culinary Hot Pepper Consumption Be a Risk Factor for Stomach Cancer in Humans?
        4. Capsaicin: A Potential Antitumor Agent?
    B. RTX
XIV. Concluding Remarks, Emerging Principles, and Future Perspectives
Appendix
Acknowledgments
Note Added in Proof.
References


1   Address for correspondence: Arpad Szallasi, Department of Pathology, St. Louis University, 1402 South Grand Blvd., St. Louis, MO 63104. E-mail: arpads{at}thalamus.wustl.edu


0031-6997/99/5102-0159$03.00/0
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E. Lizanecz, Z. Bagi, E. T. Pasztor, Z. Papp, I. Edes, N. Kedei, P. M. Blumberg, and A. Toth
Phosphorylation-Dependent Desensitization by Anandamide of Vanilloid Receptor-1 (TRPV1) Function in Rat Skeletal Muscle Arterioles and in Chinese Hamster Ovary Cells Expressing TRPV1
Mol. Pharmacol., March 1, 2006; 69(3): 1015 - 1023.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
Y. Wang and D. H. Wang
A Novel Mechanism Contributing to Development of Dahl Salt-Sensitive Hypertension: Role of the Transient Receptor Potential Vanilloid Type 1
Hypertension, March 1, 2006; 47(3): 609 - 614.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
F. Wei, K. I. Vadakkan, H. Toyoda, L.-J. Wu, M.-G. Zhao, H. Xu, F. W.F. Shum, Y. H. Jia, and M. Zhuo
Calcium Calmodulin-Stimulated Adenylyl Cyclases Contribute to Activation of Extracellular Signal-Regulated Kinase in Spinal Dorsal Horn Neurons in Adult Rats and Mice
J. Neurosci., January 18, 2006; 26(3): 851 - 861.
[Abstract] [Full Text] [PDF]