Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels

Sangsu Bang; Sungjae Yoo; Tae-Jin Yang; Hawon Cho; Sun Wook Hwang

doi:10.1016/j.pain.2011.01.044

Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels

Pain. 2011 May;152(5):1156-1164. doi: 10.1016/j.pain.2011.01.044. Epub 2011 Feb 24.

Authors

Sangsu Bang¹, Sungjae Yoo, Tae-Jin Yang, Hawon Cho, Sun Wook Hwang

Affiliation

¹ Korea University Graduate School of Medicine, Seoul 136-705, Republic of Korea Sensory Research Center, CRI, Seoul National University College of Pharmacy, Seoul 151-742, Republic of Korea.

PMID: 21353389
DOI: 10.1016/j.pain.2011.01.044

Abstract

Transient receptor potential ion channels (TRPs) expressed in the periphery sense and electrically transduce noxious stimuli to transmit the signals to the brain. Many natural and synthetic ligands for the sensory TRPs have been found, but little is known about endogenous inhibitors of these TRP channels. Recently, we reported that farnesyl pyrophosphate, an endogenous substance produced in the mevalonate pathway, is a specific activator for TRPV3. Here, we show that isopentenyl pyrophosphate (IPP), an upstream metabolite in the same pathway, is a dual inhibitor for TRPA1 and TRPV3. By using Ca(2+) imaging and voltage clamp experiments with human embryo kidney cell heterologous expression system, cultured sensory neurons, and epidermal keratinocytes, we demonstrate that micromolar IPP suppressed responses to specific agonists of TRPA1 and TRPV3. Consistently, peripheral IPP administration attenuated TRPA1 and TRPV3 agonist-specific acute pain behaviors. Furthermore, local IPP pretreatment significantly reversed mechanical and thermal hypersensitivity of inflamed animals. Taken together, the present study suggests that IPP is a novel endogenous TRPA1 and TRPV3 inhibitor that causes local antinociception. Our results may provide useful chemical information to elucidate TRP physiology in peripheral pain sensation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrolein / analogs & derivatives
Acrolein / pharmacology
Acrolein / therapeutic use
Analgesics / pharmacology*
Animals
Calcium / metabolism
Calcium Channels / deficiency
Calcium Channels / genetics
Calcium Channels / metabolism*
Cells, Cultured
Disease Models, Animal
Freund's Adjuvant / adverse effects
Ganglia, Spinal / cytology
Gene Expression Regulation / drug effects
Hemiterpenes / pharmacology*
Humans
Inflammation / chemically induced
Inflammation / complications
Membrane Potentials / drug effects
Mice
Mice, Inbred ICR
Mice, Knockout
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / deficiency
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Organophosphorus Compounds / pharmacology*
Pain / drug therapy
Pain / etiology
Patch-Clamp Techniques / methods
RNA, Messenger / metabolism
RNA, Small Interfering / pharmacology
Sensory Receptor Cells / drug effects*
TRPA1 Cation Channel
TRPV Cation Channels / antagonists & inhibitors
TRPV Cation Channels / genetics
TRPV Cation Channels / metabolism*
Transfection / methods
Transient Receptor Potential Channels / antagonists & inhibitors
Transient Receptor Potential Channels / deficiency
Transient Receptor Potential Channels / genetics
Transient Receptor Potential Channels / metabolism*

Substances

Analgesics
Calcium Channels
Hemiterpenes
Nerve Tissue Proteins
Organophosphorus Compounds
RNA, Messenger
RNA, Small Interfering
TRPA1 Cation Channel
TRPA1 protein, human
TRPV Cation Channels
TRPV3 protein, human
Transient Receptor Potential Channels
isopentenyl pyrophosphate
Acrolein
Freund's Adjuvant
cinnamaldehyde
Calcium