TRP channels and pain.

Abstract

Since the molecular identification of the capsaicin receptor, now known as TRPV1, transient receptor potential (TRP) channels have occupied an important place in the understanding of sensory nerve function in the context of pain. Several TRP channels exhibit sensitivity to substances previously known to cause pain or pain-like sensations; these include cinnamaldehyde, menthol, gingerol, and icillin. Many TRP channels also exhibit significant sensitivity to increases or decreases in temperature. Some TRP channels are sensitized in vitro by the activation of other receptors such that these channels may be activated by processes, such as inflammation that result in pain. TRP channels are suggested to be involved in processes as diverse as sensory neuron activation events, neurotransmitter release and action in the spinal cord, and release of inflammatory mediators. These functions strongly suggest that specific and selective inhibition of TRP channel activity will be of use in alleviating pain.

Full text

Page 1

???????? ??????????
TRP channels and pain
Daniel N. Cortright, James E. Krause, Daniel C. Broom
PII:
DOI:
Reference:
S0925-4439(07)00078-6
doi: 10.1016/j.bbadis.2007.03.003
BBADIS 62709
To appear in:
BBA - Molecular Basis of Disease
Received date:
Revised date:
Accepted date:
9 February 2007
7 March 2007
8 March 2007
Please cite this article as:
Broom, TRP channels and pain, BBA - Molecular Basis of Disease (2007),
10.1016/j.bbadis.2007.03.003
Daniel N. Cortright, James E. Krause, Daniel C.
doi:
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
peer-00562776, version 1 - 4 Feb 2011
Author manuscript, published in "Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1772, 8 (2007) 978"
DOI : 10.1016/j.bbadis.2007.03.003

Page 2

ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
- 1 -
TRP Channels and Pain

Daniel N. Cortright*, James E. Krause, and Daniel C. Broom

Neurogen Corporation, Branford, Connecticut, USA 06405


*Corresponding author:
Daniel N. Cortright
Neurogen Corporation
35 N.E. Industrial Road
Branford, CT 06405
dcortright@nrgn.com



peer-00562776, version 1 - 4 Feb 2011

Page 3

ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
- 2 -
Abstract
Since the molecular identification of the capsaicin receptor, now known as TRPV1,
transient receptor potential (TRP) channels have occupied an important place in the
understanding of sensory nerve function in the context of pain. Several TRP channels
exhibit sensitivity to substances previously known to cause pain or pain-like sensations;
these include cinnamaldehyde, menthol, gingerol, and icillin. Many TRP channels also
exhibit significant sensitivity to increases or decreases in temperature. Some TRP
channels are sensitized in vitro by the activation of other receptors such that these
channels may be activated by processes, such as inflammation that result in pain. TRP
channels are suggested to be involved in processes as diverse as sensory neuron
activation events, neurotransmitter release and action in the spinal cord, and release of
inflammatory mediators. These functions strongly suggest that specific and selective
inhibition of TRP channel activity will be of use in alleviating pain.


peer-00562776, version 1 - 4 Feb 2011

Page 4

ACCEPTED MANUSCRIPT
of the clinical role of molecular and physiological mechanisms that are key to animal
ACCEPTED MANUSCRIPT
- 3 -
INTRODUCTION
In the past few decades a tremendous amount of research has been performed in an
attempt to elucidate and understand the factors and mechanisms involved in normal
sensory and pain perception. Preclinical research has uncovered a multitude of factors,
pathways and mechanisms that are involved in the development and maintenance of
pathological pain-like sensory sensitivity in animal models. Key discoveries in the pain
field include the description of injury-induced alteration of neuronal function [1], the
discovery of changes in peripheral neuron functioning and in neuronal processing within
the spinal cord [2, 3], the development of animal models of neuropathic pain [4-7], and
the role of immune and glial cells in the development of pain [8-10]. These discoveries
have generated optimism that new therapeutic regimens may be forthcoming to alleviate
abnormally heightened and spontaneous pain.


However, despite these advances the translation of this preclinical research to the
treatment of pain has been slow to occur. This is partly due to the lack of understanding
research models. This is evident by the relative lack of mechanistically novel therapeutic
agents that have entered into the clinic for the treatment of pain in recent years. Although
the use of new agents for pain has risen (for example, gabapentin and the COX-2
inhibitors), the mainstay of therapy remains agents such as opiates and non-steroidal anti-
inflammatory drugs (NSAID) that have been around for a number of years, even
centuries. Of the newer agents, the COX-2 inhibitors provided an extremely promising
peer-00562776, version 1 - 4 Feb 2011

Page 5

ACCEPTED MANUSCRIPT
A recent development in the search for novel analgesics is the advance into clinical
ACCEPTED MANUSCRIPT
- 4 -
line of therapy for inflammatory conditions before side-effects have cast a shadow over
the use of the class as a whole. Neurontin (gabapentin) has offered insight into a
potentially new mechanism, the α2δ calcium channel [11]. Furthermore, although
Neurontin is one of the most prescribed pain relief medications for neuropathic
conditions, there is still room for improvement. In clinical trials of post-herpetic and
trigeminal neuralgia the number-needed-to-treat (NNT) was approximately 3-4 [12]. A
more potent successor to gabapentin, pregabalin (LYRICA), has recently reached the
market. It appears to improve on the potency of gabapentin and may provide further
clinical validation for the α2δ mechanism. Finally, ziconotide (PRIALT), a conopeptide
N-type calcium channel blocker also has beneficial use in treating pain, yet side effects
and its route of administration (intrathecal delivery) limit its use to opiate-refractory,
severe chronic pain. In summary, clinical therapy for pain relies on agents that do not
provide adequate relief in a large number of patients to which they are prescribed and,
therefore, can be significantly improved upon [13]. There remains a great need for new
therapeutic agents acting via novel mechanisms in this field of medicine.

testing of small molecule antagonists of the TRPV1 channel [14]. TRPV1 is a member of
the TRP ion channel family and is the receptor for capsaicin [15]. TRPV1 has been
shown to be an extremely promising target for the development of novel analgesic
therapeutics and beckons examination of further relevant members of this class of
channels. Indeed, in the years that have followed the isolation and cloning of TRPV1,
additional TRP family members have been identified (Figure 1), which are expressed in
peer-00562776, version 1 - 4 Feb 2011