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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 15, 2009
Contents
Ion Channels as Therapeutic Targets for Neuropathic Pain
Executive Editor: Char-Chang Shieh
Editorial: Pp. 1709-1710
Neuropathic Pain: Models and Mechanisms Pp.
1711-1716
J.M. Boyce-Rustay and M.F. Jarvis
[Abstract]
[Purchase Article] [PMID: 19442185 PubMed - indexed for MEDLINE]
Purinergic Receptors and Pain Pp.
1717-1735
G. Burnstock
[Abstract] [Purchase Article] [PMID: 19442186 PubMed - indexed for MEDLINE]
TRP Channels and Pain Pp.
1736-1749
D.N. Cortright and A. Szallasi
[Abstract] [Purchase Article] [PMID: 19442187 PubMed - indexed for MEDLINE]
Acid Sensing Ion Channels and Acid Nociception
Pp. 1750-1766
G.R. Dubé, A. Elagoz and H.
Mangat
[Abstract] [Purchase Article] [PMID: 19442188 PubMed - indexed for MEDLINE]
Hyperpolarization-Activated Cyclic Nucleotide-Gated
(HCN) Channels and Pain Pp. 1767-1772
J. Dunlop, D. Vasilyev, P. Lu, T. Cummons
and M.R. Bowlby
[Abstract] [Purchase Article] [PMID: 19442189 PubMed - indexed for MEDLINE]
Kv7 Channels as Targets for the Treatment
of Pain Pp. 1773-1798
A.D. Wickenden and G. McNaughton-Smith
[Abstract] [Purchase Article] [PMID: 19442190 PubMed - indexed for MEDLINE]
General Articles
Continuous Nanostructures for the Controlled Release of Drugs
Pp. 1799-1808
J. Venugopal, M.P. Prabhakaran, S. Low,
A.T. Choon, G. Deepika, V.R.G. Dev and S. Ramakrishna
[Abstract] [Purchase Article] [PMID: 19442191 PubMed - indexed for MEDLINE]
Cardiovascular Biology of Interleukin-6
Pp. 1809-1821
M.Y. Abeywardena, W.R. Leifert, K.E. Warnes,
J.N. Varghese and R.J. Head
[Abstract] [Purchase Article] [PMID: 19442192 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Ion Channels as Therapeutic Targets for
Neuropathic Pain
Management of neuropathic pain remains as medical
challenge although numerous drugs such as opiates, anticonvulsants
(gabapentin), antidepressants, and recent approved Prialt,
a N-type Ca2+ channel blocker,
have been prescribed to alleviate chronic pain. Their uses
are limited by addiction, the inadequacy in pain relief and
adverse side effects. Over the last decade, significant scientific
progress has been made to reveal the mechanisms underlying
neuropathic pain. The emerging novel pronociceptive mediators
and mechanisms that are involved in the development and maintenance
of chronic pain have transformed into therapeutic approaches,
which inspire significant investment from pharmaceutical industry
to identify novel efficacious analgesic agents.
Ion channels are class of membrane proteins that play important
roles in cellular excitability and pain signaling pathway.
Preclinical research has identified an array of ion channels
involved in the generation and transduction of pain as potential
targets for pharmacological intervention. In this issue of
Current Pharmaceutical Design, the leading scientists review
the advancement of researches on the efforts to discover novel
therapeutic agents by modulating ion channels. Boyce-Rustay
and Jarvis [1] review the distinct neurophysiological and
neurochemical mechanisms that contribute to pain arising from
injury to the nervous system. The preclinical rodent pain
models that have been reliably used to study nociceptive changes
in neuropathic pain and to assess the analgesic effects of
drugs are described. Burnstock [2] provides a comprehensive
review on purinergic signaling, receptor subtypes of purines
and pyrimidines and their mechanosensory transduction involved
in visceral, cutaneous and musculoskeletal nociception as
well as in neuropathic and inflammatory pain. Current developments
of compounds for the treatment of both visceral and neuropathic
pain in “pe-clinical animal pain models” are discussed.
Cortright and Szallasi [3] review roles of a family of thermosensitive
transient receptor potential channels, referred to as “thermoTRPs”,
in the transduction of a wide range of noxious stimuli. The
vanilloid (capsaicin) receptor TRPV1 represents the first
channel in this family to be identified as a pain target by
genetic deletion and pharmacological inhibition experiments.
Other members of this family including TRPA1 (transient receptor
potential, ankyrin subfamily member 1) and TRPM8 (transient
receptor potential, melastatin subfamily member 8) were demonstrated
to be involved in pain signaling pathway including mechanical
hypersensitivity and cold allodynia. The TRP channels represent
a new strategy in pain relief aiming to prevent pain by blocking
a receptor where pain is generated. Cortright and Szallasi
review significant advancement from the cloning of TRPV1 to
clinical trials with potent small molecule TRPV1 antagonists
within last decade. The emerging evidence that supports particular
TRP channels as targets for novel analgesic drugs, along with
potential adverse effects that may limit drug development
is discussed.
Acid sensing ion channels (ASICs) represent a family of diverse
cation channels expressed principally in neurons and activated
by protons. Dube et al. [4] provide an overview of
recent findings supporting the significant roles of ASICs
in acid nociception using genetic and pharmacological approaches.
The analgesic effects of newly identified ASIC antagonists
in pre-clinical “animal” pain models and human
inflammatory pain are also discussed.
Dunlop et al. [5] provide an overview of a diverse
and widespread distribution of the four subtypes of hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels in sensory neurons.
HCN channels are activated at negative membrane potentials
and specifically upon repolarization following action potential
firing resulting in a depolarizing current influencing the
threshold for subsequent action potential generation. This
review discusses the evidence implicating a role for HCN channels
underlie the pacemaker currents in neurons and their potential
involvement in pain pathophysiology.
Wickenden and McNaughton-smith [6] review a family of voltage-gated
K+ channels, Kv7.x, including
the cardiac channel Kv7.1 (formerly known as KvLQT1) and four
neuronal Kv7.2–5s. Heteromeric channels containing Kv7.3
and either Kv7.2 or Kv7.5 are thought to underlie the neuronal
M-current that has been known to regulate neuronal excitability
and serve as therapeutic drug targets for the treatment of
a variety of clinical disorders, such as epilepsy and pain.
This article updates on pre-clinical Kv7 drug discovery efforts
along with a summary of on-going clinical trials with newly
discovered Kv7 channel activators.
The topics presented in this special issue of Current Pharmaceutical
Design illustrate modulation of ion channels as promising
therapeutic approaches to alleviate chronic pain. Interventions
of ion channels by small molecules have demonstrated efficacious
analgesia in a variety of preclinical pain models. Validation
of pain relief by ion channel modulators in the early stage
of clinical trials shows promising results. However, it remains
to be seen whether ion channel modulators can truly represent
clinically effective and safe analgesics beyond the current
available therapeutic regimens. I would like to thank all
authors for their contributions by providing significant insights
in this research field focusing on ion channels associated
with chronic neuropathic pain. It is our hope that the issue
be helpful for the scientific and pharmaceutical industry
community working in this area. I would also like to thank
reviewers for their time and efforts to provide constructive
remarks.
References
[1] Boyce-Rustay JM and Jarvis MF. Neuropathic pain:
models and mechanisms. Curr Pharm Des 2009; 15(15): 1711-1716.
[2] Burnstock G. Purinergic receptors and pain. Curr Pharm
Des 2009; 15(15): 1717-1735.
[3] Cortright DN and Szallasi A. TRP channels and pain. Curr
Pharm Des 2009; 15(15): 1736-1749.
[4] Dubé GR, Elagoz A, and Mangat H. Acid sensing ion
channels and acid nociception. Curr Pharm Des 2009; 15(15):
1750-1766.
[5] Dunlop J, Vasilyev D, Lu P, Cummons T and Bowlby M. Hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels and pain. Curr Pharm
Des 2009; 15(15): 1767-1772.
[6] Wickenden AD and McNaughton-Smith G. Kv7 channels as targets
for the treatment of pain. Curr Pharm Des 2009; 15(15): 1773-1798.
Char-Chang Shieh
Neuroscience Research
Global Pharmaceutical Research and Development
Abbott Laboratories
[Back to top]
[Purchase Article] [PMID: 19442185 PubMed - indexed for MEDLINE]
Neuropathic Pain: Models and Mechanisms
J.M. Boyce-Rustay and M.F. Jarvis
Advances in the characterization of pain signaling in
recent years indicate that distinct neurophysiological and
neurochemical mechanisms contribute to pain arising from injury
to the nervous system (neuropathic pain). Tissue injury results
in the release of pro-nociceptive mediators that sensitize
peripheral nerve terminals (peripheral sensitization), leading
to neurochemical and phenotypic alterations of sensory neurons
and increased excitability of spinal cord dorsal horn neurons
(central sensitization). In addition, the response of the
nervous system to pain is not static, but is modulated by
descending systems originating in the brain that can modulate
pain thresholds. In this review, attention is given to the
experimental modeling of neuropathic pain in preclinical studies.
Recently, an increased understanding of the neurophysiological
plasticity of the nervous system in response to chronic pain
has led to the discovery and development of novel pharmacological
interventions that may have clinical utility in treating neuropathic
pain.
[Back to top]
[Purchase Article] [PMID: 19442186 PubMed - indexed for MEDLINE]
Purinergic Receptors and Pain
G. Burnstock
There is a brief summary of the early background literature
about purinergic signalling and its involvement in pain, of
ATP storage, release and ectoenzymatic breakdown and of the
current classification of receptor subtypes for purines and
pyrimidines. The review then focuses on purinergic mechanosensory
transduction involved in visceral, cutaneous and musculoskeletal
nociception and on the roles played by P2X3,
P2Y2/3, P2X4,
P2X7 and P2Y12
receptors in neuropathic and inflammatory pain. Current developments
of compounds for the therapeutic treatment of both visceral
and neuropathic pain are discussed.
[Back to top]
[Purchase Article] [PMID: 19442187 PubMed - indexed for MEDLINE]
TRP Channels and Pain
D.N. Cortright and A. Szallasi
Preclinical research has identified an array of ion channels
in sensory neurons involved in the generation and transduction
of pain as potential targets for pharmacological intervention.
Paramount among these new targets is the family of thermosensitive
transient receptor potential channels, referred to as “thermoTRPs”.
We detect a wide range of noxious stimuli via a limited
number (as of today, six) of thermoTRP channels, four of which
(TRPV1-TRPV4) respond to heat and two (TRPA1 and TRPM8) are
sensitive to cold. Targeting these thermoTRP channels represents
a new and logical strategy in pain relief. Unlike traditional
analgesic drugs that either suppress inflammation (e.g. NSAIDs
and COX-2 inhibitors) or block pain transmission (e.g. opiates),
TRP channel inhibitors aim to prevent pain by blocking a receptor
where pain is generated. The archetypal thermoTRP is the vanilloid
(capsaicin) receptor TRPV1. TRPV1 has a dynamic threshold
of activation. Agents in inflammatory soup, including endogenous
TRPV1 agonists (so-called “endovanilloids”), act
in concert to reduce the heat activation threshold of TRPV1.
In patients, the expression of TRPV1 is up-regulated in a
number of painful inflammatory disorders. TRPV1 as a pain
target has been validated by genetic deletion and pharmacological
inhibition experiments. This area of drug development has
been moving rapidly. It took less than a decade from the cloning
of TRPV1 to clinical trials with potent small molecule TRPV1
antagonists. This review evaluates current evidence that supports
particular TRP channels as targets for novel analgesic drugs,
along with potential adverse effects that may limit drug development.
[Back to top]
[Purchase Article] [PMID: 19442188 PubMed - indexed for MEDLINE]
Acid Sensing Ion Channels and Acid Nociception
G.R. Dubé, A. Elagoz and H.
Mangat
Acid Sensing Ion Channels (ASICs) are a family of cation
channels expressed principally in neurons and that are activated
by protons. The sensitivity of ASICs to acidosis and their
distribution in primary sensory neurons points to a significant
role of these channels in acid nociception. However, despite
the fact that the first ASIC was identified more than 10 years
ago the physiological and pathophysiological role of this
channel family remains poorly understood. In this paper, the
available body of data (genetic, pharmacological, and other)
on ASICs will be reviewed and the role of ASIC in normal nociception
and other pain sensations will be discussed. Some of the recent
drug discovery and development activities ongoing in our laboratory,
which point to ASICs being a relevant target for pain modulation,
will also be summarized.
[Back to top]
[Purchase Article] [PMID: 19442189 PubMed - indexed for MEDLINE]
Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN)
Channels and Pain
J. Dunlop, D. Vasilyev, P. Lu, T. Cummons
and M.R. Bowlby
Hyperpolarization-activated cyclic nucleotide-gated (HCN)
channels underlie the pacemaker currents in neurons and cardiac
cells designated as Ih
and If, respectively.
HCN channels are activated at negative membrane potentials
and specifically upon repolarization following action potential
firing resulting in a depolarizing current influencing the
threshold for subsequent action potential generation. Consequently,
HCN channels and Ih/If
play a critical role in regulating excitability and rhythmic
activity in excitable cells. The distribution of the four
HCN channel subtypes has been studied in some detail in sensory
neurons demonstrating a diverse and widespread distribution
and raising the question as to their potential involvement
in pain pathophysiology, frequently ascribed to aberrant neuronal
hyperexcitability. This review discusses the evidence implicating
a role for HCN channels in pain.
[Back to top]
[Purchase Article] [PMID: 19442190 PubMed - indexed for MEDLINE]
Kv7 Channels as Targets for the Treatment of Pain
A.D. Wickenden and G. McNaughton-Smith
Kv7.x channels are a family of six transmembrane domain,
single pore-loop, voltage-gated K+
channels. Five members of the family have been identified
to date, including the cardiac channel Kv7.1 (formerly known
as KvLQT1) and four neuronal Kv7.x channels, Kv7.2–5.
Heteromeric channels containing Kv7.3 and either Kv7.2 or
Kv7.5 are thought to underlie the neuronal M-current, a non-inactivating,
slowly deactivating, sub-threshold current that has long been
known to exert a powerful stabilizing influence on neuronal
excitability. Modulators of these channels have the potential
to influence neuronal activity in various tissues and are
of much interest as therapeutic drug targets for the treatment
of a variety of clinical disorders, such as epilepsy and pain.
The purpose of the present article is to review the molecular,
functional and behavioral evidence validating Kv7.x as drug
targets for the treatment of pain. In addition, an update
on pre-clinical Kv7 drug discovery efforts will be presented,
along with a summary of on-going clinical trials with Kv7
channel activators.
[Back to top]
[Purchase Article] [PMID: 19442191 PubMed - indexed for MEDLINE]
Continuous Nanostructures for the Controlled Release of Drugs
J. Venugopal, M.P. Prabhakaran, S. Low,
A.T. Choon, G. Deepika, V.R.G. Dev and S. Ramakrishna
The annual world wide market for controlled release of
polymer systems which extends beyond drug delivery is now
estimated to $60 billion and these systems are used by over
100 million people each year. It was estimated that drug delivery
will play a pivotal role in approximately 40% of all pharmaceutical
sales in near future. Novel methods of drug delivery will
not only result in more effective and efficacious treatments
but also generates new niche markets to provide greater intellectual
property protection to already existing drug formulations.
Recently, biodegradable electrospun polymer nanofibrous substrate
as drug carrier seems to be a promising method for delivering
anticancer drugs, especially in postoperative local chemotherapy.
Alternatively drug release can be triggered by the environment
or other external events such as changes in pH, temperature,
or the presence of analyte such as glucose. In general, controlled
release of polymer systems delivering drugs in the optimum
dosage for long periods is to increase the efficacy of drug,
reducing patient compliance. Recent research for the use of
nanotechnology (nanoparticle and nanofibers) in drug delivery
suggests that the technology might solve problems in the areas
such as controlled release, various topical administration,
gut absorption and targeted systemic delivery. This review
article described the applications of polymer nanoparticles
and nanofibers for loading potential drugs for the controlled
release to target incurable diseases.
[Back to top]
[Purchase Article] [PMID: 19442192 PubMed - indexed for MEDLINE]
Cardiovascular Biology of Interleukin-6
M.Y. Abeywardena, W.R. Leifert, K.E. Warnes,
J.N. Varghese and R.J. Head
Interleukin-6 (IL-6) is a multifunctional pro-inflammatory
cytokine that is tightly regulated and expressed at low levels
in healthy individuals. Increased IL-6 expression has been
associated with a variety of diseases, including inflammatory
conditions such as atherosclerosis and cardiovascular disease
(obesity, myocardial infarction and type II diabetes). Cytokines
including IL-6 and tumour necrosis factor alpha as well as
acute phase proteins such as C-reactive protein (CRP) and
fibrinogen are key biochemical risk factors for the development
of these disease conditions. IL-6 is the key cytokine responsible
for the stimulus of synthesis and secretion of CRP.
IL-6 activates cell surface signalling via the assembly
of IL-6, the IL-6 receptor (IL-6R) and the signalling receptor
gp130. Assembly of the (hexameric) signalling complex of IL-6,
IL-6R and gp130 occurs in a sequential manner and therefore
this signalling complex lends itself to several potential
sites for drug targeting. This review discusses some of the
mechanisms of IL-6 signalling on various aspects of cardiovascular
biology as well as some recent developments in drug targeting
of this complex.
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