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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 4, Number 3, July 2006
Contents
Pain
Guest Editors: Robert W. Gereau IV & Ferdinando Nicoletti
Editorial Pp.
173
Painful Peripheral Neuropathies Pp. 175-181
P. Marchettini, M. Lacerenza, E. Mauri and C. Marangoni
[Abstract]
The Emerging Role of TRP Channels in Mechanisms
of Temperature and Pain Sensation Pp. 183-196
G.M. Story
[Abstract]
Inflammatory Pain: The Cellular Basis of Heat
Hyperalgesia Pp. 197-206
J. Huang, X. Zhang and P.A. McNaughton
[Abstract]
Modulators of Pain: Bv8 and Prokineticins Pp.
207-215
L. Negri, R. Lattanzi, E. Giannini and P. Melchiorri
[Abstract]
PDZ Domains at Excitatory Synapses: Potential
Molecular Targets for Persistent Pain Treatment Pp.
217-223
Y.-X. Tao and R.A. Johns
[Abstract]
Metabotropic Glutamate and Cannabinoid Receptor
Crosstalk in Periaqueductal Grey Pain Processing
Pp. 225-231
E. Palazzo, V. de Novellis, I. Marabese, F. Rossi and
S. Maione
[Abstract]
L-Acetylcarnitine: A Proposed Therapeutic Agent
for Painful Peripheral Neuropathies Pp. 233-237
S. Chiechio, A. Copani, F. Nicoletti and R.W. Gereau IV
[Abstract]
Role of the Cannabinoid System in Pain Control
and Therapeutic Implications for the Management of Acute and
Chronic Pain Episodes Pp. 239-257
J. Manzanares, M.D. Julian and A. Carrascosa
[Abstract]
Abstracts
[Back to top]
Editorial
Pain
Although morphine is still the gold-standard for the treatment
of pathological pain, the increasing knowledge of the mechanisms
that regulate pain threshold breaks the ground for the development
of new potent and safe analgesic drugs. Hopefully, these drugs
will relieve some forms of pain that are partially resistant
to opiates, such as neuropathic pain. This issue of Current
Neuropharmacology includes a series of excellent reviews that
summarize the current knowledge and the most exciting perspectives
on the neurobiology of pain.
The opening review by Dr. Marchettini and collaborators is
a nice clinical classification of peripheral neuropathies,
which are a major source of neuropathic pain. If present,
pain associated with peripheral neuropathies is extremely
disabling, and its treatment is one of the major challenges
in neuroscience.
The two following reviews by Dr. Story and Dr. Mc Naughton’s
group focus on the role of Trp channels in heat sensation
and inflammatory pain. One of these channels, named TrpV1,
is expressed by neurons of dorsal root ganglia, and responds
to heat, protons, inflammatory mediators, and capsaicin. An
increased sensitivity of the TrpV1 channel is central to the
pathophysiology of heat hyperalgesia in inflammatory pain.
The review by the group of Dr. Negri and Dr. Melchiorri describes
the role of prokineticins and their receptors in the modulation
of pain. Prokineticins are the mammalian homologs of Bv8,
a small protein extracted from the frog skin that behaves
as a potent hyperalgesic agent.
The regulation of pain moves from the periphery to the CNS
in the review by Dr. Tao and Dr. Johns, which describes the
role of PDZ-domain-containing proteins associated with NMDA
receptors in persistent pain.
The review by the group of Dr. Maione and Dr. Rossi explores
the complex interaction between metabotropic glutamate receptors
and cannabinoid receptors in the periaqueductal grey, a region
of the brainstem that is critical for the regulation of pain
threshold. These two classes of receptors are considered as
potential targets for novel analgesic drugs.
Along this line, the review by Dr. Chiechio and collaborators
describes the mechanism of action of L-acetylcarnitine, a
drug that is currently used for the treatment of neuropathic
pain. L-Acetylcarnitine up-regulates the expression of a particular
metabotropic glutamate receptor subtype, the mGlu2 receptor,
which inhibits neuro-transmission at the synapse between primary
afferent pathways and neurons in the dorsal horns of the spinal
cord.
Finally, the elegant review by Dr. Manzanares, Dr. Julian,
and Dr. Carrascosa describes the multifaceted role of the
cannabinoid system in pain transmission, and the potential
therapeutic implications for the management of acute and chronic
pain. Taken together, the articles included in the issue offer
an original view of the molecular and trans-synaptic mechanisms
underlying inflammatory and neuropathic pain, and are particularly
helpful for basic scientists and clinicians interested in
the neuropharmacology of pain.
Robert W. Gereau IV
Chief, Basic Research Section
Washington University Pain Center
Associate Professor
Department of Anesthesiology
Washington University School of Medicine
660 S. Euclid Ave, Campus Box 8054
St. Louis, MO 63110
USA
Ferdinando Nicoletti
Department Human Physiology
& Pharmacology
University Rome"da Sapienza"
Piazzale Aldo Moro 5
Rome 00185
Italy
[Back to top]
Painful Peripheral Neuropathies
P. Marchettini, M. Lacerenza, E. Mauri and C. Marangoni
Peripheral neuropathies are a heterogeneous group of diseases
affecting peripheral nerves. The causes are multiple: hereditary,
metabolic, infectious, inflammatory, toxic, traumatic. The
temporal profile includes acute, subacute and chronic conditions.
The majority of peripheral neuropathies cause mainly muscle
weakness and sensory loss, positive sensory symptoms and sometimes
pain. When pain is present, however, it is usually extremely
intense and among the most disabling symptoms for the patients.
In addition, the neurological origin of the pain is often
missed and patients receive inadequate or delayed specific
treatment. Independently of the disease causing the peripheral
nerve injury, pain originating from axonal pathology or ganglionopathy
privileges neuropathies affecting smaller fibres, a clinical
observation that points towards abnormal activity within nociceptive
afferents as a main generator of pain. Natural activation
of blood vessels or perineurial nociceptive network by pathology
also causes intense pain. Pain of this kind, i.e. nerve trunk
pain, is among the heralding symptoms of inflammatory or ischemic
mononeuropathy and for its intensity represents itself a medical
emergency. Neuropathic pain quality rekindles the psychophysical
experience of peripheral nerves intraneural microstimulation
i.e. a combination of large and small fibres sensation temporally
distorted compared to physiological perception evoked by natural
stimuli. Pins and needles, burning, cramping mixed with numbness,
and tingling are the wording most used by patients. Nociceptive
pain instead is most often described as aching, deep and dull.
Good command of peripheral nerve anatomy and pathophysiology
allows timely recognition of the different pain components
and targeted treatment, selected according to intensity, type
and temporal profile of the pain.
[Back to top]
The Emerging Role of TRP Channels in Mechanisms
of Temperature and Pain Sensation
G.M. Story
Pain is universal and vital to survival. It is an essential
component of our sense of touch; together, touch and pain
have evolved to enable our awareness of the intricacies of
our environment and to warn us of danger and possible injury.
There is a clear link between temperature sensation and pain—painful
temperature sensations occur acutely and are a hallmark of
inflammatory and chronic pain disorders of the nervous system.
Mounting evidence suggests a subset of Transient Receptor
Potential (TRP) ion channels activated by temperature (thermoTRPs)
are important molecular players in acute, inflammatory and
chronic pain states. Varying degrees of heat activate four
of these channels (TRPV1-4), while cooling temperatures ranging
from pleasant to painful activate two distantly related thermoTRP
channels (TRPM8 and TRPA1). ThermoTRP channels are also chemosensitive,
being activated and or modulated by plant-derived small molecules
and endogenous inflammatory mediators. All thermoTRPs are
expressed in tissues essential to cutaneous thermal and pain
sensation. This review examines the contribution of thermoTRP
channels to our understanding of temperature and pain transduction
at the molecular level.
[Back to top]
Inflammatory Pain: The Cellular Basis of Heat
Hyperalgesia
J. Huang, X. Zhang and P.A. McNaughton
Injury or inflammation release a range of inflammatory mediators
that increase the sensitivity of sensory neurons to noxious
thermal or mechanical stimuli. The heat- and capsaicin-gated
channel TRPV1, which is an important detector of multiple
noxious stimuli, plays a critical role in the development
of thermal hyperalgesia induced by a wide range of inflammatory
mediators. We review here recent findings on the molecular
mechanisms of sensitisation of TRPV1 by inflammatory mediators,
including bradykinin, ATP, NGF and prostaglandins. We describe
the signalling pathways believed to be involved in the potentiation
of TRPV1, and our current understanding of how inflammatory
mediators couple to these pathways.
[Back to top]
Modulators of Pain: Bv8 and Prokineticins
L. Negri, R. Lattanzi, E. Giannini and P. Melchiorri
Bv8 is a small protein secreted by frog skin. Mammalian homologues
of Bv8, the prokineticins PK1 and PK2, and their G-protein
coupled receptors PKR1 and PKR2 have been identified and linked
to several biological effects. Bv8 elicits a dose-dependent
reduction in nociceptive threshold to thermal and mechanical
stimuli applied to the skin of tail and paw of rats and mice
and increases the sensitivity to nociceptive mediators as
capsaicin and prostaglandins. The receptors for Bv8/PKs are
present in a fraction of peptidergic population of C-fibre
neurons, and in a fraction of A myelinated-fibre neurons.
In mouse and rat dorsal root ganglia, PKR-expressing neurons
also express TRPV1 and the activation of PKRs sensitises TPRV1
to the action of capsaicin. Mice lacking PKR1 gene exhibit
impaired Bv8-induced hyperalgesia, develop deficient responses
to noxious heat, capsaicin and protons and show reduced thermal
and mechanical hyper-sensitivity to paw inflammation, indicating
a requirement for PKR1 signalling associated with activation
and sensitisation of primary afferent fibres. PKs are highly
expressed by neutrophils and other inflammatory cells and
must be considered as new pronociceptive mediators in inflammatory
tissues. Bv8-like hyperalgesic activity was demonstrated in
extracts of rat inflammatory granulocytes. Bv8 stimulate macrophage
and T lymphocyte to differentiate between an inflammatory
and Th1 profile indicating that Bv8/PK proteins play a role
in immuno-inflammatory responses. Blockade of PKRs may represent
a novel therapeutic strategy in acute and inflammatory pain
conditions.
[Back to top]
PDZ Domains at Excitatory Synapses: Potential
Molecular Targets for Persistent Pain Treatment
Y.-X. Tao and R.A. Johns
Persistent pain, a common clinical condition, could be caused
by inflammation, tissue injury secondary to trauma or surgery,
and nerve injuries. It is often inadequately controlled by
current treatments, such as opioids and non-steroidal anti-inflammatory
drugs. The PDZ (Postsynaptic density 95, Discs large, and
Zonula occludens-1) domains are ubiquitous protein interaction
modules often found among multi-protein signaling complexes
at neuronal synapses. Recent preclinical research shows that
targeted disruption of PDZ domain-mediated protein interaction
among N-methyl-Daspartate (NMDA) receptor signaling
complexes significantly attenuates the development and maintenance
of persistent pain without affecting nociceptive responsiveness
to acute pain. PDZ domains at excitatory synapses may be new
molecular targets for prevention and treatment of persistent
pain. Here, we illustrate expression and distribution of the
PDZ domain-containing proteins associated with NMDA receptors
in the pain-related regions of the central nervous system,
review the evidence for their roles in persistent pain states,
and discuss potential mechanisms by which these PDZ domain-containing
proteins are involved in persistent pain.
[Back to top]
Metabotropic Glutamate and Cannabinoid Receptor
Crosstalk in Periaqueductal Grey Pain Processing
E. Palazzo, V. de Novellis, I. Marabese, F. Rossi and
S. Maione
Metabotropic glutamate (mGlu) and cannabinoid receptors are
G-protein coupled receptors which have shown synaptic co-operation
through small lipid messengers in the central nervous system
(CNS). A functional interaction between these two receptor
families could have a relevant potential in the treatment
of CNS disorders, including chronic pain. Indeed, both mGlu
and cannabinoid receptors play a crucial role in the neurobiology
of pain and their simultaneous manipulation could lead to
novel strategies in pain management. In particular, as both
mGlu and cannabinoid receptors have been found in the periaqueductal
gray (PAG), a crucial station in the pain modulatory system,
these receptors could be a substrate for producing analgesia
at this level. In this review we aim to briefly illustrate
the role of mGlu and cannabinoid receptors in controlling
nociceptive processes, some points of convergence, and their
functional interaction in pain processing. Further insights
into this functional linkage between the mGlu and cannabinoid
receptors could pave the way to a new strategy for pain relief,
such as a drug cocktail acting on cannabinoid/metabotropic
glutamate receptors.
[Back to top]
L-Acetylcarnitine: A Proposed Therapeutic Agent
for Painful Peripheral Neuropathies
S. Chiechio, A. Copani, F. Nicoletti and R.W. Gereau IV
During the past two decades, many pharmacological strategies
have been investigated for the management of painful neuropathies.
However, neuropathic pain still remains a clinical challenge.
A combination of therapies is often required, but unfortunately
in most cases adequate pain relief is not achieved. Recently,
attention has been focused on the physiological and pharmacological
effects of L-acetylcarnitine in neurological disorders. There
are a number of reports indicating that L-acetylcarnitine
can be considered as a therapeutic agent in neuropathic disorders
including painful peripheral neuropathies. In this review
article, we will examine the antinociceptive and the neuroprotective
effects of L-acetylcarnitine as tested in clinical studies
and in animal models of nerve injury.
[Back to top]
Role of the Cannabinoid System in Pain Control
and Therapeutic Implications for the Management of Acute and
Chronic Pain Episodes
J. Manzanares, M.D. Julian and A. Carrascosa
Cannabis extracts and synthetic cannabinoids are still widely
considered illegal substances. Preclinical and clinical studies
have suggested that they may result useful to treat diverse
diseases, including those related with acute or chronic pain.
The discovery of cannabinoid receptors, their endogenous ligands,
and the machinery for the synthesis, transport, and degradation
of these retrograde messengers, has equipped us with neurochemical
tools for novel drug design. Agonist-activated cannabinoid
receptors, modulate nociceptive thresholds, inhibit release
of pro-inflammatory molecules, and display synergistic effects
with other systems that influence analgesia, especially the
endogenous opioid system. Cannabinoid receptor agonists have
shown therapeutic value against inflammatory and neuropathic
pains, conditions that are often refractory to therapy. Although
the psychoactive effects of these substances have limited
clinical progress to study cannabinoid actions in pain mechanisms,
preclinical research is progressing rapidly. For example,
CB1-mediated suppression of mast cell activation
responses, CB2-mediated indirect stimulation of
opioid receptors located in primary afferent pathways, and
the discovery of inhibitors for either the transporters or
the enzymes degrading endocannabinoids, are recent findings
that suggest new therapeutic approaches to avoid central nervous
system side effects. In this review, we will examine promising
indications of cannabinoid receptor agonists to alleviate
acute and chronic pain episodes. Recently, Cannabis sativa
extracts, containing known doses of tetrahydrocannabinol and
cannabidiol, have granted approval in Canada for the relief
of neuropathic pain in multiple sclerosis. Further double-blind
placebo-controlled clinical trials are needed to evaluate
the potential therapeutic effectiveness of various cannabinoid
agonists-based medications for controlling different types
of pain.
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