Current Medicinal Chemistry, 2007, 14, 1783-1787 1783

Molecular Approaches for Neuropathic Pain Treatment

Dario Siniscalco * , Francesco Rossi and Sabatino Maione

Department of Experimental Medicine-Section of Pharmacology "L. Donatelli" , Second University of Naples, Via S.
Maria di Costantinopoli, 16-80138 Naples, Italy
Abstract: Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system.
It is estimated that 75–150 million people in the United States have a chronic pain disorder. Neuropathic pain has a great impact
on the quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human
wellbeing. Moreover, the management of chronic pain is costly to the health care system. The United States Congress has
declared the present decade (2001-2010) as the “Decade of Pain Control and Research”, making pain a national healthcare
priority.
In Europe, statistics provided by the International Association on the Study of Pain (IASP) and the European Federation of the
IASP Chapters (EFIC) indicate that one in five people suffer from moderate to severe chronic pain, and that one in three are
unable or less able to maintain an independent lifestyle due to their pain. Between one-half and two-thirds of people with chronic
pain are less able or unable to exercise, enjoy normal sleep, perform household chores, attend social activities, drive a car, walk
or have sexual relations. The effect of pain means that one in four reports that relationships with family and friends are strained
or broken, according to the IASP/EFIC data.
Neuropathic pain treatment is extremely difficult. Neuropathic pain is a very complex disease, involving several molecular
pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by
peripheral nerve injury. Current available drugs are usually not acting on the several mechanisms underlying the generation and
propagation of pain.
Nowadays, pain research is directing on new molecular methods, such as gene therapy, stem cell therapy and viral vectors for
delivery of biologic antinociceptive molecules. These methods could provide a new therapeutic approach to neuropathic pain
relief.
Keywords: Neuropathic pain, gene therapy, virus vector, antisense, stem cell therapy.

NEUROPATHIC PAIN: PHYSIOLOGY also receive nociceptive input. Neurons of deeper laminae (as
well as lamina VI and VIII) may contribute to the diffuse nature
Pain initiated or caused by a primary lesion or dysfunction of many pain conditions [4].
in the nervous system is defined as neuropathic pain [1]. It
results from direct injury to nerves in the peripheral or central In response to peripheral nerve injury, the spinal cord
nervous system [2] and is associated with several clinical anatomical structure is subjected to a re-organization. Indeed,
symptoms. It has often a continuous burning state, together the myelinated primary afferent fibers sprout into lamina II of
with the presence of abnormal sensory symptoms, such as the dorsal horn, establishing synaptic contacts with second-
hyperalgesia (an increased response to a stimulus which is order neurons. In this way, they help to conduct the allodynic
normally painful; patients with hyperalgesia perceive pain transmission [5].
spontaneously) and allodynia (pain as a result of a stimulus Severe and persistent injury causes a condition of central
which does not provoke pain; patients with allodynia do not sensitization called “wind-up”: C-fibres are frequently sped on,
feel constant pain; indeed in the absence of a stimulus there is release glutamate, and the response of the neurons of the dorsal
no pain) [3]. The spinal cord is the first centre involved in the horn progressively increases [6, 7].
controlling and processing of nociceptive signalling. In this The major nociceptive excitatory neurotransmitter released
site the interactions between nociceptive and non-nociceptive from A-delta and C-fibres is glutamate. Its release triggers fast
afferent pathways control the transmission of nociceptive synaptic potentials in dorsal horn neurons by activating the
information to higher centres in the brain. In the dorsal horn of pre- and post-synaptic glutamate receptors. The ionotropic
the spinal cord nociceptive afferent fibers terminate where the NMDA receptor is most involved in the events correlated with
nociceptive neurons are located in the superficial lamina I nociception [8], and with the maintenance of central
(marginal layer) and in the lamina II (substantia gelatinosa). sensitization and hyperexcitability of dorsal horn neurons.
These neurons are responsible for projecting nociceptive Activation of NMDA receptors increases the concentration of
signalling in higher brain centres, receiving direct synaptic the calcium ion by the indirect activation of protein kinase C
input from A-delta fibers, and indirect input from C-fibers via [9].
neurons in lamina II. Neurons in the lamina II are almost
exclusively excitatory and inhibitory neurons, some of which Damaged nerve fibres send incorrect signals to higher pain
only respond to nociceptive inputs. Laminae III and IV neurons centres; indeed, peripheral nerve injury is able to induce
receive monosynaptic input from A-beta fibers and rearrangements in the spinal cord or in the peripheral nerves
predominantly respond to non-noxious stimuli. Lamina V wide themselves. It is likely that there are also alterations in the
dynamic-range neurons receive input from A-beta, A-delta and brain, but less is known about these changes.
C-fibers, and project to brain stem and thalamus, some of them In the brain, the insular cortex is directly involved in the
pain modulation. Increasing the GABA neurotransmission in
this area enhances the anti-nociceptive response [10]. GABAa
*Address correspondence to this author at the Department of Experimental
Medicine-Section of Pharmacology "L. Donatelli" , Second University of Naples, receptors can modulate the nociceptive threshold affecting the
Via S. Maria di Costantinopoli, 16-80138 Naples, Italy; Tel: +39 (0)81 5667532; noradrenergic bulbo-spinal projections from the insular cortex
Fax: +39 (0)81 5667503; E-mail: [email protected] to the locus coeruleus. GABAb receptors modulate the

0929-8673/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

1784 Current Medicinal Chemistry, 2007, Vol. 14, No. 16 Siniscalco et al.

projections from cortex to amygdala [10]. Both the projections neuropathic pain behaviour, such as thermal hyperalgesia and
modulate the nociceptive responses and are under the control of mechanical allodynia [25].
GABAergic neurons. As mentioned above, glutamate plays a key role in pain
The pain sympthomatology is a complex mix of central and processing. NMDA glutamate receptors are involved in
peripheral effects, such as: central sensitization, cortical and inflammation and in central sensitization. NMDA receptor
spinal re-organization, changes in the inhibitory pathways antagonists are able to attenuate neuropathic pain. Indeed, the
(central effects); collateral sprouting of primary afferent NMDA receptor antagonist MK-801 has a potent protective
neurons, sprouting of sympathetic neurons into the DRG, effect [26, 27, 28], but it shows high toxic properties and low
nociceptor sensitization, alterations in ion channel expression, safety margins excluding its clinical use on human patients.
ectopic and spontaneous discharge (peripheral effects). Nowadays, dextromethorphan, ketamine, memantine,
Molecular evidences support the fact that there are changes amantadine are commercially available NMDA-receptor
in DNA expression in the neuropathic pain syndrome. After antagonists. The opioids methadone, dextropropoxyphene and
peripheral noxious stimuli, dorsal horn neurons show an over- ketobemidone are also NMDA-antagonists, as well as the
expression of immediate early genes encoding transcription triciclic antidepressant amitriptiline [29, 30]. Due to the fact
factors such as c-jun and c-fos. These genes are involved in cell that the NMDA-receptor antagonists have an important impact
death induction via a long-lasting cascade of transcriptional on the development of tolerance to opioid analgesics, NMDA-
processes [11]. It has been demonstrated that the apoptotic receptor antagonists might represent a new class of analgesic
genes mRNA expression levels of the bcl-2 cell death- and might have potential as a co-analgesic in combination with
associated family in the lumbar dorsal horn of the spinal cord of opioids [31].
neuropathic rats are modified by peripheral nerve injury [12]. Moreover, antagonists direct to the glycine site on the
Ectopic discharge, proven also in humans with neuropathic NMDA receptors can prevent the development of hyperalgesia
pain [13, 14] is a massive increase in the level of normal firing [32]. It has been shown that glycine and the NMDA antagonist
in the afferent neurons (injured sensory neurons and their (+)HA966, administered at the same time, are able to relieve
uninjured neighbours) following nerve injury, close to the site behavioural pain in a rat model of neuropathic pain [33].
of the injury. This ectopic firing after nerve injury is due to an Group I metabotropic glutamate receptors (mGluRs) play
altered expression of several types of sodium channels, such as also a key role in chronic pain transmission. Both peripheral
the voltage-gated sodium channels [15, 16]. The mechanisms and central mGluR5 receptors are responsible of the nociceptive
responsible for the changes in the channel expression are not transmission observed during post-operative pain [34]. MPEP,
yet unclear. Recent findings indicate the involvement of the the potent and selective antagonist for metabotropic glutamate
neurotrophin (such as NGF, GDNF) supply [17]. receptor subtype 5 (mGlu5), prevents the development of
The calcium channels may also contribute to the induction thermal hyperalgesia, transiently reduces mechanical
of hyperalgesia and allodynia [18]. hyperalgesia in neuropathic rats, and prevents the over-
Sprouting of collateral fibres from sensory axons in the skin expression of pro-apoptotic genes in dorsal horn spinal cord
into denervated areas has been observed after peripheral nerve neurons [2].
injury [19, 20]. Given that, this subtype of metabotropic glutamate
Neurotrophic factors and several cytokines, such as receptors could be a new potential drug target in pain treatment.
interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF- The typical mu-opioid analgesics, such as morphine, can be
alpha), may be involved in the sprouting formation and in relatively ineffective in treating neuropathic pain since
pathophysiology of neuropathic pain [21, 22]. different opioids can produce analgesia by affecting different
pain pathways [35].
NEUROPATHIC PAIN: CLASSICALPHARMACOLOGICAL The ideal drugs in the treatment of neuropathic pain are the
TREATMENT anticonvulsant gabapentin, and its successor pregabalin [36,
37, 38]. Although their mechanism of action remains unclear,
Several drugs are used for the classical pharmacological
they are able to decrease the hyperexcitability of dorsal horn
treatment of neuropathic pain: lidocaine, lamotrigine,
neurons induced by tissue injury, therefore they only have an
acetaminophen, dextromethorphan, carbamazepine, gabapentin,
effect in a condition of sensitization of a nociceptive pathway.
valproic acid, opioid analgesics, tramadol hydrochloride, and
Gabapentin binds the alpha2sigma subunit of voltage gated
tricyclic antidepressants.
calcium channels contributing to the antinociceptive effect
Clinical research is studying new direct-acting compounds [38]. Gabapentin is widely used in post-operative pain
to sodium and calcium channels since the ability of these treatment [39], and has antihyperalgesic and antiallodynic
channels to contribute to the development of neuronal effects.
hyperexcitability and the production of pain-associated
behaviour. The sodium channel blocker lidocaine is effective in Pain has a complex nature. Every key molecule involved in
the pain relief [23], however, the available blockers are not the nociceptive modulation and transmission could open new
specific between the several types of sodium channels. perspectives on the treatment of various pain syndromes. Pain
Ralfinamide, a sodium channel blocker, is under development research is focalizing on the molecular aspects of pain,
by a private company for the potential treatment of neuropathic indicating new cellular targets in the treatment.
pain [24]. The glucocorticoid receptors (GRs) antagonist RU38486 or
It has been demonstrated that specific antagonists for the a GR antisense oligonucleotide administered intrathecally are
neuronal calcium channel are able to reduce heat hyperalgesia able to attenuate the development of neuropathic pain
and mechanical allodynia in a pain model, the chronic behaviour in neuropathic rats [40], indicating that peripheral
constriction injury of the sciatic nerve, if administered locally GRs are a role in the anti-inflammatory effects of
on the site of nerve injury [17]. glucocorticoids and suggesting a potential role for GR
antagonists in the clinical treatment of neuropathic pain.
Activation of the cannabinoid receptor subtype 1 is able to
decrease the calcium flux. Treatment with Win 55,212-2, a It has been shown that the somatostatin released from
synthetic cannabinoid CB1 receptor agonist, decreases capsaicin-sensitive sensory nerves exerts systemic anti-
Molecular Approaches for Neuropathic Pain Treatment Current Medicinal Chemistry, 2007 Vol. 14, No. 16 1785

inflammatory and anti-nociceptive action. The heptapeptide TT- specific molecular target for neuropathic pain treatment.
232, a somatostatin analogue, inhibits acute and chronic Antisense knock-down oligonucleotides targeting sodium
inflammatory responses and diminishes chronic mechanical channel reversed neuropathic pain induced by spinal nerve
allodynia associated with diabetic neuropathy [41]. damage [51].
p38 mitogen-activated protein kinase (MAPK) takes a novel Spinal nerve ligation triggers up-regulation of the
role in neuronal plasticity and pain hypersensitivity [42]. The expression of alpha-2/delta-1 subunit of the voltage-gated
p38 MAPK inhibitor SB203580, intrathecally administered in calcium channel (VGCC) in dorsal root neurons [52]. Intrathecal
neuropathic rats, as well as the inhibitor PD198306, is able to antisense oligonucleotide treatment decreased alpha-2/delta-1
reduce mechanical allodynia [43, 44]. Interesting, MAPK family subunit of voltage-gated calcium channel expression in the
shows other kinases involved in neuropathic pain development. dorsal root ganglion and spinal cord and partially decreased
c-Jun N-terminal kinase (JNK) is activated in dorsal root allodynia [53]. The pre-synaptic expression of alpha-2/delta-1
ganglion and spinal cord in a neuropathic pain state [45]. It has subunit calcium channel is increased after peripheral nerve
been demonstrated a dual role for JNK in controlling injury. This pre-synaptic plasticity could modulate neuropathic
neuropathic pain. First, JNK shows transient activation in DRG pain development and maintenance. The incomplete effect on
neurons in the early phase of induction of neuropathic pain; allodynia is likely due to the pharmacological properties of
second, it shows persistent activation in spinal astrocytes in administered oligonucleotides.
neuropathic pain maintenance [45]. In spinal astrocytes,
activated JNK could be regulate gene transcription via Nerve injury is able to increase the expression of the alpha-5
activation of several transcription factors, such as c-Jun, subtype of the nicotinic acetylcholine receptors in the spinal
activating transcription factor-2 and nuclear factor-kB, and in cord. Nicotinic acetylcholine receptor agonists are able to
this way affects pain responses. Given that, JNK cascade could alleviate neuropathic pain, although the role of in the
be a novel option to pharmacological treatment of neuropathic maintenance of chronic pain is not yet clear. However,
pain. intrathecal alpha-5 antisense oligonucleotides reduced
mechanical allodynia [54].
Extracellular signal-regulated kinase (ERK) is another
member of MAPK family involved in neuropathic pain. ERK is NMDA glutamate receptors and opioid receptors have been
sequentially activated in spinal cord dorsal horn, first in used as target for antisense knock-downing strategy, showing a
microglia and then in astrocytes, indicating a different decrease in nociceptive behaviour [55, 56].
involvement of these two subtype of glial cells in neuropathic The P2X receptors are also involved in nociception [57]. The
pain. The ERK inhibitor PD98059, intrathecally administered, is subtype P2X3 receptor is preferentially expressed on
able to reduce mechanical allodynia [46]. Besides, the distinct nociceptive C-fibers. Intrathecal administration of P2X3
role taken by different neural cells at different time could offer antisense oligonucleotides decreased mechanical allodynia in
the possibility to control the temporal evolution of neuropathic neuropathic rats [58].
pain.
Peripheral nerve injury is able to induce over-expression of
It has been demonstrated that the competitive noradrenaline early genes, such as c-fos, in dorsal horn neurons of the spinal
transporter inhibitor Reboxetine is able to reduce cord. Intrathecal administration into the lumbar region L1-L5 of
hypersensitivity in response to noxious stimuli [47], c-fos antisense oligonucleotides has shown a role played by the
indicating that the neurotransmitter noradrenaline is involved c-fos gene in neuropathic pain [59].
in the suppression of nociceptive transmission.
Novel findings have clarified the role of 5-
NEUROPATHIC PAIN: MOLECULAR METHODS hydroxytryptamine (5-HT) in pain modulation [60]. 5-HT is
released in dorsal horn spinal cord following sciatic nerve
Newer molecular methods, such as gene therapy, stem cell stimulation. Intracerebroventricular administration of antisense
therapy and viral vector for the delivery of biologic anti- oligonucleotides targeting the sub-type 5-HT1A receptor
nociceptive molecules, could provide a novel therapeutic decreases the mechanical hyperalgesia [61]. Another strategy
approach to the neuropathic pain treatment. directs toward serotonin system uses serotonergic neural
precursor cell grafts that are able to reduce hyperexcitability
The altered gene expression, caused by peripheral nerve
caused by spinal injury [62].
injury, is correlated with spinal re-organization and changes in
the excitatory or inhibitory pathways controlling neuropathic These data highlight that antisense knock-down strategy
pain development. Novel molecular pharmacological strategy is could represent a novel approach to the neuropathic pain
directed toward to the control of the gene up- or down- therapy in the nearest future. As next step, antisense research
regulation. has to elucidate the pharmacodynamics, pharmacokinetics and
As expected, several sodium channels show altered gene distributions of antisense oligonucleotides.
expression in neuropathic pain. Indeed, many studies report A brand-new tool for neuropathic pain management is stem
that the voltage gate channel isoform Nav 1.3 is up-regulated in cells therapy. Indeed, stem cell implantation appears as a
spinal cord higher-order sensory neurons after peripheral nerve possible solution for spinal cord injury. Stem cells have the
damage [16, 48, 49], probably contributing to the hyper- ability to incorporate into spinal cord, differentiate, and to
responsiveness of dorsal horn sensory neurons and to improve locomotor recovery [63].
hyperalgesia and allodynia. A novel pharmacological treatment
is based on gene silencing by the use of antisense Most recent studies show that stem cells transplanted
oligonucleotides. Intrathecal administration of Nav 1.3 following spinal cord injury are able to reduce allodynia and
antisense oligonucleotides is able to antagonize the mechanical improve functional recovery if they produce more
allodynia [50]. The down-regulation of Nav 1.3 mRNA and oligodendrocytes than astrocytes. Astrocytes can promote
protein, as result of this antisense knock-down strategy, causes aberrant sprouting of sensory neurons, leading to allodynia
a reduction in the firing of dorsal horn neurons and a decrease [64].
in pain-related behavior. A report shows that intrathecal implantation of spinal
The tetrodotoxin (TTX)-resistant sodium channel Nav 1.8 is progenitor cells in neuropathic rats is able to provide a means
expressed in sensory neurons and it might provide a novel and of alleviating neuropathic pain [65].
1786 Current Medicinal Chemistry, 2007, Vol. 14, No. 16 Siniscalco et al.

Neuropathic pain causes a decrease in the number and injury has been demonstrated to decrease secondary damage
activity of GABAergic neurons, the spinal progenitor cells show [75].
glutamic acid decarboxylase immunocompetence, in this way
We have recently demonstrated the occurrence of neuronal
they can supply the decreased GABA profile [66].
apoptosis in the dorsal horn spinal cord of neuropathic rats [2].
Another research uses viral vector technology to delivery In the last step of the apoptotic pathway, there is activation of
anti-nociceptive molecules. It has been demonstrated that caspases, thus, they could offer a new potential target for novel
dorsal root ganglion neurons transduced with replication- pharmacological agents in the treatment of neuropathic pain.
incompetent herpes simplex virus (HSV-) based vector, Sub-type selective caspase inhibitors are able to attenuate pain-
encoding the GAD67 isoform of human glutamic acid related behaviours in rats [76].
decarboxylase, have successfully produced GAD and released
GABA, thus reducing neuropathic pain following a spinal cord In the mechanisms of inflammation, in the induction and in
injury [67]. the maintenance of pain are involved several pro-inflammatory
cytokines. There is evidence that the intrathecal delivery of the
Herpes-mediated, gene-based tools for neuropathic pain adenovirus-mediated IL-2 gene has a relatively long anti-
treatment are promising in therapy in humans. Virus encoding nociceptive effect [77]. Novel gene-based strategies will have as
human preproenkephalin (hPPE) has decreased the activation of target in ideally abolishing, or at least reducing, chronic pain,
nociceptors by capsaicin treatment in mice and macaques [68]. some of the most recently discovered molecules involved in
Another strategy using virus is the use of a viral vector for pain transduction mechanisms, sensory nerve sensitization or
antisense delivery. Antisense cDNA versus calcitonin gene- pain perpetuation.
related peptide precursor (ACGRP) delivered virally has A very brand new and interesting developing technology in
reversed C-fiber hyperalgesia due to the application of the treatment of neuropathic pain is the use of cell lines as
capsaicin on the skin in mice [68]. biologic minipumps to chronically deliver anti-nociceptive
Other molecules taking a role in neuropathic pain are the molecules, such as the peptide galanin near the pain processing
neurotrophic factors, and, therefore, their delivery by centers of the spinal cord following nerve injury. Low local
adenovirus-based gene therapy could represent a future strategy doses of galanin chronically applied by transplanted cells near
for the prevention of pain. Neurotrophin-3 (NT-3) negatively the lumbar spinal dorsal horn are able to reverse the
modulates nerve growth factor (NGF) receptor expression and development of chronic neuropathic pain after sciatic nerve
associated nociceptive phenotype in intact neurons, suggesting injury [78].
a beneficial role in treating aspects of neuropathic pain
mediated by NGF. Intramuscular injection of recombinant
adenovirus encoding NT-3 into streptozotocin-induced diabetic CONCLUSIONS
rats has decreased the denervation observed in this model of About 75–150 million people in the United States have a
diabetic neuropathy [69]. chronic pain disorder [79, 80]. According to MarketData
Recombinant adeno-associated viral vector-mediated over- Enterprises (1995), only 2.9 million (2.5%–5%) people seek
expression of BDNF (brain-derived neurotrophic factor) has treatment by pain specialists. Sometime, remaining people have
reversed the pain-like behaviours in neuropathic rats [70]. learnt ways to adapt themselves despite the presence of
Semaphorin3A has inhibited the sprouting of nociceptive persistent pain.
afferent fibres involved in neuropathic pain in rats [71].
Neuropathic pain has a great impact on the quality of life. It
Novel strategies of alleviating pain suffering are in is debilitating and often has an associated degree of depression
progress: electroacupuncture has a potent analgesic effect on that contributes to decreasing human wellbeing. Moreover, the
neuropathic pain by activating various endogenous management of chronic pain is costly to the health care system.
transmitters, such as the opioid peptides and neurotrophic The United States Congress has declared the present decade
factors, especially glial cell line-derived neurotrophic factor (2001-2010) as the “Decade of Pain Control and Research”,
(GDNF) [72]. making pain a national healthcare priority.
A new system of gene delivery has been studying: In Europe, statistics provided by the International
electroporation. Intrathecal pro-opiomelanocortin gene Association on the Study of Pain (IASP) and the European
electroporation reduces pain sensitivity induced by an animal Federation of the IASP Chapters (EFIC) indicate that one in five
model of neuropathy in rats [73]. Electroporation is also used people suffer from moderate to severe chronic pain, and that one
for non-viral gene transferring. Electro-transfecting a plasmid in three are unable or less able to maintain an independent
coding for pro-opiomelanocortin gene (pTRE2-POMC) into the lifestyle due to their pain. Between one-half and two-thirds of
spinal cord of mononeuropathic rats has shown analgesic people with chronic pain are less able or unable to exercise,
effects. The relatively low expression levels achieved from enjoy normal sleep, perform household chores, attend social
transferred genes is the major problem of the application of activities, drive a car, walk or have sexual relations. The effect of
non-viral vectors for gene transfer into the spinal cord in vivo. pain means that one in four reports that relationships with
The electroporation-mediated pro-opiomelanocortin (POMC) family and friends are strained or broken, according to the
gene therapy for neuropathic pain could be a useful and IASP/EFIC data.
promising tool in neuropathic pain.
Neuropathic pain is a very complex disease, involving
Primary damage occurring in the central nervous system several molecular pathways. It has an individual character,
following injury is due to glutamate excitotoxicity [2], calcium making its treatment extremely difficult. Current available
overload, and oxidative stress. Oxidative stress is responsible drugs are usually not acting on the several mechanisms
for secondary damage activating neutrophil-mediated underlying the generation and propagation of pain; they have a
inflammation. Another strategy targets oxidative stress for generalized nature, and, sometime, act only on the temporal pain
decreasing post-traumatic inflammation: using cysteine properties rather than being targeted towards the several
precursors to maintain reduced-glutathione levels, blocking mechanisms underlying the generation and propagation of pain.
neutrophil invasion by platelet-activating factor antagonists
and using flavonoids as antioxidants could have therapeutic Novel molecular methods, such as antisense strategy, gene
effects [74]. Promoting glutathione synthesis after spinal cord therapy, stem cell, virus therapy, are emergent ways for pain
Molecular Approaches for Neuropathic Pain Treatment Current Medicinal Chemistry, 2007 Vol. 14, No. 16 1787

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Received: January 01, 2007 Revised: April 23, 2007 Accepted: April 26, 2007