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Neuropathic pain: A Physiological perspective
The word pain is thought to be derived from the Latin word poena, meaning punishment (Gu et
al., 2005). “Pain is an unpleasant sensory and emotional experience, associated with actual or
potential tissue damage, or described in terms of such damage” (Merskey, 1979, IASP). Pain is
among the most common and distressing symptoms encountered by individuals, being one of the
most common conditions limiting efficiency and diminishing quality of life (Mert et al., 2013).
Pain serves an important vital function, i.e as a warning signal of tissue damage, resulting from
an accidental trauma, infection, or inflammation. The process through which potentially damaging
stimuli is detected is nociception. Thermal, chemical, or mechanical stimuli are strong enough to
be capable of causing tissue damage (i.e.; noxious or nociceptive stimuli), activate specialized
sensory neurons, commonly referred to as nociceptors, and to transmit the noxious signal to the
central nervous system (CNS).
Pain can be classified according to several variables, that includes; its duration (acute,
convalescent, chronic), its pathophysiologic mechanisms (physiologic, nociceptive, neuropathic),
and its clinical context (eg, postsurgical, malignancy related, neuropathic, degenerative) (Vadivelu
et al., 2009).
Pain is an early warning system that serves a protective function, which helps to limit exposure to
damaging noxious stimuli, thus detection of noxious stimuli to prevent further contact is described
as nociceptive pain (Woolf, 2010).
A second kind of pain is described as being adaptive and protective by increasing pain sensitivity
(low threshold to pain) to avoid tissue damage, thus allowing for proper healing by limiting
physical movement. This kind of pain is called inflammatory pain because it involves the
activation of the immune system by tissue injury (Woolf, 2010). The inflammation results in the
generation of a plethora of chemical agents that are intended to fight infection and assist in the
repair of injured tissue (White et al., 2010). Unfortunately, the body’s inflammatory response to
injury, or disease, is often disproportionate, resulting in pain that is sometimes of such severity
that it may hamper recovery or, in the longer term, result in disability (White et al., 2010).
The third type of pain is not adaptive, lacks any protective role and serves no useful purpose; it is
referred to as pathological pain (Meintjes, 2012). It may result from abnormal functioning of the
nervous system (Neuropathic pain) or pain elicited in the absence of any noxious stimuli
(Dysfunctional pain). It is characterized by intensified pain sensitivity, low threshold of pain in
the absence of any noxious stimuli. Pathological pain has clinical significance and accounts for
patients seeking medical attention (Woolf, 2010).
Classification of pain based on speed include fast/first pain (pin prick pain) which is a sharp,
localized and last no longer than the applied stimulus usually accompanied by withdrawal reflex
(Motoc et al., 2010). Secondary/second pain (true pain) is characterized as burning, aching, longer
lasting and mediated by inflammatory substances as a result of tissue damage (Motoc et al., 2010;
Meintjes, 2012).
Pain can also be classified as physiologic and clinical pain (neuropathic and inflammatory pain)
Clinical pain can arise either from damage to the nervous system (neuropathic pain) or
inflammatory states (inflammatory pain) (Cury et al., 2011).
Chronic pain can be described as pain said to have persisted for more than 30 days, 3 months, 6
months or 12 months. Chronic pain is sometimes referred to as persistent pain. It could be
described as pain that extends beyond the expected period of healing while acute pain is typically
temporary; resulting from traumatic tissue injury or infection and it is generally limited in duration
(Vadivelu et al., 2009; Meintjes, 2012). Chronic pain may have multiple causes and characterized
by gradual onset, may be symptom or diagnosis, serves no adaptive purpose and may be refractory
to treatment. Acute pain usually results from obvious tissue damage, has distinct onset, it is well
localized, resolves after healing, has a useful biologic purpose and responds effectively to
treatment (Vadivelu et al., 2009; Sweiboda et al., 2013).
Perception of pain involves the activation of peripheral nociceptors, generation of a nerve signal
and the transmission of this signal to the somatosensory cortex (Merighi et al., 2008). Conveyance
of nociceptive stimuli follow different pathways which consist at least three neurons; (i) a first
order sensory neuron in the dorsal root ganglia (DRGs); (ii) a second order neuron in the spinal
cord dorsal horn; (iii) a third order neuron which is generally located in the ventral posterolateral
nucleus of the thalamus (Merighi et al., 2008).
Peripheral nervous system
The pseudounipolar sensory neurons have a cell body in the dorsal root ganglion (DRG) or the
trigeminal ganglion and axonal projections that terminate in the periphery and the dorsal horn of
the spinal cord. Thus, nociceptive stimuli applied at the periphery result in release of excitatory
neurotransmitters in the CNS. The nociceptors are either small-diameter thinly myelinated A𝛿
fibers or unmyelinated C-fibers. The A𝛿 nociceptors are subdivided into the Type I nociceptors,
that respond preferentially to strong mechanical or chemical stimuli, but can also respond to high
(>50∘C) temperatures, and the Type II nociceptors, that respond preferentially to noxious thermal
stimuli over mechanical stimuli. Whereas most C-fiber nociceptors are polymodal, responding to
thermal, mechanical, and chemical stimuli, there are subpopulations of C- fiber that are selectively
heat sensitive or mechanosensitive (Ossipov, 2012).
Transduction Mechanisms
Many stimuli have been found to activate ion channels present on nociceptor terminals that act as
molecular transducers to depolarize these neurons, thereby setting off nociceptive impulses along
the pain pathways. Among these ion channels are the members of the transient receptor potential
(TRP) family. To date, the most studied member of the TRP family is the TRPV1 receptor
(Rosenbaum and Simon 2007).
Noxious signals are transduced into activation of sensory ion channels. The TRP channels are
seemingly the most investigated of these channels that contribute to nociceptive processing.
Opening the pore allows influx of Na+ and Ca2+, resulting in depolarization and generation of an
action potential. The TRPV1 channel, initially identified as the vanilloid receptor 1 (VR1), was
the first “pain” channel to be discovered and was characterized by its activation by noxious heat
(temperatures >43∘C), low pH (<6) and by capsaicin, the ingredient in hot peppers responsible for
the burning sensation. The TRPV1 channel is found on most heat-sensitive C and A𝛿 nociceptors.
Other channels involved in the transduction of pain include; the degenerin/epithelial Na+ channel
family (DEG/ENaC), the acid-sensing channels (ASIC).
Central Nervous System (CNS)
Ascending Pathways
The central terminals of the peripheral sensory fibers enter the CNS through the dorsal horn of the
spinal cord. The substantia gelatinosa, consisting of laminae I and lamina II outer, receives inputs
from myelinated A𝛿 nociceptors and the peptidergic unmyelinated C-fiber nociceptors, and most
of the nonpeptidergic C-fiber nociceptors terminate on interneurons of the inner lamina II. The
deeper laminae, III through V, receive inputs from the large-diameter myelinated A𝛽 fibers, which
normally transmit innocuous sensory inputs. Moreover, the wide dynamic range neurons of lamina
V receive inputs from nonnociceptive primary afferents and from A𝛿 nociceptors and also receive
indirect inputs from C-fibers terminating on lamina II interneurons via multisynaptic projections.
Neurons of laminae I and V project along the spinothalamic and spinoreticulothalamic tracts to
supraspinal sites such as the thalamus, parabrachial nucleus, and amygdala, where pain signals are
processed and sent on to higher cortical centers. The central terminals of the primary afferent
neurons release the excitatory neurotransmitters glutamate, substance P and CGRP to activate the
second order neurons of the spinal dorsal horn (Ossipov, 2012).
Descending Pathways
The periaqueductal grey (PAG) is the source of descending opioid-mediated inhibition of
nociceptive inputs. The PAG receives nociceptive inputs from the spinal cord through connections
with the parabrachial nucleus. Neuroanatomical studies revealed that the PAG sends projections
to noradrenergic pontine nuclei and the rostroventromedial medulla (RVM), resulting in inhibition
of nociceptive inputs at the level of the spinal cord by the release of norepinephrine and serotonin.
Bidirectional Pathways.
Along with the inputs from the PAG, the RVM also communicates with the noradrenergic nucleus
locus coeruleus and the thalamus and is considered to be the final common relay in descending
modulation of nociceptive inputs. Numerous early studies showed that electrical stimulation or
morphine microinjection in the RVM produced antinociception in animal models.
The RVM sends projections to the dorsal horn of the spinal cord and to the trigeminal nucleus
caudalis and forms synapses with interneurons or second-order neurons that send ascending
nociceptive projections. Several electrophysiologic and behavioral studies indicate that the RVM
produces “bidirectional” pain modulation, in that it can inhibit or enhance nociceptive inputs.
RVM stimulation facilitates, and higher levels of stimulation inhibits, nocifensive responses in the
rat. This property of the RVM may play a significant role in endogenous pain inhibitory systems
as well as maintenance of enhanced abnormal pain states.
Neuropathic pain
Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured
neurons and along nociceptive and descending modulatory pathways in the central nervous system.
The myriad neurotransmitters and other substances involved in the development and maintenance
of neuropathic pain also play a part in other neurobiological disorders.
The International Association for the Study of Pain (IASP) defined neuropathic pain (NP) as “
pain initiated or caused by a primary lesion or dysfunction of the nervous system. An alternative
definition was proposed by the IASP Neuropathic Pain Special Interest Group as pain emerging
as a direct consequence of a lesion or a disease of the somatosensory systems. Neuropathic pain is
generally characterized by the sensory abnormalities such as unpleasant abnormal sensation
(dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a
stimulus that does not normally provoke pain (allodynia) (Kaur et al., 2010)
Peripheral neuropathic pain is frequently observed in patients with cancer, AIDS, long-standing
diabetes, lumbar disc syndrome, herpes infection, traumatic spinal cord injury (SCI), multiple
sclerosis and stroke.
Mechanisms of Neuropathic pain
Neuropathic pain can result from nerve injury or disease affecting the peripheral or central nervous
system. Nerve damage may result from compression, ischemia, metabolic, traumatic, toxic,
infectious, immune mediated or even hereditary (Rathmell and Fine, 2012).
Peripheral Mechanisms
Neuropathic pain commonly affects the nociceptive pathways. Pathological changes have been
described in peripheral axons and dorsal root ganglia after nerve lesions and have been the
underlying the mechanisms of Neuropathic pain. This peripheral neuropathies that usually involve
selectively the large (Aα and Aβ) fibers do not normally cause pain while those affecting small
nerve fibers (c nerve fibres) are mostly painful (Raja and Sommer, 2014).
The following have reported to be involved in the mechanism of peripheral neuropathies:
1. Ectopic discharges in lesioned fibers and their corresponding ganglia.
2. Abnormal activity in axons undamaged by the lesion.
3. Phenotypic switch
4. Alterations in the expression and regulation of intracellular Ca2+ ion and modulatory
receptors on primary afferent terminals.
5. Neuroimmune interactions resulting in enhanced and/or altered production of
inflammatory signaling molecules.
6. Sensory-sympathetic coupling and other alterations in receptor signaling.
7. Disinhibition.
Ectopic Discharges in Injured Fibers
This may be described as spontaneous production action potential within the injured axon due to
alteration of voltage gated Na channels. These alterations may either lead to excessive activity or
loss of function. K+ ion hyperpolarization may also be involved leading membrane instability thus
spontaneous activity. Generation of spontaneous action potential may also occur in uninjured
adjacent nerve fibres as a result of a process called “ephaptic transmission”.
Abnormal activity in axons not damaged by lesions
Lesions that involve the distal to the dorsal root ganglia leads to Wallerian degeneration that
develops into inflammation, activation of macrophage and edema in the axon separated from the
cell body. All these encourage abnormal activities in the neuron which may involve overexpression
of TRPV1, neurochemicals, neutrophic factors (BDNF), pronociceptive neurotransmitters (CGRP)
and abnormal discharges from neurons.
Alterations in the Expression ion channels on Primary Afferent Terminals
Over expression of sodium channels in the dorsal root ganglia and around the injury site
contributes to spontaneous firing of nerve fibres. After nerve damage the increase in expression of
sodium channels may lead to ectopic discharge, lower stimulation threshold and subsequently
spontaneous pain. Several drugs such as carbamazepine, act through the blockade of sodium
Calcium channels and plays a role in neuropathic pain. Calcium influx is required for release of
neurotransmitters from nociceptive terminal. Thus overexpression of Ca2+ channel in the dorsal
ganglia can cause excessive release of pronociceptive neurotransmitters like glutamate which is
the major excitatory neurotransmitter. This calcium channels are primary targets of Gabapentin in
the treatment of neuropathic pain.
Neuroimmune Interactions Resulting in Enhanced and/or Altered Production of
Inflammatory Signaling Molecules
Nerve injury have been reported with increasing frequency to be associated with activation of
peripheral immune system which can alter sensory processing. Cytokines and chemokines like
interleukins (IL-1β, IL-6), TNFα etc released from immune cells can cause sensitization of
channels resulting in firing of nociceptors. These inflammatory cytokines play a crucial role in
inflammatory response after nerve injury through intracellular mediators like protein kinase C and
cAMP resulting in allodynia and hyperalgesia.
Sensory-Sympathetic Coupling (Sympathetic maintained pain)
Sympathetically maintained pain is pain that is enhanced or maintained by an abnormality in the
sympathetic nervous system. It occurs as a result of functional coupling of sympathetic nerves and
somatosensory nerves after nerve injury (Cohen and Mao, 2014). Sympathetically maintained pain
is most commonly associated with complex regional pain syndrome as well as postherpetic
Nerve growth factor (NGF) is crucial for the development and maintenance of small-diameter
somatic and sympathetic neurons most which have nociceptive function (McMahon and Bennet,
1994, Garcia-Larrea, 2014). NGF have been reported to induce neuronal sprouting and behavioural
signs of hyperalgesia in rats. Increased levels of NGF induces sympathetic neurons innervating
blood vessels in the dorsal root ganglia to send new sprouting branches towards the ganglion
neuron themselves. Norepinephrine produced in these fiber elicits abnormal discharges of
polymodal nociceptors, which also express abnormally increased levels of α-adrenoceptors in their
axon and soma. It has been reported nonlesioned unmyelinated nociceptors projecting into a
damaged peripheral nerve start to develop a low activation discharge and can acquire a novel
sensitivity to catecholamines
Adrenergic receptor–bearing neurons become so sensitive that they may respond to circulating
norepinephrine, and this mechanism might contribute to a number of “sympathetically maintained”
or complex regional pain syndromes previously called sympathetic dystrophy. These data also
support the therapeutic use of sympathetic block to treat complex regional pain syndromes.
Central Mechanisms
Within the central nervous systems the nociceptive system is also affected but it is mostly
associated with loss of thermoalgesic sensitivity. Hyperexcitability of second-order neurons,
selective neuronal loss, failure of inhibitory mechanisms, and structural reorganization have each
been suggested or experimentally demonstrated after lesions inducing Neuropathic pain.
The most crucial in the central mechanism of neuropathic pain is central sensitization, which is
defined as an abnormal increase of spontaneous and evoked activity of CNS nociceptive neurons.
Central sensitization exists at both the spinal and supraspinal levels, though studies in the spinal
dorsal horn have been extensively investigated. Central sensitization is mostly characterized by
primary hyperalgesia to mechanothermal stimuli at the level of the lesion, and secondary
hyperalgesia to mechanical stimuli over non-affected sites around the lesion.
Central sensitization is characterized by increases in the spontaneous activity, evoked responses
and of the receptive field, the presence of neuronal after discharge, and lowered response
thresholds of wide dynamic range (WDR) dorsal horn neurons. This in turn results in activation of
downstream signaling cascades that, by modulating NMDA receptor activity, enhance neuronal
excitability. These proexcitatory neuroplastic changes suggest that enhanced pain states are
mediated in part by development of long term potentiation.
The peripheral changes described above provide a number of plausible mechanisms leading to
sensitization including abnormal ectopic discharges in injured fibers, abnormal hyperexcitability
of noninjured C fibers. Repeated and exaggerated discharge of spinal nociceptive neurons via the
mechanisms described above gives rise to phenomenon termed long-term potentiation (LTP),
defined as an increase in synaptic efficacy (i.e., increased probability of fi ring) resulting from
coincident activity of pre- and postsynaptic elements. This phenomenon brings about a facilitation
of chemical transmission that lasts for hours in vitro and that can persist for periods of weeks or
months in vivo.
Once a nociceptive stimulus is transmitted to higher cortical centers, a series of events occurs that
results in the activation of inhibitory neurons that attenuate pain. At the spinal cord level, there is
increased release of GABA and glycine from primary afferent terminals, and enhanced activity in
inhibitory GABAergic and glycinergic dorsal horn interneurons. After nerve injury, a loss of
inhibitory currents occurs as a result of dysfunctional GABA production and release mechanisms;
impaired intracellular homeostasis from reduced activity of K+ Cl− cotransporter or increased
activity of Na+ K - Cl− cotransporter (or both), leading to increased Cl− levels; and apoptosis of
spinal inhibitory interneurons. Loss of inhibitory control has been shown to provoke tactile
allodynia and hyperalgesia, and to facilitate structural changes that increase transmission from Aβ
fibers that normally transmit non-painful stimuli to nociceptive specific secondary order neurons
in the dorsal horn.
Injury or damage to peripheral or central nervous systems results in maladaptive changes in
neurons involved in nociceptive processing that can cause neuropathic pain. It is a disease rather
than a symptom. A plethora of mechanisms have been identified to play crucial role in neuropathic
pain and some of them overlap despite the current evidence supports mechanism based treatments
these overlaps of mechanism makes it difficult because one treatment may not be effective in
managing the pain.
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