Comprehensive Analysis of Neuropathic Pain: Mechanisms and Management

This report provides a detailed examination of neuropathic pain, a complex condition arising from nerve injury and characterized by various cellular, peripheral, and central mechanisms. It explores the nociceptive system, including the role of nociceptors in detecting and transmitting pain signals, and delves into the development of neuropathic pain, discussing how nerve injuries lead to maladaptive changes in the nervous system. The report highlights the mechanisms of peripheral and central sensitization, the involvement of neuroglia, and specific examples such as diabetic neuropathy and postherpetic neuralgia. It also examines cellular mechanisms, including ion channel alterations, neurotransmitter changes, and gene expression modifications. Furthermore, the report discusses the roles of non-neuronal cells, such as glial cells and immune cells, in the pathogenesis and resolution of pain, and the potential for targeting these cells in treatment strategies. Overall, the report offers a comprehensive overview of the intricate mechanisms underlying neuropathic pain and its clinical implications, supported by relevant research and examples.

Running head: NEUROPATHIC PAIN
Neuropathic pain
Name of the Student
Name of the University
Author note

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1) Nociceptive system is a part of sensory nervous system that gets activated in response to
potentially harmful stimuli like intense chemical, thermal or mechanical stimulation
(types of stimuli). This system comprises of the receptors in periphery with molecular
properties that are specific for differential noxious submodalities coding, descending and
ascending tracts (Bastuji et al. 2014). This tracts control input into spinal cord dorsal horn
as supraspinal processing. This processing regulates nociceptive information integration
with autonomic function and sensory modalities. This result in sensory nerve cells
stimulation called nociceptors resulting in subjective pain experience in sentient
organisms. When there is potential damage detected by nerve endings, nociceptors found
on internal surfaces in skin (nociceptive system) like joint surfaces, periosteum and
internal organs response to damaging stimuli. Nociceptors (a type of receptor) send
‘possible threat’ signals to the brain and spinal cord. Nociceptors are a part of nociceptive
system comprising of specialized peripheral sensory neurons that alert the body towards
damaging stimuli through the detection of extremes in pressure, temperature and injury-
related chemicals (Gilron, Baron and Jensen 2015).
Nociceptors are the sensors of pain pathway that are activated by noxious stimuli called
nociception (physiological process) where body tissues are protected from damage.
Nociceptive pain arises when nociceptors are activated as per tissue type like visceral
(internal organs), superficial somatic (skin) or deep somatic
(tendons/ligaments/muscles/bones). Nociceptor stimulation threshold is below tissue
damaging intensity having heterogeneous properties that respond to multiple stimuli
called polymodal. Nociceptors are the nerve endings that are responsible for assessing the
body damage experiencing pain (Schaible 2015).

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2) Neuropathic pain develops after nerve injury when there are deleterious changes
occurring in injured neurons, nociceptive, descending modulatory pathways. Cellular,
neurophysiological and molecular mechanisms contribute to neuropathic pain. In the
recent studies, there are six classes of maladaptive changes in autonomic, peripheral and
central nervous system leading to neuropathic pain mechanisms (Nickel et al. 2012).
Central neuropathic pain is caused due to injury in spinal cord or multiple sclerosis.
Metabolic conditions like diabetes cause neuropathic pain being the most common cause
of pain. Other conditions like HIV-related neuropathies, herpes zoster infection, toxins,
nutritional deficiencies, physical trauma to nerve trunk or immune related disorders.
Peripheral mechanism includes a condition called ‘peripheral sensitization’. In this,
there is aberrant regeneration occurrence after peripheral nerve lesion. They unusually
become sensitive and there is development of spontaneous pathological activity,
heightened sensitivity to thermal, mechanical and chemical stimuli with abnormal
excitability (Cohen and Mao 2014).
Central mechanism comprises of dorsal horn of spinal cord neurons giving rise to
spinothelamic tract (STT) constituting of nociceptive major ascending pathway. Due to
spontaneous rise in activity of periphery mechanism pathway, there is development of
background activity increase, receptive field enlargement and increase in responses to
impulses of afferent neurons of STT neurons. This also includes innocuous tactile
stimulation called central sensitization that is important mechanism for the neuropathic
pain persistence (Vardeh, Mannion and Woolf 2016). Other mechanisms include:
peripheral nerve damage at the central level. There is afferent signal loss inducing

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functional changes in neurons of dorsal horns. Decrease in input of large fibre decreases
the interneurons activity that in turn inhibits the nociceptive neurons (afferent inhibition
loss). This loss in neuronal input in STT neurons is called ‘deafferentation
hypersensitivity’. Neuroglia also plays a major role in this sensitization inducing glia for
releasing proinflammatory glutamate and cytokines influencing neurons.
For example, in diabetic neuropathy, the actual mechanism of neuropathic pain is not
known. According to Schreiber et al. (2015) central sensitization occurs in
hypersensitivity of spinal neurons where there is increase in glutamate release from
primary efferents in spinal cord. Spinal N-Methyl-D-aspartate (NMDA) receptor
expression augmentation generates excitatory post synaptic response in lamina. The
signalling by cAMP response element-binding protein regulates activity of NMDA
receptor. Therefore, it is plausible that glutamate release and NMDA expression
contributes to hypersensitivity of spinal neurons leading to pain and sensorial
manifestations.
Another example, postherpetic neuralgia (PHN) a form of neuropathic pain is
characterized after herpes zoster rash resolution. It stems from central and peripheral
neurons being a byproduct of inflammatory/immune response that accompanies
reactivation of varicella zoster virus. PHN occurs in infection rash that stems from
damage of central and peripheral neurons that accompany infection reactivation and
migration. This results in low threshold for the action potentials, exhibition of
disproportionate stimuli responses and spontaneous discharge leading to peripheral
sensitization and neuropathic pain or without stimuli (allodynia). Patients experience

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abnormal sensations called paresthesias or dysesthesias (Mallick-Searle, Snodgrass and
Brant 2016).
Cellular mechanism occurs at the cellular level where the above mentioned phenomena
alter ion channel expression, neurotransmitter changes and receptors, gene expression
alteration in response to the neural input.
3) Non-neuronal cells like glial cells, immune cells, stem cells and cancer cells also play
significant roles in resolution and pathogenesis of pain. There is interaction of
nociceptive neurons and non-neuronal cells through secretion of neuroactive signalling
molecules modulating pain.
For example, glial cells activation is the key mechanism for neuropathic pain associated
with chronic conditions. Three types of glial cells develop and maintain chronic pain:
astrocytes and microglia in central nervous system (CNS), trigeminal ganglia and dorsal
root satellite glial cells. Glial activation mechanism where there is upregulation of
markers like glial fibrillary acidic protein (GFAP) and IBA1 and morphological changes
like proliferation, hypertrophy and glial networks modification.
In the glial mechanism, microglia and astrocytes are activated during neuropathic pain
leading to pro-inflammatory responses and pathological effects like neurotoxicity, hyper
excitability and chronic inflammation. The best mechanism that is characterized is
microglial purigenic receptors P2X4 activation by ATP that is secreted from astrocytes or
damaged neurons (Ji, Chamessian and Zhang 2016). This leads to the stimulation of
microglia releasing brain-derived neurotrophic factor (BDNF), activating neuronal
receptors. Finally, mediation of inhibitory signalling by γ-aminobutyric acid A (GABA A)
receptors diminishes and culminates enhanced pain.

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For example in preclinical models, in a study conducted by Bettoni et al. (2013) mice
were subjected to constriction injury of neuropathic pain and endogenous lipid
palmitoylethanolamide (PEA) induced treatment. After three days of nerve injury, there
was increase in mast cells, but no activation. After eight days, there was marked
activation of mast cells, but no increase in number. This showed that PEA delayed
recruitment of mast cells and protected degranulation and abolish with increase in nerve
growth factor in sciatic nerve. This preserved the nerve degeneration and reduction of
microglia activation in spinal cord. This finding showed that non-neuronal cells
(microglia) can be targeted for treatment of neuropathic pain.

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References
Bastuji, H., Frot, M., Mazza, S., Perchet, C., Magnin, M. and Garcia-Larrea, L., 2014. P994:
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Bettoni, I., Comelli, F., Colombo, A., Bonfanti, P. and Costa, B., 2013. Non-neuronal cell
modulation relieves neuropathic pain: efficacy of the endogenous lipid
palmitoylethanolamide. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug
Targets-CNS & Neurological Disorders), 12(1), pp.34-44.
Cohen, S.P. and Mao, J., 2014. Neuropathic pain: mechanisms and their clinical
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Gilron, I., Baron, R. and Jensen, T., 2015, April. Neuropathic pain: principles of diagnosis and
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Ji, R.R., Chamessian, A. and Zhang, Y.Q., 2016. Pain regulation by non-neuronal cells and
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Mallick-Searle, T., Snodgrass, B. and Brant, J.M., 2016. Postherpetic neuralgia: epidemiology,
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Nickel, F.T., Seifert, F., Lanz, S. and Maihöfner, C., 2012. Mechanisms of neuropathic
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Schreiber, A.K., Nones, C.F., Reis, R.C., Chichorro, J.G. and Cunha, J.M., 2015. Diabetic
neuropathic pain: physiopathology and treatment. World journal of diabetes, 6(3), p.432.
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