Causes and Genetic Variability in Neuropathic Pain
By JOYCE TANG


Neuropathic pain often manifests as the secondary symptom of a disease or physical trauma that induces lesions in the central or peripheral nervous system. The damage which causes neuropathic pain is often polyneuropathic in nature but may be mononeuropathic as well. Metabolic diseases like chronic alcoholism and diabetes induce polyneuropathy but different aspects of the nervous system are affected. Alcoholic neuropathy is characterized by a reduction in small nerve fibres where the remaining neurons become hypersensitized and fire in the absence of noxious stimuli.1 Similarly, diabetic patients experience neuropathic pain from small nerve fiber loss along with arteriovenous shunting that induces endoneurial hypoxia in the PNS.2,3 The physical trauma that results in phantom limb is polyneuropathic as well and is characterized by formation of neuromas, expansion of neuronal receptive fields and ultimately hyperexcitability of the spinal cord.4,5 Multiple sclerosis, an inherently neurological disease, likewise causes polyneuropathy as multiple axons in the CNS are demyelinated and the inhibitory functions of GABA interneurons are reduced to ultimately increase neuronal excitability.6 Carpal tunnel is among the fewer neuropathies that affects a single nerve but the pain symptoms induced are identical to disorders that affect multiple nerves.7 Although various causes may induce neuropathy, the development of neuropathic pain is not absolute. Alleles for specific genes are found to confer resistance or increase vulnerability to this syndrome. Investigation of the etiology of neuropathic pain and the genes that contribute to its onset will allow for better prevention and screening procedures to minimize the repercussions of neuropathy.


2 Causes



2.1 Polyneuropathic Causes


Polyneuropathy is a disorder where multiple nerves within the central or peripheral nervous system are damaged. It may be induced as the side-effects of drugs or be the secondary symptom of metabolic or neurological diseases; these would have implications on all the nerves within the body. It may also be a result of neuronal mal-adaptation after nerves are transected in physical traumas. Furthermore, it may be caused by infections that directly induce lesions on the nerves or initiate inflammatory responses that indirectly cause neuronal damage. Despite the different etiologies, the final pathophysiology is lesions along multiple nerves that may lead to neuropathic pain.




2.1a Chronic Alcoholism


Chronic alcoholism has global effects on the nervous system and may cause neuropathic pain.8 Alcohol is known to decrease thiamine absorption in the intestine, prevent hepatic thiamine storage and reduce the active phosphorylated form of thiamine in the bloodstream.9 The resultant thiamine deficiency leads to neuronal damage and neurodegeneration as it hinders the function of thiamine dependent enzymes, alters mitochondrial function and impedes oxidative metabolism.10 When lesions are induced along peripheral nerves, neuropathic pain may develop as the damaged nociceptive C and Aδ fibers become hyersensitive and spontaneously discharge in the absence of noxious stimuli.11 Ethanol induced neuropathic pain is also associated with proliferation and activation of microglia at the dorsal root ganglion.12 As microglia is involved in regulating neuronal functions, more microglia may increase the firing of nociceptive fibers and amplify the transmission of noxious stimuli to the spinal cord.12 Furthermore, ethanol has direct neurotoxic effects as it is oxidized into acetaldehyde, which increases the amount of reactive oxygen species (ROS) that subsequently induces oxidative stress on neurons.13 This damages the neurons' lipids, proteins and DNA which ultimately results in cell injury or death.8 The consequence is typically small fiber loss followed by a subsequent reduction in large myelinated fibers in chronic conditions.1 This induces lesions along the nerves which then leads to neuropathic pain.

ethanol_neurowiki.jpg
Figure 1. Ethanol and acetaldehyde induce damage to cell lipids and DNA and inhibit cellular repair systems.


2.1b Diabetes


Figure 2. The epineurium and endoneurium are connective tissue sheaths that surround the nerve bundles. The epineurium is the green outermost layer in the illustration while the endoneurium is the red sheath underneath the epineurium.
Figure 2. The epineurium and endoneurium are connective tissue sheaths that surround the nerve bundles. The epineurium is the green outermost layer in the illustration while the endoneurium is the red sheath underneath the epineurium.

Diabetes is a metabolic disease which causes polyneuropathy in the peripheral and central nervous system.2,15 Sensory nerves are most vulnerable in this disease as they are particularly sensitive to elevated glucose levels.3 The pathogenesis of painful diabetic neuropathy is multifaceted and one mechanism may involve the increased production of reactive dicarbonyls within the neuron.35 This compound prevents normal cellular activities by modifying intra- and extra-cellular proteins, nucleic acids and lipids and is the by-product of processes which are accelerated in hyperglycemic conditions (lipid peroxidation, glycolysis and degradation of glycated proteins).35 As a result, the sensory neurons in diabetic patients accumulate more harmful reactive dicarbonyls and begin to discharge aberrantly, leading to neuropathic pain.35 Abnormal haemodynamics in the epineurium and endoneurium connective tissue sheaths that surround the nerve bundles is another source of nerve pain.3 Sympathetic denervations, characteristic to diabetes, cause arteriovenous shunting in the endoneurium which diverts blood to the epineurium.2,3 As a result, the endoneurium that is directly contacting the nerves becomes hypoxic and stimulates neuropathic pain.3 Similarly, small fiber loss typical of diabetes also contributes to painful sensations as it causes lesions in the peripheral nerves.14 Another abnormality implicated in painful diabetic neuropathy is elevated thalamic perfusion.15 Since the thalamus is the relay center for somatosensory information, elevated perfusion may represent an increase in neuronal activity within this region.15 The neuropathic pain may be the exaggerated sensation that results from an amplification of non-noxious somatosensory information that is relayed to the cerebral cortex.15


2.1c Phantom Limb


Severed peripheral nerves are the primary wounds after an amputation but overtime, the central nervous system also suffers the consequences of aberrant sensory input and phantom limb pain develops. Initially, the proximal region of severed nerves will form neuromas which have increased expression of sodium channels on their surfaces.7 As more neuromas develop, the nerves become hyperexcitable and spontaneously discharge onto the dorsal horn.16 This is followed by central sensitization where additional neurons within the spinal cord project into lamina II of the dorsal horn, thereby amplifying the neuronal receptive field and transmission of stimuli.16 The combination of sensory neuron hyperexcitability and central sensitization then results in exaggerated and spontaneous nociceptive sensations. It should be noted that neuropathic pain resulting from nerve transections in physical traumas (without the amputation of a limb) follows the same process described above.

Furthermore, the brain is also implicated in the development of neuropathic pain. The severity of phantom limb pain is positively correlated with the degree of cortical reorganization where the neighboring somatosensory and motor areas invade the region that originally corresponded with the amputated limb.17 Although cortical reorganization is frequently found in patients with phantom limb pain, it is still unclear how it contributes to this syndrome.17 However, phantom limb pain is hypothesized to be the result of discordance between the motor and somatosensory cortices. Normally, efferent motor commands are dampened by afferent sensory feedback which confirms that the intended motion was executed.18 However, in patients with phantom limb pain, activation of motor regions corresponding to the amputated limb is not inhibited by somatosensory information that confirms the motion.18 After prolonged activation of the motor region, the phantom limb becomes overflexed and induces the pathological cramping pain.18


2.1d Multiple Sclerosis


Figure 3. Multiple Sclerosis is characterized by demyelination.
Figure 3. Multiple Sclerosis is characterized by demyelination.

Multiple sclerosis is a neurological disease that induces polyneuropathy in the central nervous system.19 The onset is characterized by focal lesions in the brain and spinal cord which subsequently attract immune cells that induce inflammation along the axons.6 The T cells recruited to the site directly bind to myelin epitopes and this activates macrophages that will phagocytose the myelin sheath.6 Moreover, T cells and macrophages release free radicals, nitric oxide and glutamic acid that target the glial cells that produce myelin.6 Free radicals induce oxidative stress which eventually damages cellular components like DNA, lipids and proteins8. Nitric oxide causes permanent conduction block in demyelinated cells and glutamic acid induces excitotoxicity.20,21 In combination, these substances lead to neuroaxonal damage and demyelination. Damage to the axons may cause neurons to fire ectopically, resulting in spontaneous sensations of pain.11 Furthermore, lesions in the spinal cord may reduce the inhibitory functions of GABA interneurons, resulting in hyperexcitability of the central nervous system.22 Consequently, non-noxious stimuli would be perceived as neuropathic pain.


2.1e Other Polyneuropathic Causes



The etiologies described above are not exhaustive. Other polyneuropathic causes include herpes zoster, mastectomy, hypothyroidism, beriberi, trench foot, traumatic brain injury, epilepsy, Parkinson's disease, Guillain-Barré syndrome...etc.35




2.2 Mononeuropathic Causes


Mononeuropathy is characterized as damage induced on a single nerve. Compared to polyneuropathy, the etiologies which cause mononeuropathy are less varied, with the majority being a single nerve transection or chronic nerve compression. The single nerve transection may be the result of surgery or physical trauma where the pathophysiology leading to neuropathic pain is identical to the increase in sensory neuron excitability and central sensitization found in phantom limb pain. The second etiology, chronic nerve compression, results from disorders where an abnormal tissue mass exerts pressure onto a nerve.



2.2a Chronic Nerve Compression

Figure 4. The carpal tunnel is a passageway between the carpal bones of the wrist and the transverse carpal ligament. Carpal Tunnel Syndrome occurs when the medial nerve inside the passageway is compressed within the confined space.
Figure 4. The carpal tunnel is a passageway between the carpal bones of the wrist and the transverse carpal ligament. Carpal Tunnel Syndrome occurs when the medial nerve inside the passageway is compressed within the confined space.


A common etiology for Chronic Nerve Compression (CNC) is Carpal Tunnel Syndrome which is characterized by compression of the medial nerve.7 The medial nerve and the flexor tendons of the fingers are accommodated within a bone and ligament passageway called the carpal tunnel.7 This passageway may narrow and exert pressure upon the medial nerve.7 Volumetric changes in the tendons and tendon sheathes may also press the nerve against the inner walls of the carpal tunnel.7 The resultant nerve compression induces concurrent local demyelination and remyelination which result in abnormally thin myelin sheaths along the medial nerve.23 The impulse transmission and nerve conduction consequently becomes less effective and persistent compression results in direct axonal damage.23 The medial nerve which transmits sensory information from the thumb, index, middle and ring finger then aberrantly discharges and may induce spontaneous sensations of pain.7

Chronic Nerve Compression (CNC) is also prevalent among cancer patients where a tumor presses onto a single nerve.24 Although cancer and Carpal Tunnel Syndrome are very different etiologies of neuropathic pain, they both induce chronic nerve compression which results in local demyelination and axonal damage.24

Schwann_Cells_demyelinated.jpg
Figure 5. Chronic nerve compression (CNC) induces concurrent local demyelination and remyelination which result in abnormally thin myelin sheaths at the site of compression. The arrow to the right points to a localized area where CNC had reduced the thickness of the myelin sheath.





3 Genetic Variability


3.1 Genes that confer Resistance to Neuropathic Pain Development




3.1a APP and SOD-1 Overexpression


Amyloid precursor protein (APP) and super oxide dismutase-1 (SOD-1) overexpression is characteristic in Down's Syndrome (DS) as those genes are encoded on three copies of chromosome 21 in those patients.25 Although Down's Syndrome patients are more vulnerable to physical trauma, they are less susceptible to neuropathic pain.26 Transgenic mice studies that induce APP and SOD-1 overexpression produce mice with symptoms analogous to Down's Syndrome and the mice exhibit relatively less autotomy behavior after sensory nerve transections.26 Autotomy in animals is an indicator of neuropathic pain so its reduction in mice with excess APP and SOD-1 suggests that these genes protect individuals from neuropathic pain development.26 Interestingly, neuroma formation is more common at lesion sites but this would usually result in the hyperexcitability and spontaneous neuronal firing that forewarns the onset of neuropathic pain.26,7 Therefore, overexpression of APP and SOD-1 does not reduce neuroma formation but it diminishes the sensitivity to painful stimuli induced by neuromas at the severed nerves.26


3.1b GCH1 haplotype


GTP cyclohydrolase is the rate limiting enzyme in the production of tetrahydrobiopterin (BH4) which subsequently serves as a cofactor involved in nitric oxide synthesis.27 Nitric oxide is implicated in the release of prostaglandins and cytokines during the immune response to a nerve injury and this sensitizes the nociceptor terminals to promote hyperexcitability.28 BH4 also directly acts on the dorsal root ganglion by activiating Ca2+ channels to induce spontaneous sensory nerve discharge onto the spinal cord.28 Excessive amounts of BH4 and nitric oxide contribute to neuropathic pain.

A specific GTP cyclohydrolase 1 haplotype is found to be expressed at lower frequencies within the body so less of the enzyme would be present around the site of nerve injury.28 As a result, less BH4 and nitric oxide are produced downstream of the pathway so their detrimental effects on neurons are reduced.28 Individuals with this GTP cyclohydrolase haplotype are therefore more resistant against the development of neuropathic pain.28



3.2 Genes that confer Vulnerability to Neuropathic Pain Development




3.2a KCNS1 allele rs734784


Voltage-gated potassium channels are essential in neuronal discharge as they maintain the resting membrane potential and affect the frequency and shape of action potentials.29 These channels are tetramers composed of alpha and beta subunits where the alpha subunits in the Kv9 family are incapable of forming functional channels by themselves and can only serve to modulate other potassium channel subunits.30,31 Notably, the KCNS1 gene encodes for a specific alpha subunit within the Kv9 family that suppresses the potassium currents mediated by the Kv2 and Kv3 alpha subunit families.31 This gene is constitutively expressed in the dorsal root ganglia of healthy patients but is down-regulated upon peripheral nerve transection, suggesting a contribution to neuropathic pain by allowing hyperexcitability in severed sensory neurons.31 Furthermore, a single nucleotide substitution in the rs734784 allele that incorporates an abnormal valine into the gene is associated with lower pain thresholds in healthy patients and higher risks of developing neuropathic pain.31 Individuals with one or both copies of the rs734784 allele are predisposed to neuropathic pain, with homozygous individuals being the most susceptible to its development.31


3.2b CACNG2 Polymorphism

stargazin.jpg
Figure 6. Stargazin promotes the delivery of AMPA receptors to the postsynaptic membrane.

CACNG2 gene encodes for a protein that affects susceptibility to neuropathic pain. The protein, stargazin, is a transmembrane subunit in neuronal voltage-gated Ca2+ channels which modulate ionic conductance.32 Increased cytosolic Ca2+ influx would initially excite the neurons but Ca2+-gated K+ channels are subsequently activated to result in membrane hyperpolarization.32 As a consequence, less sensory information passes into the spinal cord and this ultimately suppresses the sensation of pain. Furthermore, stargazin is involved in trafficking AMPA glutamate receptors to neuronal membranes.33 Since the activation of AMPA receptors result in excitatory neurotransmission, the insertion of excess AMPA receptors on sensory postsynaptic neurons may lead to hyperexcitability and spontaneous neuronal discharge.32 However, excess AMPA receptors on presynpatic
inhibitory neurons have the opposite effect and may increase inhibition on the sensory neurons that synapse onto the spinal cord.32 Nonetheless, the overall effect of the CACNG2 wild-type is reduced susceptibility to neuropathic pain.32

Mice studies investigating the effects of the CACNG2 gene suggest that single nucleotide polymorphisms result in differential susceptibility to developing nerve pain.32 Specifically, a group of naturally occurring CACNG2 hypomorphic mice shows increased autotomy (a hallmark of animal neuropathic pain) after a nerve transection and increased susceptibility to chronic pain.26,32 Similarly, human cancer patients with certain CACNG2 polymorphisms report higher incidences of developing neuropathic pain as well.32



Videos




Video 1. One minute overview of neuropathic pain by Dr. David O'Gorman. [40]




Video 2. One minute overview of Carpal Tunnel Syndrome. [41]



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