Mechanisms+of+Neuropathic+Pain

By: Shun-Hsiang Hu toc
 * Neuropathic Pain – Mechanisms **

=**Overview – Mechanism of Neuropathic pain **=

The mechanism underlying neuropathic pain is complex yet it is essential for the perception of pain. The onset for neuropathic pain is due to the lesions in the somatosensory system induced either in the peripheral or the central part of the nervous system. Hyperalgesia, an increase in sensitivity due to enhancement of the function of the neurons in the pathway, is caused by the increase in release of excitatory neurotransmitters such as glutamate or substance P and the synaptic efficacy. This phenomenon that occurs in both the peripheral and central nerve is thought to cause the persistence of the chronic neuropathic pain. While different neurotransmitters play key roles in the system, receptors and enzymes such the AMP-activated protein kinase (AMPK) activators also play critical roles in the sensation of pain and the regulation of the mechanisms. Over the years, clinical studies have explored the different bases of neuropathic pains from post-surgical cases to diabetics; specifically, one recent neuropathic pain study focuses on pain inducing a-toxin and the convergent evolution behind the mechanisms of neuropathic pain. Furthermore, the mechanism behind the immunity of neuropathic pain is also one of the current topics which interest researchers.

=1. Peripheral & Central Nervous system general overview =

**1.1 **//Receptor, neurotransmitters, enzymes, channels //
 Signs of neuropathic pain can be related to the tingling, inching, and burning sensations. The locality of the pain is also important indicators to determine the origin and the sprout of the pain, usually from the peripheral nerves and then extending to the central nerves. However, these sensations of pain can be furthered analyzed on the molecular basis through signal transduction. Some key players involved during pain signalling may include the release of neurotransmitters and neuropeptides such as glutamate and substance P; receptors such as the AMPA, NMDA, and Glu receptors; the enzymes such as AMP-activated protein kinase activators ; and the gate keepers which include the sodium and calcium channels ** [1]. **

 In addition, brain-derived neurotrophic factors (BDNF), nerve growth factors (NGF), and glia-cell derived neurtrophic factors (GDNF) also influence neuropathic pain. Neurotrophins, which are usually involved in the development of sensory systems and neuronal plasticity, can mediate and indicate the underlying mechanisms of neuropathic pain. Moreover, a number of other neuropeptides such as endomorphins, dynorphin A, and galanin can also induce nerve stimulation. The modulation and alteration of each player in the signal transductions cascade contribute to the primary afferent hyperexcitability; all in all, leading to the perception of neuropathic pain.



1.2 Pre/post – synaptic mechanisms
  The mechanism of neuropathic pain can be first evaluated at the pre- and post- synaptic regions. In a normal undamaged neuron, Glutamate, which is an excitatory neurotransmitter, is usually restrained by the inhibitory g-protein coupled receptors (ie. adenosine and GABA-B receptors) ** [1]. **However, once an injury has occurred on the site of peripheral nerves, anatomical changes can take place in excitatory synaptic transmission to upregulate the activity of postsynaptic glutamate AMPA receptor-mediated response and the glutamate release. The increased glutamate release leads to the amplification of neuronal firing rate and depolarization resulting in the sensitisation of the nerves to produce pain **[4] **. The upregulation of GluR1 receptors in the post-synapse is a well defined marker for the augmentation of glutamate release **[5] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The damages to the peripheral sensory neurons consequently affect the central nervous system through further release of glutamate, substance P and brain-derived neuropathic factor (BDNF)in the primary nociceptor afferent at the central terminal. Substance P binds to the neurokinin 1 (NK1) whereas the BDNF binds to the tyrosine kinase receptor (trk) on the post synaptic membrane**<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[1] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. The gradual depolarization and phosphorylation of the NMDA glutamate receptor in the post-synaptic surface is followed by the increase in calcium concentration and cAMP subsequently activates the protein kinases C (PKC) **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[1] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. Furthermore, the NMDA receptor will also stimulate the production of nitric oxide synthetase to promote other excitatory amino acid and neuropeptide release from the pain fibers. The overall signalling cascade sensitizes the dorsal horn by spontaneous activation and contributes to the modulation of pain.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">1.3 Disinhibition mechanisms
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The descending pain-control pathways are neural pathways belonging to the central nervous system which modulates the signalling of pain and in turn the perception of pain. When the inhibitory interneurons are injured, the inhibitory responses which are usually suppressed are altered resulting in spontaneous firing of the neurons and increase the sensitivity. A study conducted on the differentiated neuronal circuitry in allodynia patients show that the inhibitory transmitters such as γ-aminobutyric acid (GABA) receptors and endogenous opioid peptides is downregulated in the dorsal horn whereas the endogenous inhibitors of opiodergic transmission (cholecystokinin) is upregulated**<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[3] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Knowledge on the disinhibition pathway of pain is beneficial for the development of new treatments for inflammatory response in neuropathic pain patients. One study looks at glycine receptors as a crucial transmitter since it serves as a novel target for the development of analgesic drugs **<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[3] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. Given that glycine receptors plays a role in the gating of sensory throughput into the spinal cord, specifically the dorsal horn, the disinhibition transmission can be used to regulate signals to the brain.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> [|Central Nervous System Pain Mechanism] media type="youtube" key="FbJF8gijf8E" width="425" height="350" align="center"

=<span style="font-family: 'Times New Roman',serif; font-size: 16px;">2. Convergent evolution of pain-inducing toxins =

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">2.1 Venom inducing mechanisms (CvIV4)
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Scorpion toxin can be diverged into the ‘Old’ and New’ World toxins and also into classes alpha- and beta- toxins. The venom from the scorpion species (//<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">C. vittatus //<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">) contains a pain-inducing a-toxin (CvIV4) which can slow the fast inactivation of voltage-gated sodium channels. The toxin produced from these animals can recognize and bind to the sodium and potassium channels to alter its gating mechanisms. First of all, the binding of the toxins to sodium channels can cause prolonged opening of sodium through the pore since the toxin makes the channel activate near resting membrane potential followed by the inhibition of fast inactivation. Secondly, the toxin also binds to the potassium channel and blocks the flow of potassium ion to prevent the potential to drop back to resting potential after depolarization. The effect of the toxin alters the neuronal function and cause hyperexcitability and sensitises the nerves to cause pain. Even though the different categories of scorpion toxins (‘Old’ & ‘New’ World a-toxin) have diverse genetic sequences, the mechanistic activity still remain similar illustrates the convergent evolution of the pain-inducing pathways.

=<span style="font-family: 'Times New Roman',serif; font-size: 16px;">3. Immunity mechanism for pain = <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">3.1 Inflammatory mediators (IL-1β, TNFα)
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Inflammation in the nerve can be an important indicator to understand neuropathic pain. Inflammation not only effects the damaged nerves but also activating the surrounding receptors by the neuropeptides (Substance P and Prostaglandins)3. Innervations of nerve and sensitisation can be achieved through various methods. Tumor necrosis factor (TNF) protein is one of the players involved during protein inflammation; this protein can insert sodium channels into the lipid layers to increase chance of depolarization. Furthermore, proinflammatory cytokines such as interleukin-1 and 6 can also prolong activation of calcium and sodium channels3.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> A cascade of signalling is proposed in an inflammatory signalling event. After Schwann cells denervate, leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 (MCP-1) is secreted followed by cytokine IL-1β1. The cytokine release would increase the nerve growth factor (NGF) which lead to the sensitisation of the nerve to provoke pain. Other factors such as TNFα, IL-1 and IL-6 can also initiate and attenuate hyperalgesia pain after inflmmation.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">3.2 Voltage-gated calcium channel inhibition (CaV2.2)
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Immunity of pain can be controlled by the voltage-gated calcium channel (CaV2.2) inhibitors. In one study, neuropathic hypersensitivity was suppressed through the inhibition of collapsin response mediator protein 2 (CRMP-2) binding in the CaV2.2. The decrease activation lead to the reduction in channel functioning, thereby reducing and alleviating the neuropathic and inflammatory hypersensitivity**<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[19] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. Understanding the mechanism to immunity is advantageous to the development of new techniques and drugs to treat neuropathic pain; therefore, researches that pertain to the mechanisms of neuropathic pain are.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">3.3 AMP-activated protein kinase (AMPK)
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> ERK and mTOR are pathways that sensitises the neurons. In a recent immunostudy that explores sensitisation, the AMP-activated protein kinase (AMPK) activator is known to inhibit ERK or mTOR to control the pain sensation. Interleukin-6 (IL-6) is also a factor in incision-induced pain which works with the ERK signalling pathway ** [2] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. The study showed that by inhibiting the IL-6 mediated signalling to the ERK with AMPK, allodynia could be blocked. Thereby, the ERK pathway is essential for the treatment of neuropathic pain.

=<span style="font-family: 'Times New Roman',serif; font-size: 16px;">4. Case studies =

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">4.1 Chronic post-surgical pain (CPSP)
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> media type="youtube" key="6Nox7sb8GTA" width="425" height="350" align="right" <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The persistent pain after a surgical wound has healed is known as the post-surgical pain. This phenomenon is caused by the damage in the major peripheral nerve pathway which heightens the sensitivity; hypersensitivities may include hyperalgesia, hyperpathia, and allodynia. The hypersensitivities are mainly due to the alteration in the trafficking of sodium channels which contribute to the constant firing of action potentials at the site of the injured primary sensory neurons. The stimulus-evoked hypersensitive area can also phosphorylate the nearby ion channels and receptors in the non-injured areas which surround the injured site to be activated. The upregulation of the α2δ subunit of the voltage-gated calcium channels and other binding sites all play a role in the lowering of the pain threshold which causes central sensitisation. As a result, the sensitisation or hyperexcitability in the nerve would cause the overall feeling on pain.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **Hyperalgesia**– The increase in sensitivity to pain due to the damage to the peripheral nerves **<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[9] ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Hyperpathia **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">– A neural disorder where patients feel an exaggerated level of pain (do not confuse with Allodynia) **<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[9] ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **Allodynia**– A type pain caused by a stimulus that normally does that arouse pain (do not confuse with hyperpatia) **<span style="background-color: white; font-family: Arial,sans-serif; font-size: 9pt;"> [9]. **

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">4.2 Diabetics
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Neuropathic pain exists in diabetic patients as a side effect is known as the diabetic neuropathy. In diabetic patients, hyperglycemia can cause high sugar deposit in the blood vessels and lead to modifications in the structure and function throughout the body. However, one of the detrimental causes of diabetes is the nerve damaging aspect. Diabetic neuropathy is associated with the elevated thermal and mechanical sensitivity by the spontaneous firing of the neurons caused by the increased expression in the AMPA and NMDA receptors to the cell surface <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">For instance, diabetic patients have upregulated and ectopically expressed transient receptor potential channel TRPV1, also known as the vanilloid receptor, sensitized by inflammatory mediators (prostaglandin and bradykinin) **<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[3] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. The activation of this particular channel is normally caused by capsaicin which stimulates noxious heat sensation3. The release of neurotransmitters as well as modulators such as glutatmate, calcitonin, nitric oxide, and somatostatin are good indicators of the presence of capsaicin. The spinal dorsal horn neurons activated by the capsaicin can activate the protein kinase A (PKA) and protein kinase C (PKC) to trigger the phosphorylation of AMPA receptor (GluR1) and the NMDA receptors**<span style="background-color: white; font-family: Arial,sans-serif; font-size: 80%; vertical-align: super;">[12] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. Moreover, capsaicin can also induce phosphorylation of enzymes and transcriptional factors (calcium/calmodulin-depedent protein kinase II) to evoke Calcium ion movement followed by the opening of voltage-gated sodium channels leading to action potentials. As a result of the capsaicin mechanism, sensitisation occurs to produce neuropathic pain in various body parts.

<span style="font-family: 'Times New Roman',serif; font-size: 16px;">4.3 Alcoholism
<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Alcoholism may induce neuropathic pain through the harmful toxins directly poisoning the nerves or indirect malnutrition issue such as vitamin and thiamine deficiencies. Although the pathobiology aspect of the association between alcohol and neuropathic pain may not be fully understood, many explanations have been proposed. Due to long term alcohol consumption, oxidative stress may cause the metabotropic glutamate 5 (mGlu5) receptors in the spinal cord to be activated and also the sympathoadrenal pathway to be stimulated which causes the increased secretion of epinephrine and/or norepinephrine at the nerve endings.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> One study shows the mediation of the protein kinase C (PKCε) to the effect of ethanol treated rats. The results portray the attenuation of a hyperalgesia in chronic ethanol treated rats which had PKC inhibitors. Furthermore, the inhibition of mGlu5 receptors also implicated the attenuation of neuropathic pain-like state by the decrease in threshold of the receptors. The related mechanism between alcoholism and neuropathic pain is currently ambiguous, but the animal experiments can narrow down the search for candidate receptors or neurotransmitters responsible for the pathway.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Concluding Remarks **

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Since mechanisms underlie the basis of functionality, understanding the mechanisms can help scientists comprehend more about neuropathic pain. However, the main purpose to understanding the mechanisms of neuropathic pain is for the development of treatments that can target and relieve neuropathic pain. Overall, many mechanisms are still poorly understood and the mechanisms of diseases associated with neuropathic pain have not been fully identified. Therefore, more research is being conducted in this field to help prevent and treat neuropathic pain.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **__<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">References: __**