Rare Pain Disorders: What They Can Teach Us
How would you describe the experience of pain to someone who has never felt it? It is an experience you are probably very familiar with, but one that is challenging to put into words. From the unpleasant throbbing of a stubbed toe to the intense agony of a severely broken bone, itis something we all wish we could live without. For a select few in the human population, life without pain is a reality. There are a variety of disorders that involve reduced or complete lack of ability to perceive pain, each involving different genes, sensory pathways, and symptoms. One of these is congenital insensitivity to pain (CIP), an extremely rare disease. The exact prevalence of CIP is unknown, but at least 20 cases have been described in scientific literature.1 The first case, published in 1932, depicted the “Human Pincushion” – a performer who allowed people to stick pins in his body.2 In his lifetime, he had broken his nose, cut himself several times with a hatchet, and shot himself in the finger with a pistol, but did not experience pain in any of these situations.2
“CIP is described as an impaired ability to perceive the type, intensity, and quality of painful stimuli.”
CIP is described as an impaired ability to perceive the type, intensity, and quality of painful stimuli.3 Despite its unpleasantness, pain is adaptive – it alerts us to things that are going wrong in our bodies. Because of this, people with CIP often die in childhood because they fail to notice injuries and illnesses.3 Mutations in a gene called SCN9A have been implicated as a likely cause of CIP.4,5 The SCN9A gene encodes a protein that is a subunit of the NaV1.7 sodium channel.1 Sodium channels are a key factor in the transmission of electrical signals along nerves.1 The NaV1.7 channel is expressed by a specific type of sensory neuron located in the dorsal root ganglion (DRG) of the spinal cord. DRG neurons can be sensitive to various types of sensory information, but NaV1.7 is mainly present in those that are nociceptive, or pain-sensitive.6 In a healthy person, sensory information travels from the body’s periphery through the DRG and spinal cord to the brain. However, when there is a loss-of-function mutation in SCN9A, it produces incomplete NaV1.7 subunits that cannot be incorporated into NaV1.7. Thus, the patient will not have any working NaV1.7 channels in their DRG neurons, which means that sodium cannot enter these neurons when it needs to and pain signals cannot be transmitted properly from the site of injury to the brain.1
“Perhaps not surprisingly, SCN9A and NaV1.7 are also involved in rare diseases of the opposite nature – diseases whose primary symptom is severe pain. ”
Perhaps not surprisingly, SCN9A and NaV1.7 are also involved in rare diseases of the opposite nature – diseases whose primary symptom is severe pain. Primary erythermalgia (PE) is an autosomal dominant inherited disorder.7 It is characterized by red, warm, and painful extremities.8 The pain is provoked by exercise, prolonged standing, and exposure to warmth, and is alleviated by cold.7 It often severely affects patients’ happiness and quality of life.8 Paroxysmal extreme pain disorder (PEPD) is also an autosomal dominant disorder; it is characterized by sudden episodes of pain at different body sites, accompanied by skin flushing.7 Data from several sources suggests that mutations in SCN9A cause PE.9-11 Unlike the loss-of-function mutations that cause CIP, PE is likely caused by a gain-of-function mutation that makes the NaV1.7 channel abnormally excitable.9 Specifically, it makes the channel slower to deactivate and allows it to become activated by smaller stimuli than normal. Increased excitability in pain-sensitive DRG neurons would result in extreme sensitivity to pain.7 Similarly, PEPD is linked to a gain-of-function mutation in SCN9A. These mutations cause PEPD by producing NaV1.7 channels that do not close properly when turned off. This results in increased sodium flow into the neurons, which causes enhanced transmission of pain signals in DRG neurons.12
“This has led many scientists to theorize that NaV1.7 could potentially be targeted in pain treatment.”
It is clear that the SCN9A gene and the NaV1.7 channel are key in the process of pain perception. This has led many scientists to theorize that NaV1.7 could potentially be targeted in pain treatment. Currently used pain therapeutics are flawed for a number of reasons, including their limited efficacy, side effects, and potential for abuse13; the search for better ways to treat pain is a rapidly expanding field in medical research. Several classes of analgesics act as sodium channel blockers. However, none of them have high specificity, and therefore may inhibit many more sodium channels than just NaV1.7.7 In an ideal scenario, a therapy would prevent the transmission of pain signals without interfering with other nervous system functions. Thus, the development of a drug that specifically blocks NaV1.7 channels was identified by many authors as a promising area of research.5,7
A study published in January 2017 takes a step in this direction. Protoxin II is a protein found in tarantula venom; it is known to selectively block NaV1.7.13 The researchers used Protoxin II as a template to engineer a library of NaV1.7 blockers. They identified JNJ63955918 as a “potent, highly selective” NaV1.7 blocking peptide. In rats, JNJ63955918 resulted in insensitivity to pain similar to that observed in humans with CIP.13 Another study, published in February 2018, examines the use of another NaV1.7 blocker, called Huwentoxin-IV (HWTx-IV), in pain management. This molecule is also derived from the venom of a tarantula species and is known to selectively block NaV1.7 channels.14 The scientists developed a modified version of the HWTx-IV molecule, called ssHwTx, that could be stably produced in human cells. Next, they bioengineered a cell line called “AromaCell” from human embryonic kidney cells. In these cells, they developed a way to link ssHwTx production to an olfactory receptor that responds to the smell of spearmint. The idea is that AromaCells can be implanted in chronic pain patients, and they will release ssHwTx when the patient smells spearmint.14
To study whether ssHwTx was effective in managing pain, the scientists used a mouse model. Mice who were implanted with ssHwTx-secreting cells showed significantly reduced chronic pain behavior (such as licking and biting) when compared to control mice, who received non-ssHwTx-secreting cell implants. ssHwTx resulted in suppression of pain over 9 days – a massive effect when compared to the 6-hour time frame of standard pain medications.14 It did not cause any cardiovascular, locomotor, or behavioral side effects in the mice.
AromaCell is an ingenious method of drug administration. Cells that continuously release ssHwTx are not ideal, because pain is adaptive and we don’t want to eliminate it entirely. However, intermittently re-implanting cells in patients for pain relief would be an inefficient and invasive process. Stimulating ssHwTx release with the smell of spearmint allows for the quick and easy release of pain medication when it is needed. Although further research is required, the promising results from these studies clearly demonstrate the potential of NaV1.7 blockers in human pain treatment.
“Yet it is clear that studying the mechanisms of rare diseases can lead to significant advancement in our understanding of how the human body works and, consequently, advances in medical care that are far beyond the scope of the rare disease itself.”
Some may question the value of studying diseases as rare as CIP, saying that our limited time and resources would be better allocated to common diseases such as cancer. Yet it is clear that studying the mechanisms of rare diseases can lead to significant advancement in our understanding of how the human body works and, consequently, advances in medical care that are far beyond the scope of the rare disease itself.
Works Cited:
1. Congenital insensitivity to pain. Genetics Home Reference website. 2020. https://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain
2. Dearborn GVN. A case of congenital pure analgesia. J Nerv Ment Dis, 1932;75:612–615.
3. Nagasako EM, Oaklander AL, Dworkin RH. Congenital insensitivity to pain: an update. Pain, 2003;101(3):213-219. doi:10.1016/S0304-3959(02)00482-7
4. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to feel pain. Nature, 2006;444:894-898. doi:10.1038/nature05413
5. Goldberg YP, MacFarlane J, MacDonald ML, et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet, 2007;71(4):311-319. doi:10.1111/j.1399-0004.2007.00790.x
6. Djouhri L, Newton R, Levinson SR, Berry CM, Carruthers B, Lawson SN. Sensory and electrophysiological properties of guinea-pig sensory neurons expressing NaV1.7 (PN1) Na+ channel α subunit protein. J Physiol, 2003;546:565-576. doi:10.1113/jphysiol.2002.026559
7. Drenth JPH, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest, 2007;117:3603-3609. doi:10.1172/JCI33297
8. Drenth JPH, Vuzevski V, Van Joost T, Casteels-Van Daele M, Vermylen J, Michiels JJ. Cutaneous pathology in primary erythermalgia. Am J Dermatopathol, 1996;18(1):30-34.
9.Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Met Genet, 2004;41:171-174. doi:10.1136/jmg.2003.012153
10. VDrenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol, 2005;124(6):1333-1338. doi:10.1111/j.0022-202X.2005.23737.x
11. Han BS, Rush AM, Dib-Hajj SD, et al. Sporadic onset of erythermalgia: a gain-of-function mutation in NaV1.7. Ann Neurol, 2006;59:553-558. doi:10.1002/ana.20776
12.Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron, 2006;52(5):767-774. doi:10.1016/j.neuron.2006.10.006
13. Flinspach M, Xu Q, Piekarz AD, et al. Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor. Sci Rep, 2017;7. doi:10.1038/srep39662
14. Wang H, Xie M, Charpin-El Hamri G, Ye H, Fussenegger M. Treatment of chronic pain by designer cells controlled by spearmint aromatherapy. Nat Biomed Eng, 2018;2:114-123. doi:10.1038/s41551-018-0192-3
Cite This Article:
Hunter R, Chan G., Lewis K., Ho J. Rare Pain Disorders: What They Can Teach Us. Illustrated by Qian C. Rare Disease Review. February 2020.
DOI:10.13140/RG.2.2.20252.64645.
