TY - JOUR
AU - Bennett, Gary J.
AB - Abstract There are undoubtedly several causes of painful peripheral neuropathy in cancer patients. Some mechanisms are directly attributable to the tumor; others lie with the therapy, be it surgery, radiation, or chemotherapy. Several animal models have been developed to study the pathophysiological mechanisms that contribute to neuropathic pain. These include inflammation-based models, nerve trauma–induced models, and chemotherapy-induced models of neuropathic pain. My colleagues and I recently identified abnormalities in mitochondrial structure and function in peripheral sensory fibers that are associated with neuropathic pain induced by common chemotherapeutic agents and that can be reversed by agents that enhance mitochondrial function. Our hope is that further identification and clarification of the pathophysiological mechanisms involved at the periphery will help us to develop new classes of medicines and treatment options. Cancer, Neuropathy, Pain, Chemotherapy Introduction Neuropathic pain in a single cancer patient often results from multiple causes. Nerves become injured in these patients through a variety of mechanisms, all of which can contribute to neuropathic pain. Some mechanisms are directly attributable to the tumor; for example, a tumor that grows in and around the nerve can cause nerve compression through mechanical distortion, loss of blood supply leading to ischemia, and exposure to an inflammatory microenvironment. Other causes lie with the cancer therapy—surgical debridement, radiation (especially of the plexi), and chemotherapy can also injure nerves. Most of these pathophysiological mechanisms have been reproduced and studied in the peripheral nervous systems of laboratory animals. In this article, I briefly review some of the work that has been done to study the peripheral causes of neuropathic pain as it relates to cancer. Unquestionably, the central nervous system is also affected in neuropathic pain, either directly or through interaction with the periphery, but I focus here on peripheral mechanisms. Recent findings point to pathophysiological mechanisms that might serve as novel therapeutic targets. Inflammation-Induced Neuropathic Pain Several studies have examined the role of inflammatory cytokines in generating neuropathic pain. For example, tumor necrosis factor (TNF)-α, a molecule ubiquitously present in any inflammatory environment and also associated with the immune response to tumors, has been found to affect the firing of pain fibers. In one study, Linda Sorkin and her colleagues measured the discharge of normal C-fibers in situ with and without the application of TNF-α to the nerve in which the fibers travel [1]. Normal C-fibers are almost completely silent in the absence of a painful stimulus, and begin to fire with the application of injurious levels of force to the skin. TNF-α induced spontaneous discharge in these fibers and greater sensitivity to peripheral stimulation. Spontaneous discharge in normally silent pain fibers translates into spontaneous pain, whereas a lowered activation threshold in pain fibers results in pain upon normally innocuous stimulation (allodynia). Nerve Trauma–Induced Neuropathic Pain The classic model of nerve trauma–induced neuropathic pain—studied since 1988—is the chronic constriction injury (CCI) model. In this model, the rat sciatic nerve is loosely ligated with chromic gut suture such that the epineurial vasculature is partly occluded. This causes the nerve to swell gradually and self-strangulate [2]. Whereas a completely transected sciatic nerve results in flaccid paralysis and an almost completely insensate foot (except for a small strip of skin on the medial edge of the foot that is innervated by the saphenous nerve) CCI, despite massive injury, results in hypersensitivity to touch within a few days. To assess touch sensitivity, von Frey hairs can be used to exert various levels of pressure to discrete locations on the rat foot. In normal animals, von Frey hairs that exert modest pressure elicit an occasional behavioral response (withdrawal), which occurs more frequently with the application of stiffer hairs. When applied to our own skin, these hairs produce a mild pricking pain sensation. A few days after CCI, animals begin withdrawing their feet from very thin hairs that normally produce only a gentle touch sensation. Such pain-related withdrawals occur even with very gentle stimuli that are near the normal detection threshold. Similarly, in patients with painful peripheral neuropathy, it is commonly reported that the gentlest touch stimulus causes a strong burning sensation. Despite sparing of the saphenous nerve in this model, it is interesting to note that hypersensitivity extends into the territory innervated by the saphenous nerve. That is, the area of hypersensitivity is distributed like a stocking or glove, and does not anatomically match the territory of the damaged nerve. Similar distributions have been reported in cases of neuropathic pain, suggesting that peripheral nerve injury evokes a secondary pathological process in the central nervous system. Recordings from the axons interrupted at the site of injury demonstrate abnormal spontaneous activity in approximately one third of Aβ-fibers and one fifth of Aδ-fibers and a smaller percentage of C-fiber sensory afferents beginning within 1–2 days after nerve injury [3]. The firing is almost always characterized by a highly regular, almost clock-like discharge. Sometimes bursting is observed, but the bursts themselves incorporate the same highly regular pattern of discharge, suggestive of sodium channel abnormalities. As in the case of inflammation-induced neuropathy, spontaneous discharge appears to give rise to the spontaneous sensation of pain. Patients often report that the pain has a different quality—an odd tingling or buzzing—which may be explained by the simultaneous spontaneous discharge of both touch and pain fibers [4]. Chemotherapy-Induced Neuropathic Pain The most effective drugs for the treatment of solid tumors invariably have peripheral neuropathy as a dose-limiting side effect, and this is accompanied by a neuropathic pain syndrome in about 20% of patients receiving standard doses and nearly all patients receiving high-dose therapy. Neurotoxicity is the main reason for dose reduction and discontinuation of life-saving therapy. Similar to patients with diabetic neuropathy, these patients complain of a distal symmetrical burning pain, disproportionately present on the hands and feet. However, unlike neuropathic pain associated with diabetes, which starts in the feet and spreads to the hands over a time course that can be months to years, neuropathic pain in chemotherapy-treated patients often begins simultaneously in the hands and feet [5]. It is relatively straightforward to replicate chemotherapy-induced neuropathic pain in animal models. High doses of the drug paclitaxel kill sensory fibers as well as motor neurons in rats; however, lower doses (2 mg/kg administered on four alternate days for a total of 8 mg/kg) result in a painful peripheral neuropathy that begins simultaneously in the distal extremities. There is a distinct delay between the last exposure to paclitaxel and the onset of hypersensitivity, which mimics the “coasting” phenomenon described in patients [6]. Hypersensitivity is manifested not only in response to touch stimuli; cooling stimuli also produce a pain response in these rats. Gentle cooling is also perceived as painful in patients with chemotherapy-induced neuropathic pain. Hypersensitivity to heat is common in animal models of traumatic nerve injury pain like the CCI model, but heat hypersensitivity is very minor or absent in the rat model of paclitaxel-evoked neuropathy. Such dissociations indicate that the pathophysiological mechanisms responsible for neuropathic pain are at least partly different depending on the cause of the nerve damage. Recording neural discharge in the fibers of rats treated with paclitaxel, vincristine, or oxaliplatin shows that both A-fibers and C-fibers have a very high incidence of abnormal spontaneous discharge. This spontaneous discharge does not resemble the pattern observed in trauma models of neuropathic pain. Instead of being 20–30 spikes per second, it is only two to three spikes per second [7]. However, such low-frequency discharge, especially when present in a large number of fibers, likely accounts for the sensation of pain or dysesthesia. Previous work has proposed that paclitaxel binds to microtubules, interrupts axonal transport, and causes neuronal death. However, in the rat models, paclitaxel, vincristine, and oxaliplatin do not cause axonal degeneration at the level of the saphenous nerve, nor is there significant abnormality in the axonal microtubules [8, 9]. Instead, all three chemotherapeutic agents tested cause partial degeneration of the intraepidermal sensory fibers [9]. In addition, the axonal mitochondria are abnormally swollen—the cristae have collapsed and the intermembrane space has expanded [8]. Furthermore, oxygen consumption in the axons from animals treated with paclitaxel is deficient, with decreased amounts of ATP produced by both respiratory complex I and complex II (Bennett et al., unpublished data). Our current model is that these drugs interfere with mitochondrial energetics, resulting in an energy deficiency that leads to dysfunction of the sodium-potassium pump that maintains the normal resting potential. As a result, the axons depolarize to the threshold necessary for spontaneous discharge. Such a mechanism could also operate in other forms of toxic neuropathies, for example, in diabetic neuropathy. Looking Ahead There are unquestionably many distinct mechanisms in the peripheral and central nervous systems that occur simultaneously to account for painful peripheral neuropathy, and these mechanisms probably coexist fairly frequently in any given patient. This is highly complicated pathology. How much of the cancer patient's pain is a result of the nerve trauma? How much is a result of chemotherapy? How much is a result of radiation causing vasculolytic neuropathy? We cannot yet answer these questions satisfactorily. Our hope is that further identification and clarification of the pathophysiological mechanisms involved at the periphery will help us to develop new classes of medicines and treatment options. In the case of chemotherapy-induced neuropathy, there is further hope that because we know exactly when the cause of nerve injury is introduced, we have a unique opportunity for prevention. We have evidence in animals that we can prevent chemotherapy-induced neuropathy completely with drugs that enhance mitochondrial function. We have already identified two candidate drugs that could be tested in human trials (Fig. 1) [10–12]. Figure 1 Open in new tabDownload slide Effects of acetyl-L-carnitine (ALC) on paclitaxel-evoked neuropathic pain. Pre: response frequency to a von Frey Hair (VFH) exerting 15 g of force applied to the bottom of the hind paw. This is a barely painful stimulus and evokes a low rate of withdrawal prior to paclitaxel. Rats receiving vehicle treatment have the expected paclitaxel-evoked hypersensitivity to this stimulus. (A): Prophylactic daily doses of ALC beginning 1 day before paclitaxel treatment prevent the neuropathic pain hypersensitivity. (B): ALC treatment also reverses the pain when given to rats with established paclitaxel-evoked pain. Thus, ALC, which is believed to work via a mitochondrial site of action, can both prevent and reverse the chemotherapy-evoked pain syndrome. *Different from the vehicle control with p ≤ .05 (repeated measures analysis of variance followed by Dunnett's t-test). Data redrawn from Flatters SJ, Xiao WH, Bennett GJ. Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful neuropathy. Neurosci Lett 2006;397:219–223. Figure 1 Open in new tabDownload slide Effects of acetyl-L-carnitine (ALC) on paclitaxel-evoked neuropathic pain. Pre: response frequency to a von Frey Hair (VFH) exerting 15 g of force applied to the bottom of the hind paw. This is a barely painful stimulus and evokes a low rate of withdrawal prior to paclitaxel. Rats receiving vehicle treatment have the expected paclitaxel-evoked hypersensitivity to this stimulus. (A): Prophylactic daily doses of ALC beginning 1 day before paclitaxel treatment prevent the neuropathic pain hypersensitivity. (B): ALC treatment also reverses the pain when given to rats with established paclitaxel-evoked pain. Thus, ALC, which is believed to work via a mitochondrial site of action, can both prevent and reverse the chemotherapy-evoked pain syndrome. *Different from the vehicle control with p ≤ .05 (repeated measures analysis of variance followed by Dunnett's t-test). Data redrawn from Flatters SJ, Xiao WH, Bennett GJ. Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful neuropathy. Neurosci Lett 2006;397:219–223. Acknowledgment The author's research on cancer-related neuropathic pain is supported by the Louise and Alan Edwards Foundation of Montreal, the Neuropathy Association, the Canada Research Chairs Program, and the National Institute of Neurological Disorders and Stroke, National Institutes of Health (R01-NS052255). G.J.B. is a Canada Senior Research Chair. References 1 Sorkin LS , Xiao WH, Wagner R et al. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres Neuroscience 1997 81 255 – 261 Google Scholar Crossref Search ADS PubMed WorldCat 2 Bennett GJ , Xie YK A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man Pain 1988 33 87 – 107 Google Scholar Crossref Search ADS PubMed WorldCat 3 Kajander KC , Bennett GJ Onset of a painful peripheral neuropathy in rat: A partial and differential deafferentation and spontaneous discharge in A beta and A delta primary afferent neurons J Neurophysiol 1992 68 734 – 744 Google Scholar Crossref Search ADS PubMed WorldCat 4 GJ Bennett . Neuropathic pain. In PD Wall, R Melzack, eds. Textbook of Pain , Third Edition, Edinburgh, Scotland : Churchill Livingstone , 1994 , 201 – 224 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5 Dougherty PM , Cata JP, Cordella JV et al. Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients Pain 2004 109 132 – 142 Google Scholar Crossref Search ADS PubMed WorldCat 6 Flatters SJ , Bennett GJ Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy Pain 2004 109 150 – 161 Google Scholar Crossref Search ADS PubMed WorldCat 7 Xiao WH , Bennett GJ Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine Pain 2008 135 262 – 270 Google Scholar Crossref Search ADS PubMed WorldCat 8 Flatters SJ , Bennett GJ Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction Pain 2006 122 245 – 257 Google Scholar Crossref Search ADS PubMed WorldCat 9 Siau C , Xiao W, Bennett GJ Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells Exp Neurol 2006 201 507 – 514 Google Scholar Crossref Search ADS PubMed WorldCat 10 Jin HW , Flatters SJ, Xiao WH et al. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells Exp Neurol 2008 210 229 – 237 Google Scholar Crossref Search ADS PubMed WorldCat 11 Xiao WH , Zheng FY, Bennett GJ et al. Olesoxime (cholest-4-en-3-one, oxime): Analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel Pain 2009 147 202 – 209 Google Scholar Crossref Search ADS PubMed WorldCat 12 Flatters SJ , Xiao WH, Bennett GJ Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful neuropathy Neurosci Lett 2006 397 219 – 223 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Disclosures: Gary J. Bennett: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the author or independent peer reviewers. © 2010 AlphaMed Press This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Pathophysiology and Animal Models of Cancer-Related Painful Peripheral Neuropathy
JO - The Oncologist
DO - 10.1634/theoncologist.2009-s503
DA - 2010-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pathophysiology-and-animal-models-of-cancer-related-painful-peripheral-P4fO0MBl2s
SP - 9
EP - 12
VL - 15
IS - S2
DP - DeepDyve
ER -