Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy

Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1–2 days after and 3–4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.     

Diagnosis and management of neuropathic pain: Review of literature and recommendations of the Polish Association for the Study of Pain and the Polish Neurological Society – Part Two

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis.A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.     

Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy

The mechanisms of diabetic painful neuropathy are complicated and comprise of peripheral and central pathophysiological phenomena. A number of proinflammatory cytokines are involved in this process. Tumor necrosis factor α (TNF-α) is considered to be one of the major contributors of neuropathic pain. In order to explore the potential role of inflammation in the peripheral nervous system of Type 1 diabetic animals with painful neuropathy, we investigated whether TNF-α is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNFα soluble receptor from damaged axons achieved by HSV vector mediated transduction of DRG would block or alter the pain perception in animals with diabetic neuropathy. Diabetic animals exhibited changes in threshold of mechanical and thermal pain perception compared to control rats and also demonstrated increases in TNFα in the DRG, spinal cord dorsal horn, sciatic nerve and in the foot skin, 6 weeks after the onset of diabetes. Therapeutic approaches by HSV mediated expression of p55 TNF soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNFα with reduction in the phosphorylation of p38MAPK in the spinal cord dorsal horn and DRG. The overall outcome of this study suggests that neuroinflammatory activation in the peripheral nervous system may be involved in the pathogenesis of painful neuropathy in Type 1 diabetes which can be alleviated by local expression of HSV vector expressing p55 TNF soluble receptor.     

Chemotherapy-evoked painful peripheral neuropathy

Vincristine and paclitaxel, two of the most effective drugs in the battle against cancer, produce a dose-limiting neurotoxicity that sometimes presents as a painful peripheral neuropathy. For the first time, investigators have been able to produce these chemotherapy-evoked painful peripheral neuropathies in the laboratory rat. These new models have already begun to elucidate the causes of the neuropathic pain associated with these antineoplastic drugs, which will now make it possible to search for effective ways to prevent and treat it.     

疼痛性周围神经病

神经痛的病因和治疗在疼痛性周围神经病患者处理中是最关键的。本病的病因、发病机制和临床症状之间关系紧密联系在一起。抗抑郁和抗惊厥药物是治疗神经痛的一线药物。     

Painful peripheral neuropathy and its nonsurgical treatment

Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely studied and represent first-line agents in the management of neuropathic pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably between patients, and pain relief is rarely complete, a majority of patients can benefit from monotherapy using a well-chosen agent or polypharmacy that combines medications with different mechanisms of action.     

Neuropathies douloureuses et atteinte des petites fibres

It is customary to consider that a purely sensory and painful neuropathy accompanied by normal electroneuromyographic examination may be or must be a small fiber neuropathy. This leads to perform specific tests, such as measuring the intra-epidermal nerve fiber density on skin biopsy or neurophysiological tests, such as evoked potentials to noxious stimuli (laser) or quantification of thermal sensory thresholds. However, these tests are only sensitive to the loss of small fibers (A-delta and C), which does not reflect the mechanisms responsible for peripheral neuropathic pain. Selective loss of small sensory fibers inherently generates a sensory deficit that does not necessarily present a painful character. Also, assigning the cause of a painful neuropathy to a small fiber neuropathy has no pathophysiological sense, although there are indirect links between these two conditions. In fact, it is not possible to explain univocally peripheral neuropathic pain, which reflects complex and diverse mechanisms, involving different types of nerve fibers. In this context, the clinical and laboratory approach must be improved to better understand the underlying mechanisms. It is imperative to interpret the data provided by laboratory tests and to correlate these data to the clinical signs and symptoms presented by the patients. Thus, one must go beyond many a priori and misinterpretations that unfortunately exist in this area at present and are not based on any solid pathophysiological basis.     

Current issues in peripheral neuropathy

Twenty million people in the United States are estimated to have peripheral neuropathy. However, many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Currently, the only treatments available for neuropathy are aimed at treating the underlying medical conditions that cause the neuropathy or treating symptoms such as pain. Neither treats the actual nerve fiber dysfunction or fiber loss, or helps nerve fibers regenerate. Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% in all neuropathy patients and 50% or more of patients with small fiber neuropathy. Currently, there is only one FDA-approved medication for a specific neuropathy (chronic inflammatory demyelinating polyneuropathy) while there are two FDA approved medications for diabetic neuropathy pain and four that are approved for post-herpetic neuralgia pain. For many patients with painful neuropathy, these medications are ineffective or not tolerated. Continued research into the underlying mechanisms of neuropathy and an increased understanding of nerve regeneration and neuropathic pain are needed to address this unmet medical need among patients with neuropathy.     

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells

Experimental painful peripheral neuropathies produced by the chemotherapeutic drugs, paclitaxel and vincristine, are produced by relatively low doses that do not cause axonal degeneration in peripheral nerve. Using quantitative immunolabeling with the PGP9.5 antibody, we have investigated whether these painful neuropathies might be associated with degeneration that is confined to the region of the sensory fiber's receptor terminals in the skin. Because complete and partial nerve transections are known to cause an increase in PGP9.5 in epidermal Langerhans cells (LCs), we also examined whether this effect occurs in chemotherapy-treated animals. At the time of peak pain severity, rats with paclitaxel- and vincristine-evoked painful peripheral neuropathies had a significant decrease (24% and 44%, respectively) in the number of intraepidermal nerve fibers (IENF) in the hind paw glabrous skin and an increase (217% and 121%, respectively) in the number of PGP9.5-positive LCs, relative to control. However, neither loss of IENF nor an increase in PGP9.5-positive LCs was found in rats with a painful peripheral neuropathy evoked by the anti-HIV agent, 2',3'-dideoxycytidine. We also confirmed that there is a decrease in IENF and an increase in PGP9.5-positive LCs in rats with neuropathic pain following a partial nerve injury (CCI model) and in rats with a complete sciatic nerve transection. Partial degeneration of the intraepidermal innervation suggests mechanisms that might produce chemotherapy-evoked neuropathic pain, and activation of cutaneous LCs suggests possible neuroimmune interactions that might also have a role.     

Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis

Painful sensory neuropathy is a common and debilitating consequence of human immunodeficiency virus (HIV). The underlying causes of neuropathic pain are most likely not due to direct infection of the nervous system by active virus. The goal of this study was to determine whether epineural exposure to the HIV-1 envelope protein gp120 could lead to chronic painful peripheral neuropathy. Two doses of gp120 or BSA control were transiently delivered epineurally via oxidized cellulose wrapped around the rat sciatic nerve. Animals were assessed for neuropathic pain behaviors at several intervals from 1-30 days following nerve surgery. Allodynia and hyperalgesia were observed within 1-3 days following gp120 and sustained throughout the testing period. The gp120-exposed sciatic nerve exhibited early but transient pathology, notably axonal swelling and increased tumor necrosis factor alpha (TNF-alpha) within the nerve trunk. In contrast, intense astrocytic and microglial activation was observed in the spinal cord, and this gliosis persisted for at least 30 days following epineural gp120, in parallel with neuropathic pain behaviors. These findings demonstrate that limited peripheral nerve exposure to HIV protein can induce persistent painful sensory neuropathy that may be sustained and magnified by long-term spinal neuropathology.     

Botulinum toxin and painful peripheral neuropathies: what should be expected?

Botulinum toxin type A (BTX-A) is a potent neurotoxin that blocks acetylcholine release from presynaptic nerve terminals by cleaving the SNARE complex. BTX-A has been reported to have analgesic effects independent of its action on muscle tone. The most robust results have been observed in patients with neuropathic pain. Neuropathic pain due to peripheral lesions has been the most widely studied. BTX-A has shown its efficacy on pain and allodynia in various animal models of inflammatory neuropathic pain. The only randomized, double-blind, placebo-controlled trial in patients with focal painful neuropathies due to nerve trauma or postherpetic neuralgia demonstrated significant effects on average pain intensity from 2 weeks after the injections to 14 weeks. Most patients reported pain during the injections, but there were no further local or systemic side effects. The efficacy of BTX-A in painful peripheral neuropathies has been more recently studied. Results were positive in the only study in an animal model of peripheral neuropathy. One study in patients with diabetic painful peripheral neuropathy demonstrated a significant decrease in Visual Analog Scale. In conclusion, one session of multiple intradermal injection of BTX-A produces long-lasting analgesic effects in patients with focal painful neuropathies and diabetic neuropathic pain, and is particularly well tolerated. The findings are consistent with a reduction of peripheral sensitisation, the place of a possible central effect remaining to define. Further studies are needed to assess some important issues, i.e. BTX-A efficacy in patients with small fiber neuropathies and the relevance of early and repeated injections. Future studies could also provide valuable insights into pathophysiology of neuropathic pain.     

The impact of neuropathic pain on health-related quality of life: review and implications

A number of high-quality studies have recently been published that examine the association between neuropathic pain and health-related quality of life (HRQoL). The current review identified 52 such studies in patients with six neuropathic pain conditions associated with lesions of either the peripheral (postsurgical neuropathic pain associated with breast and amputation surgery, postherpetic neuralgia, and painful diabetic neuropathy) or central (poststroke pain, spinal cord injury pain, multiple sclerosis pain) nervous system. The results provide strong evidence that the presence and severity of neuropathic pain are associated with greater impairments in a number of important HRQoL domains. However, the evidence also indicates that this impact varies somewhat as a function of the HRQoL domain being considered and that different measures of HRQoL are differentially sensitive to the effects of neuropathic pain. The findings have important implications for the selection of HRQoL domains and measures to use in clinical trials and in clinical research on HRQoL in persons with neuropathic pain and suggest that a biopsychosocial (as opposed to a primarily biomedical) approach would be appropriate for understanding and treating neuropathic pain.     

Effect of lumbar 5 ventral root transection on pain behaviors: a novel rat model for neuropathic pain without axotomy of primary sensory neurons

A peripheral nerve injury often causes neuropathic pain but the underlying mechanisms remain obscure. Several established animal models of peripheral neuropathic pain have greatly advanced our understanding of the diverse mechanisms of neuropathic pain. A common feature of these models is primary sensory neuron injury and the commingle of intact axons with degenerating axons in the sciatic nerve. Here we investigated whether neuropathic pain could be induced without sensory neuron injury following exposure of their peripheral axons to the milieu of Wallerian degeneration. We developed a unilateral lumbar 5 ventral root transection (L5 VRT) model in adult rats, in which L5 ventral root fibers entering the sciatic nerve were sectioned in the spinal canal. This model differs from previous ones in that DRG neurons and their afferents are kept uninjured and intact afferents expose to products of degenerating efferent ventral root fibers in the sciatic nerve and the denervated muscles. We found that the L5 VRT produced rapid (24 h after transection), robust and prolonged (56 days) bilateral mechanical allodynia, to a similar extent to that in rats with L5 spinal nerve transection (L5 SNT), cold allodynia and short-term thermal hyperalgesia (14 days). Furthermore, L5 VRT led to significant inflammation as demonstrated by infiltration of ED-1-positive monocytes/macrophages in the DRG, sciatic nerve and muscle fibers. These findings demonstrated that L5 VRT produced behavioral signs of neuropathic pain with high mechanical sensitivity and thermal responsiveness, and suggested that neuropathic pain can be induced without damage to sensory neurons. We propose that neuropathic pain in this model may be mediated by primed intact sensory neurons, which run through the milieu of Wallerian degeneration and inflammation after nerve injury. The L5 VRT model manifests the complex regional pain syndrome in some human patients, and it may provide an additional dimension to dissect out the mechanisms underlying neuropathic pain.     

Pregabalin for the treatment of painful neuropathy

Pregabalin is an alpha(2)-delta ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain. Pregabalin is the second of only two medications that are US FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is also the third medication for the treatment of postherpetic neuralgia. Currently, there are three pivotal clinical studies documenting the efficacy and safety of pregabalin for the treatment of painful diabetic neuropathy, and three clinical studies regarding the use of pregabalin for pain associated with postherpetic neuralgia. This article will review each of these studies, as well as provide a clinical review for the use of pregabalin in the treatment of neuropathic pain.     

1000/Symptomatic and pathogenetic treatment of diabetic neuropathy. The role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy worldwide, presents in different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, i.e. oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns the therapy of neuropathic pain with antidepressants (tricyclics and serotonin-norepinephrine inhibitors), anticonvulsants (in particular, alpha2delta calcium channel modulator), opioids (oxycodone CR and tramadol), and local treatment and physical therapy. Symptomatic treatment of autonomic neuropathy includes different interventions targeted at the organ systems involved. The management of diabetic foot is directed at the various combined factors resulting in foot ulceration, such as infection, peripheral ischemia, and pressure relief. Various therapeutic approaches pathogenetically oriented have been proposed and investigated in experimental and clinical studies, targeted to the different components involved in the causation of nerve damage. In particular, oxidative stress has been demonstrated to play a central role in the cascade of events triggered by hyperglycemia, thus it appears as an ideal target for a pathogenetic therapeutic approach. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in a series of controlled randomized clinical trials in patients with diabetic neuropathy, with either oral administration or intravenous infusion. Most of the trials demonstrated the efficacy of alpha-lipoic acid on the chief symptoms of diabetic neuropathy, and in particular on neuropathic pain, also indicating that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for modifying the natural history of diabetic neuropathy. The potential role of alpha-lipoic acid in contrasting the progression of diabetic neuropathy is being explored in the NATHAN 1 study, using an oral dose of 600 mg once daily over 4 years in diabetic patients with mild to moderate distal symmetric polyneuropathy, and evaluating the long-term effects with a composite score that combines clinical and neurophysiological assessment.     

An experimental painful peripheral neuropathy due to nerve constriction. I. Axonal pathology in the sciatic nerve.

A constriction injury to the sciatic nerve of the rat produces a painful peripheral neuropathy that is similar to the conditions seen in man. The pathology of the sciatic nerve in these animals was examined at 10 days postinjury, when the abnormal pain sensations are near maximal severity. The nerves were examined with (1) complete series of silver-stained longitudinal sections of pieces of the nerve (3 cm or more) that contained the constriction injury in the center, (2) toluidine blue-stained semithin sections taken at least 1 cm proximal and 1 cm distal to the constriction, and (3) EM sections taken adjacent to those stained with toluidine blue. One centimeter or more proximal to the constriction, both myelinated and unmyelinated axons were all normal. Nearer to the constriction, extensive degeneration of myelinated axons became increasingly common, as did signs of endoneurial edema. Distal to the constriction, the nerve was uniformly edematous and full of myelinic degeneration. There was a profound loss of large myelinated axons and a distinctly less severe loss of small myelinated and unmyelinated axons. These observations show that at 10 days postinjury the constriction produces a partial and differential deafferentation of the sciatic nerve's territory. The absence of degeneration in the nerve 1 cm proximal to the constriction indicates the survival of the primary afferent neurons whose axons are interrupted.     

Animal models of chemotherapy-evoked painful peripheral neuropathies

This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy-induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized.     

Neuropathic pain: experimental advances and clinical applications

Neuropathic pain is a clinical entity designating the different types of pain associated with a lesion of the nervous system including a wide range of pathological conditions from painful peripheral lesions (for example diabetic neuropathy, post-zoster pain, trauma-induced nerve injury) and central pain (particularly stroke-induced pain, spinal lesions, and multiple sclerosis). Despite this wide range of etiologies, neuropathic pain has well characterized clinical features which generally allow distinction from other types of pain: continuous often burn-like pain, paroxysmal pain (electrical discharge, knife stab), evoked pain, highly invalidating pain (allodynia, hyperalgesia), and associated dysethesia and/or paresthesia. Over the last ten Years, very little work has been published on neuropathic pain, which is now becoming a very active domain of research in neurobiology. Advances to date have not been spectacular although better tolerated agents have been recently marketed. Future progress should enable an appropriate response to the therapeutic challenge of neuropathic pain.     

Pain and death: neurodegenerative disease mechanisms in the nociceptor

Chronic peripheral neuropathic pain is the result of abnormal activity in sensory nerves. It is well recognized that this sensory nerve dysfunction can be caused by traumatic, toxic, or metabolic insult to the nerve. In addition, there is growing recognition that neuropathic pain is a frequent manifestation of neurodegenerative diseases. In this regard, important clues to the cellular mechanisms of neuropathic pain may be found by close examination of neurodegenerative diseases (including Parkinson's disease) in which neuropathic pain is often an underappreciated but important clinical manifestation. This approach identifies specific mitochondrial and cytoskeletal mechanisms, previously implicated in the pathophysiology of neurodegenerative diseases in the central nervous system, that might contribute to neuropathic dysfunction in peripheral sensory nerve fibers. Investigations in preclinical models of common peripheral neuropathic pain conditions have supported the idea that a subset of these cellular mechanisms of neurodegeneration can produce painful hyperactivity in primary afferent nociceptors. Importantly, this emerging concept of neurodegenerative disease mechanisms in the primary afferent nociceptor identifies novel molecular targets for the treatment neuropathic pain.     

Sensory correlates of pain in peripheral neuropathies

ObjectiveTo characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain.MethodsSeventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds.ResultsBetween patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds.ConclusionsQuantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity.SignificanceThere is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy.