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Abstract
Painful neuropathy, like the other complications of diabetes, is a growing healthcare concern. Unfortunately, current treatments are of variable efficacy and do not target underlying pathogenic mechanisms, in part because these mechanisms are not well defined. Rat and mouse models of type 1 diabetes are frequently used to study diabetic neuropathy, with rats in particular being consistently reported to show allodynia and hyperalgesia. Models of type 2 diabetes are being used with increasing frequency, but the current literature on the progression of indices of neuropathic pain is variable and relatively few therapeutics have yet been developed in these models. While evidence for spontaneous pain in rodent models is sparse, measures of evoked mechanical, thermal and chemical pain can provide insight into the pathogenesis of the condition. The stocking and glove distribution of pain tantalizingly suggests that the generator site of neuropathic pain is found within the peripheral nervous system. However, emerging evidence demonstrates that amplification in the spinal cord, via spinal disinhibition and neuroinflammation, and also in the brain, via enhanced thalamic activity or decreased cortical inhibition, likely contribute to the pathogenesis of painful diabetic neuropathy. Several potential therapeutic strategies have emerged from preclinical studies, including prophylactic treatments that intervene against underlying mechanisms of disease, treatments that prevent gains of nociceptive function, treatments that suppress enhancements of nociceptive function, and treatments that impede normal nociceptive mechanisms. Ongoing challenges include unraveling the complexity of underlying pathogenic mechanisms, addressing the potential disconnect between the perceived location of pain and the actual pain generator and amplifier sites, and finding ways to identify which mechanisms operate in specific patients to allow rational and individualized choice of targeted therapies.
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Affiliation(s)
- Corinne A Lee-Kubli
- Graduate School of Biomedical Sciences, Sanford-Burnham Institute for Molecular Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Nigel A Calcutt
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
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2
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[Neuropathic pain. How to open the blackbox]. Schmerz 2015; 29:479-80, 482-5. [PMID: 26264897 DOI: 10.1007/s00482-015-0028-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
This article, without presuming to be comprehensive, gives a brief outline of the development of research on neuropathic pain in Germany. Current clinical research on this subject focusses on the validation of human models, patient phenotyping, mechanism-based classification and treatment as well as on molecular pathomechanisms. This clinical research is based to a large extent on the work of several internationally recognized basic researchers in the 1990s. In particular, findings from system physiology led to the analysis of clinical phenotypes and the underlying pathophysiology. In parallel, basic research achieved international top levels through the development of innovative methods. Close cooperation, building of consortia and European networking made major contributions to the success of this research.
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Buonocore M, Gagliano MC, Bonezzi C. Dynamic mechanical allodynia following finger amputation: Unexpected skin hyperinnervation. World J Clin Cases 2013; 1:197-201. [PMID: 24303500 PMCID: PMC3845956 DOI: 10.12998/wjcc.v1.i6.197] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/08/2013] [Accepted: 08/20/2013] [Indexed: 02/05/2023] Open
Abstract
The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sensation evoked by gently stroking the skin. Despite the growing interest in understanding pain mechanisms, little is known about the mechanism sustaining this peculiar type of pain. We present here the case of a 53-year-old female patient who complained of severe tactile allodynia in the hand after amputation of her left second finger, resistant to several medical and surgical treatments. In order to gain information about the pain mechanism, two neurodiagnostic skin biopsies were obtained from the area of tactile allodynia and from the contralateral, normal skin area. Skin biopsies showed an unexpected increased innervation of the allodynic skin compared to the contralateral, normal skin area (+ 80.1%). Hyperinnervation has been proposed as a mechanism of pain following nerve lesions, but the increased innervation described here could be also attributed to neuronal plasticity occurring in chronic inflammatory conditions. Independently from the uncertain cause of the epidermal hyperinnervation, in this patient we tried to reduce the elevated number of epidermal nerve fibres by treating the skin with topical capsaicin (0.075%) three times a day, and obtained a persistent pain relief. In conclusion, neurodiagnostic skin biopsy might represent an useful tool for detecting derangements of epidermal innervation in patients with dynamic mechanical allodynia and can help to select an individually tailored therapeutic strategy in such difficult clinical conditions. Further studies are needed to clarify this issue and try to gain better understanding of chronic pain mechanisms in patients who underwent finger amputation.
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Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkühler J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain 2011; 7:20. [PMID: 21443797 PMCID: PMC3078873 DOI: 10.1186/1744-8069-7-20] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 03/28/2011] [Indexed: 01/19/2023] Open
Abstract
Long-term potentiation (LTP) in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents.
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Affiliation(s)
- Ruth Ruscheweyh
- Department of Neurology, University of Münster, Münster, Germany
| | - Oliver Wilder-Smith
- Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Ruth Drdla
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Xian-Guo Liu
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jürgen Sandkühler
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Hulse R, Wynick D, Donaldson LF. Intact cutaneous C fibre afferent properties in mechanical and cold neuropathic allodynia. Eur J Pain 2009; 14:565.e1-565.e10. [PMID: 19942464 PMCID: PMC2895510 DOI: 10.1016/j.ejpain.2009.10.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2009] [Revised: 08/24/2009] [Accepted: 10/02/2009] [Indexed: 12/29/2022]
Abstract
Patients with neuropathy, report changes in sensory perception, particularly mechanical and thermal allodynia, and spontaneous pain. Similar sensory changes are seen in experimental neuropathies, in which alteration in primary afferent properties can also be determined. The neural correlate of spontaneous pain is ongoing activity in sensory afferents. Mechanical and heat allodynia are thought to result from lowered activation thresholds in primary afferent and/or central neurones, but the mechanisms underlying cold allodynia are very poorly understood. We investigated nociceptive behaviours and the properties of C and A fibre intact afferents running adjacent to damaged afferents following a partial ligation injury of the saphenous nerve (PSNI). Animals developed mechanical and cold allodynia by 3 days after PSNI. Intact mechanosensitive C fibre afferents developed ongoing activity, and had slower conduction velocities 3 and 7 days following nerve injury, with no change in mechanical threshold. There was a large increase (∼46-fold) in calculated afferent input 3 days after nerve injury, as a result of the ongoing activity in these fibres. Mechano-cooling-sensitive C fibre afferents showed both enhanced cooling-evoked firing, and increased ongoing activity. The afferent barrage associated with mechano-cooling-sensitive afferents was increased 26-fold 7 days after nerve injury. We observed no differences in the properties of intact A fibre mechanosensitive afferents. These studies demonstrate for the first time that the altered nociception seen after PSNI is associated with ongoing activity and enhanced cooling-evoked activity in intact C fibre afferents in the saphenous nerve, with no concurrent alteration in A fibre afferents.
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Affiliation(s)
- Richard Hulse
- Department of Physiology and Pharmacology, University of Bristol, Bristol, UK
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Kang YJ, Song HK, Chon JY, You JH. Alterations in NK Cell Cytotoxicity Induced by Peripheral Nerve Injury in Mice. Korean J Anesthesiol 2007. [DOI: 10.4097/kjae.2007.52.2.219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Affiliation(s)
- You Jin Kang
- Department of Anesthesiology and Pain Medicine, St. Vincent's Hospital, Suwon, Korea
| | - Ho-Kyung Song
- Department of Anesthesiology and Pain Medicine, Our Lady of Mercy Hospital, Incheon, Korea
| | - Jin Young Chon
- Department of Anesthesiology and Pain Medicine, St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Joo Hyun You
- Department of Anesthesiology and Pain Medicine, Our Lady of Mercy Hospital, Incheon, Korea
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Cui JG, Zhang X, Zhao YH, Chen C, Bazan N. Allodynia and hyperalgesia suppression by a novel analgesic in experimental neuropathic pain. Biochem Biophys Res Commun 2006; 350:358-63. [PMID: 17010939 DOI: 10.1016/j.bbrc.2006.09.055] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Accepted: 09/09/2006] [Indexed: 11/29/2022]
Abstract
SCP-1, n-[alpha-(benzisothiazol-3(2ho-ona,1-dioxide-2yl)-acetyl]-p-aminophenol (100 nmol), when intrathecally injected, suppressed tactile allodynia and thermal hyperalgesia in a rat neuropathic pain model. The tactile allodynia suppression lasted for at least 4h and SCP-M1 (100 nmol), the main metabolite of SCP-1, displayed similar suppression as SCP-1, but shorter latency, indicating SCP-M1 may be the bioactive component of SCP-1. Acetaminophen was less potent than SCP-1 and SCP-M1. To study mechanisms underlying SCP-1 action, we recorded voltage-gated Ca(2+) channel currents in acutely isolated dorsal root ganglion neurons using the whole-cell patch-clamp technique. SCP-1 and SCP-M1 inhibited non-L-type calcium channel currents up to 23.0+/-2.3% and 23.1+/-3.5%, respectively, at a depolarized pulse to -10 mV from a holding potential of -80 mV. Acetaminophen only induced 6.8+/-1.0% inhibition. The results suggest SCP-1 possesses anti-nociceptive activity in the rat model involving calcium channel blocking properties.
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Affiliation(s)
- Jian-Guo Cui
- Neuroscience Center of Excellence, Louisiana State University, Health Sciences Center, New Orleans, LA 70112, USA.
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Abstract
Quantitative sensory testing (QST) refers to a group of protocols that allows for quantitative measures of somesthetic function. Several protocols evaluate perceptual threshold, whereas others evaluate perception of stimuli above threshold. Each protocol has its own advantages and disadvantages, but one must always weigh a trade-off between accuracy (with longer protocols) and expediency (with shorter protocols). In assessing patients with neuropathic pain, one is interested in both positive and negative sensory symptoms. QST studies, using either neuropathic pain patients or healthy volunteers who have been rendered temporarily hyperalgesic, have demonstrated that pain abnormalities can be modality specific. The fact that various pain abnormalities can exist independently of each other suggests that (at least partially) different neuropathologic processes are responsible for each one. Current research suggests that both peripheral sensitization and central sensitization play a role in these abnormal pain conditions, and identification of precise neuropathologic mechanisms is under active investigation.
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Affiliation(s)
- J D Greenspan
- Department of Oral and Craniofacial Biological Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA.
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Authier N, Gillet JP, Fialip J, Eschalier A, Coudore F. Description of a short-term Taxol-induced nociceptive neuropathy in rats. Brain Res 2000; 887:239-49. [PMID: 11134612 DOI: 10.1016/s0006-8993(00)02910-3] [Citation(s) in RCA: 132] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol (32 mg/kg) to male Sprague-Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were performed. Taxol administration produced an important and rapidly developing mechanical hyperalgesia, a thermal hypoalgesia but no mechanical or thermal allodynia. Degenerative changes were observed in the sciatic nerve, the nerve fibres in the paw subcutaneous tissue and in the lumbar spinal cord. When Taxol or vehicle (a mix of Cremophor and ethanol) were repeatedly injected once a week for 5 weeks, similar nociceptive disorders were observed in addition to a decrease in peripheral nerve conduction velocity. The selective dysfunction of high-diameter myelinated fibres observed after one single administration of Taxol (32 mg/kg) may be attributable to paclitaxel-induced neuropathy, however other mechanisms causing neurochemical dysfunction must also be involved.
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Affiliation(s)
- N Authier
- Laboratoire de Toxicologie, Faculté de Pharmacie, Equipe NeuroPsychoPharmacologie Université d'Auvergne (INSERM EMI 9904), 28 Place H. Dunant, BP 38, 63001 Clermont-Ferrand, France
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Lindenlaub T, Sommer C. Partial sciatic nerve transection as a model of neuropathic pain: a qualitative and quantitative neuropathological study. Pain 2000; 89:97-106. [PMID: 11113298 DOI: 10.1016/s0304-3959(00)00354-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
One of the most commonly used experimental animal models for neuropathic pain is the chronic constriction injury (CCI) where four loose ligatures are tied around the sciatic nerve. One disadvantage of this model is the introduction of foreign material into the wound, which causes a local inflammatory reaction. Thus the distinction between the neuropathic and the inflammatory component of pain is difficult in this model. In order to produce a pure nerve lesion, we performed a partial sciatic nerve transection (PST; a modification of the Seltzer model) in female Sprague-Dawley rats and compared behavior and nerve pathology. These rats developed thermal hyperalgesia and mechanical allodynia comparable to the CCI model. Recovery of these symptoms was found between days 40 and 60 after the nerve lesion. Some animals still showed symptoms on day 101, which was associated with a neuroma formation. The main pathological findings in the endoneurium in nerve segments distal to the lesion were edema, loss of myelinated fibers and increase in endoneurial cells, especially macrophages. In the epineurium the number of macrophages was strikingly increased after CCI compared with PST, indicating that the response of the immune system is different in a structural lesion with and without foreign material. In conclusion, PST is a pure nerve injury model without an epineurial inflammatory component due to foreign material and is therefore well suited for studying the role of local endoneurial processes in the development and maintenance of neuropathic pain. Also, the importance of regeneration in the termination of hyperalgesia can convincingly be shown in this model.
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Affiliation(s)
- Thies Lindenlaub
- Neurologische Klinik, Universität Würzburg, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany
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Lindenlaub T, Teuteberg P, Hartung T, Sommer C. Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res 2000; 866:15-22. [PMID: 10825476 DOI: 10.1016/s0006-8993(00)02190-9] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor-alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57/BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody-treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25-47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.
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Affiliation(s)
- T Lindenlaub
- Neurologische Klinik, Universität Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
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Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain 1999; 83:303-11. [PMID: 10534603 DOI: 10.1016/s0304-3959(99)00111-6] [Citation(s) in RCA: 163] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In the present study, chronic constrictive injury (CCI model) of the sciatic nerve or tight ligation of L5 and L6 spinal nerves (Chung model) produced both dynamic and static components of mechanical allodynia in rats. The two responses were detected, respectively, by lightly stroking the hind paw with cotton wool or application of pressure using von Frey hairs. Animals with spinal nerve ligation developed both types of responses at a faster rate compared to animals with the CCI. Morphine (1-3 mg/kg, s.c.) dose-dependently blocked static but not dynamic allodynia. In contrast, pregabalin (previously S-isobutylgaba and CI-1008) dose-dependently (3-30 mg/kg, p.o.) blocked both types of allodynia. In CCI animals, two administrations of capsaicin (100 microg/50 microl) into the plantar surface of the ipsilateral paw at 1-h intervals blocked the maintenance of thermal hyperalgesia without affecting either static or dynamic allodynia. The similar administration of a further two doses of capsaicin into the same animals blocked the maintenance of static allodynia without affecting the dynamic response. These data indicate that thermal hyperalgesia, static and dynamic allodynia are respectively signalled by C-, Adelta- and Abeta/capsaicin insensitive Adelta- primary sensory neurones. It is suggested that pregabalin possesses a superior antiallodynic profile than morphine and may represent a novel class of therapeutic agents for the treatment of neuropathic pain.
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Affiliation(s)
- M J Field
- Department of Biology, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge, UK
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Gilliar WG, Kuchera ML, Giulianetti DA. Neurologic Basis of Manual Medicine. Phys Med Rehabil Clin N Am 1996. [DOI: 10.1016/s1047-9651(18)30360-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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