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1.
Front Pharmacol ; 13: 818690, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250568

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side-effect of cancer therapies. So far, the development of CIPN cannot be prevented, neither can established CIPN be reverted, often leading to the cessation of necessary chemotherapy. Thus, there is an urgent need to explore the mechanistic basis of CIPN to facilitate its treatment. Here we used an integrated approach of quantitative proteome profiling and network analysis in a clinically relevant rat model of paclitaxel-induced peripheral neuropathy. We analysed lumbar rat DRG at two critical time points: (1) day 7, right after cessation of paclitaxel treatment, but prior to neuropathy development (pre-CIPN); (2) 4 weeks after paclitaxel initiation, when neuropathy has developed (peak-CIPN). In this way we identified a differential protein signature, which shows how changes in the proteome correlate with the development and maintenance of CIPN, respectively. Extensive biological pathway and network analysis reveals that, at pre-CIPN, regulated proteins are prominently implicated in mitochondrial (dys)function, immune signalling, neuronal damage/regeneration, and neuronal transcription. Orthogonal validation in an independent rat cohort confirmed the increase of ß-catenin (CTNNB1) at pre-CIPN. More importantly, detailed analysis of protein networks associated with ß-catenin highlights translationally relevant and potentially druggable targets. Overall, this study demonstrates the enormous value of combining animal behaviour with proteome and network analysis to provide unprecedented insights into the molecular basis of CIPN. In line with emerging approaches of network medicine our results highlight new avenues for developing improved therapeutic options aimed at preventing and treating CIPN.

2.
PLoS One ; 17(1): e0262544, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35015774

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting side effect of several first-line chemotherapeutic agents including paclitaxel, oxaliplatin and bortezomib, for which no predictive marker is currently available. We have previously shown that mitochondrial dysfunction is associated with the development and maintenance of CIPN. The aim of this study was to evaluate the potential use of mitochondrial DNA (mtDNA) levels and complex I enzyme activity as blood biomarkers for CIPN. Real-time qPCR was used to measure mtDNA levels in whole blood collected from chemotherapy- and vehicle-treated rats at three key time-points of pain-like behaviour: prior to pain development, at the peak of mechanical hypersensitivity and at resolution of pain-like behaviour. Systemic oxaliplatin significantly increased mtDNA levels in whole blood prior to pain development. Furthermore, paclitaxel- and bortezomib-treated animals displayed significantly higher levels of mtDNA at the peak of mechanical hypersensitivity. Mitochondrial complex I activity in whole blood was assessed with an ELISA-based Complex I Enzyme Activity Dipstick Assay. Complex I activity was not altered by any of the three chemotherapeutic agents, either prior to or during pain-like behaviour. These data demonstrate that blood levels of mtDNA are altered after systemic administration of chemotherapy. Oxaliplatin, in particular, is associated with higher mtDNA levels before animals show any pain-like behaviour, thus suggesting a potential role for circulating mtDNA levels as non-invasive predictive biomarker for CIPN.


Assuntos
Antineoplásicos/toxicidade , Biomarcadores/sangue , DNA Mitocondrial/sangue , DNA Mitocondrial/genética , Mitocôndrias/patologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Animais , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Ratos , Ratos Sprague-Dawley
3.
Int Rev Neurobiol ; 145: 83-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208528

RESUMO

Several first-line chemotherapeutic agents, including taxanes, platinum agents and proteasome inhibitors, are associated with the dose-limiting side effect of chemotherapy-induced peripheral neuropathy (CIPN). CIPN predominantly manifests as sensory symptoms, which are likely due to drug accumulation within peripheral nervous tissues rather than the central nervous system. No treatment is currently available to prevent or reverse CIPN. The causal mechanisms underlying CIPN are not yet fully understood. Mitochondrial dysfunction has emerged as a major factor contributing to the development and maintenance of CIPN. This chapter will provide an overview of both clinical and preclinical data supporting this hypothesis. We will review the studies reporting the nature of mitochondrial dysfunction evoked by chemotherapy in terms of changes in mitochondrial morphology, bioenergetics and reactive oxygen species (ROS) generation. Furthermore, we will discuss the in vivo effects of pharmacological interventions that counteract chemotherapy-evoked mitochondrial dysfunction and ameliorate pain-like behavior.


Assuntos
Antineoplásicos/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Espécies Reativas de Oxigênio/metabolismo
4.
Pain Res Manag ; 2018: 8217613, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29973969

RESUMO

Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Neuralgia/etiologia , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/complicações , Análise de Variância , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Fatores de Tempo
5.
Br J Pharmacol ; 174(24): 4812-4825, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28972650

RESUMO

BACKGROUND AND PURPOSE: Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterize a clinically relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery. EXPERIMENTAL APPROACH: Adult male Sprague-Dawley rats were injected i.p. with 0.1 and 0.2 mg·kg-1 bortezomib, or its vehicle, on days 0, 3, 7 and 10. Multiple behavioural approaches were utilized: mechanical hypersensitivity, cold allodynia, heat hypersensitivity, motor co-ordination, burrowing and voluntary wheel running. At maximal bortezomib-induced mechanical hypersensitivity, 200 mg·kg-1 ethosuximide/vehicle and 100 mg·kg-1 phenyl N-tert-butylnitrone (PBN)/vehicle were administered i.p. in separate experiments, and mechanical hypersensitivity assessed 1, 3 and 24 h later. KEY RESULTS: Bortezomib induced dose-related mechanical hypersensitivity for up to 80 days. Bortezomib induced short-term cold allodynia, but no significant change in heat hypersensitivity, motor co-ordination, voluntary wheel running and burrowing behaviour compared to vehicle-treated controls. Systemic PBN and ethosuximide significantly ameliorated bortezomib-induced mechanical hypersensitivity. CONCLUSIONS AND IMPLICATIONS: These data characterize a reproducible rat model of clinical-grade bortezomib-induced neuropathy demonstrating long-lasting pain behaviours to evoked stimuli. Inhibition by ethosuximide and PBN suggests involvement of calcium and/or ROS in bortezomib-induced painful neuropathy. These drugs could be used as preclinical positive controls to assess novel analgesics. As ethosuximide is widely used clinically, translation to the clinic to treat bortezomib-induced painful neuropathy may be possible.


Assuntos
Bortezomib/efeitos adversos , Modelos Animais de Doenças , Hipersensibilidade/complicações , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Hipersensibilidade/patologia , Masculino , Dor/patologia , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley
6.
Pain ; 158(8): 1499-1508, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28541258

RESUMO

Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Paclitaxel/farmacologia , Dor/complicações , Doenças do Sistema Nervoso Periférico/complicações , Animais , Antineoplásicos Fitogênicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Gânglios Espinais/metabolismo , Glicólise/efeitos dos fármacos , Masculino , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos Sprague-Dawley
7.
Neuroscience ; 333: 13-26, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27393249

RESUMO

Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROSinthe development and maintenance ofpaclitaxel-inducedpainful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H2XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Paclitaxel/toxicidade , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Vértebras Lombares , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
8.
Curr Opin Support Palliat Care ; 10(2): 119-128, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27054288

RESUMO

PURPOSE OF REVIEW: Chemotherapy-induced painful neuropathy (CIPN) is a major dose-limiting side-effect of several widely used chemotherapeutics. Rodent models of CIPN have been developed using a range of dosing regimens to reproduce pain-like behaviours akin to patient-reported symptoms. This review aims to connect recent evidence-based suggestions for clinical treatment to preclinical data. RECENT FINDINGS: We will discuss CIPN models evoked by systemic administration of taxanes (paclitaxel and docetaxel), platinum-based agents (oxaliplatin and cisplatin), and the proteasome-inhibitor - bortezomib. We present an overview of dosing regimens to produce CIPN models and their phenotype of pain-like behaviours. In addition, we will discuss how potential, clinically available treatments affect pain-like behaviours in these rodent models, relating those effects to clinical trial data wherever possible. We have focussed on antidepressants, opioids, and gabapentinoids given their broad usage. SUMMARY: The review outlines the latest description of the most-relevant rodent models of CIPN enabling comparison between chemotherapeutics, dosing regimen, rodent strain, and sex. Preclinical data support many of the recent suggestions for clinical management of established CIPN and provides evidence for potential treatments warranting clinical investigation. Continued research using rodent CIPN models will provide much needed understanding of the causal mechanisms of CIPN, leading to new treatments for this major clinical problem.


Assuntos
Antineoplásicos/efeitos adversos , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Aminas/uso terapêutico , Analgésicos Opioides/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Antineoplásicos/administração & dosagem , Cisplatino/efeitos adversos , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gabapentina , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Inibidores de Proteassoma/efeitos adversos , Roedores , Taxoides/efeitos adversos , Ácido gama-Aminobutírico/uso terapêutico
9.
J Pain ; 16(10): 981-94, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26142652

RESUMO

UNLABELLED: Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. PERSPECTIVE: This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Paclitaxel/toxicidade , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Antimicina A/análogos & derivados , Antimicina A/farmacologia , Modelos Animais de Doenças , Transporte de Elétrons , Inibidores Enzimáticos/farmacologia , Hiperalgesia/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Medição da Dor , Transtornos Psicomotores/etiologia , Ratos , Ratos Sprague-Dawley , Rotenona/farmacologia , Método Simples-Cego , Fatores de Tempo
10.
Prog Mol Biol Transl Sci ; 131: 119-46, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25744672

RESUMO

Mitochondria have a variety of essential functions within neurons including oxygen consumption, ATP generation, calcium buffering, and reactive oxygen species (ROS) generation. Despite extensive research into the contribution of mitochondrial function in other neurological disorders such as Parkinson's disease, the role of mitochondrial function in sensory processing and pain has been relatively unexplored until recent years. As this area of pain research is in its infancy, this review will be a descriptive summary-rather than a critical review-of data that suggests mitochondrial function/dysfunction as a causal or contributory mechanism of normal sensory processing and chronic pain. Evidence for mitochondrial dysfunction from both chronic pain patients and animal models of chronic pain will be described. Such evidence involves different aspects of mitochondria and their function including mitochondrial ultrastructure, distribution, oxygen consumption, oxidative phosphorylation, calcium buffering, ROS, and ATP levels. Most recently, substantial amounts of data have demonstrated mitochondrial involvement in painful peripheral neuropathies evoked by chemotherapy, diabetes, and HIV and these topics will be particularly highlighted in this review.


Assuntos
Mitocôndrias/metabolismo , Dor/metabolismo , Dor/fisiopatologia , Sensação , Animais , Dor Crônica/metabolismo , Modelos Animais de Doenças , Humanos , Mitocôndrias/patologia
11.
PLoS One ; 6(9): e25212, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21966458

RESUMO

Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone.


Assuntos
Óxidos N-Cíclicos/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Masculino , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Sprague-Dawley , Marcadores de Spin
12.
Neurosci Lett ; 477(1): 43-7, 2010 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-20417687

RESUMO

Various common surgeries such as thoracotomy and inguinal hernia repair involve essential prolonged tissue retraction, often causing persistent postoperative pain. A new model was developed to mimic this clinical scenario, whereby skin/muscle incision and retraction (SMIR) in the medial thigh evoked persistent postoperative pain (Flatters (2008) [Pain 135:119-130]). This study examines the response of SMIR-evoked mechanical hypersensitivity to analgesic standards commonly used as positive controls in behavioural pain studies. Rats were anaesthetised, the skin and superficial muscle of the medial thigh was then incised and retracted for 1h. In separate experiments, morphine, gabapentin and MK-801 were intraperitoneally administered to SMIR-operated rats, at maximally tolerated doses, on postoperative day 9-13. Mechanical hypersensitivity was measured by withdrawal responses to von Frey stimulation of the plantar hindpaws. Morphine (6mg/kg) and gabapentin (100mg/kg) elicited an almost complete reversal of SMIR-evoked mechanical hypersensitivity. In contrast, MK-801 (0.1mg/kg) did not affect SMIR-evoked mechanical hypersensitivity. Contralateral hindpaw responses to von Frey stimulation were unaffected by SMIR surgery or any drug treatment. In conclusion, the SMIR model displays persistent mechanical hypersensitivity that is reversible by morphine or gabapentin treatment. As previously demonstrated, SMIR-evoked pain is not driven by neuronal damage and these data show that NMDA receptor activation does not play a role in the maintenance of SMIR-evoked pain. This study further demonstrates the value of the SMIR model as a tool to understand persistent postoperative/postsurgical pain mechanisms and evaluate potential treatments.


Assuntos
Analgésicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Modelos Animais de Doenças , Músculo Esquelético/cirurgia , Dor Pós-Operatória/fisiopatologia , Aminas/uso terapêutico , Animais , Doença Crônica , Ácidos Cicloexanocarboxílicos/uso terapêutico , Maleato de Dizocilpina/uso terapêutico , Gabapentina , Membro Posterior , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Morfina/uso terapêutico , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Tato , Ácido gama-Aminobutírico/uso terapêutico
13.
Brain Res Rev ; 60(1): 187-201, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19166876

RESUMO

Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.


Assuntos
Artralgia/fisiopatologia , Doenças Musculoesqueléticas/fisiopatologia , Animais , Artralgia/tratamento farmacológico , Artralgia/etiologia , Osso e Ossos/inervação , Osso e Ossos/fisiopatologia , Modelos Animais de Doenças , Fraturas Ósseas/fisiopatologia , Humanos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Camundongos , Osteoartrite/fisiopatologia , Dor Pós-Operatória/fisiopatologia , Ratos , Toracotomia/efeitos adversos
14.
Exp Neurol ; 210(1): 229-37, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18078936

RESUMO

Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.


Assuntos
Acetilcarnitina/uso terapêutico , Células de Langerhans/patologia , Mitocôndrias/patologia , Paclitaxel , Dor/prevenção & controle , Doenças do Sistema Nervoso Periférico , Células Receptoras Sensoriais/patologia , Pele/patologia , Animais , Axônios/patologia , Axônios/ultraestrutura , Comportamento Animal , Modelos Animais de Doenças , Interações Medicamentosas , Células de Langerhans/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão/métodos , Mitocôndrias/efeitos dos fármacos , Dor/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos
15.
Pain ; 135(1-2): 119-30, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17590272

RESUMO

Various surgical procedures, e.g. thoracotomy and inguinal hernia repair, frequently evoke persistent pain lasting for many months following the initial surgery. The essential prolonged tissue retraction required during such surgeries may account for the persistence and high incidence of postoperative pain in these patient populations. This study describes a new rat model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR), akin to a clinical procedure. Under anaesthesia, skin and superficial muscle of the medial thigh were incised and a small pair of retractors inserted. This tissue was retracted for 1h causing potential stretch of the saphenous nerve. SMIR surgery evoked persistent significant mechanical hypersensitivity to von Frey stimulation of the plantar ipsilateral hindpaw, compared to either pre-surgery responses or concurrent responses of sham-operated rats. SMIR-evoked mechanical hypersensitivity was observed by postoperative day 3, most prominent between postoperative days 10 and 13, persisted until at least postoperative day 22 and had dissipated by postoperative day 32. Overall, mechanical sensitivity of the SMIR contralateral paw and the sham ipsilateral paw did not significantly change from pre-surgery responses. SMIR did not evoke significant heat hyperalgesia or cold allodynia. Light microscopy of saphenous nerve sections did not show degeneration or oedema in the saphenous nerve at, or proximally or distally to, the surgical site. In addition, very little to no degeneration was detected with ATF3 staining in DRG from SMIR-operated rats. These data suggest that prolonged retraction of superficial tissue evokes a persistent pain syndrome that is not driven by neuronal damage.


Assuntos
Modelos Animais de Doenças , Músculo Esquelético/lesões , Limiar da Dor/fisiologia , Dor Pós-Operatória/fisiopatologia , Pele/lesões , Fator 3 Ativador da Transcrição/metabolismo , Análise de Variância , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Hiperalgesia/fisiopatologia , Músculo Esquelético/inervação , Fibras Nervosas Mielinizadas/patologia , Medição da Dor/métodos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/patologia , Ratos , Pele/inervação , Fatores de Tempo
16.
Pain ; 122(3): 245-257, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16530964

RESUMO

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.


Assuntos
Antineoplásicos Fitogênicos , Mitocôndrias , Neurônios Aferentes , Paclitaxel , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Axônios/ultraestrutura , Comportamento Animal , Masculino , Microscopia Eletrônica , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/ultraestrutura , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/ultraestrutura , Paclitaxel/farmacologia , Dor/fisiopatologia , Dor/psicologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/psicologia , Ratos , Ratos Sprague-Dawley
17.
Neurosci Lett ; 397(3): 219-23, 2006 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-16406309

RESUMO

This study examines the potential efficacy of acetyl-L-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2 mg/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50 mg/kg and 100 mg/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect was long lasting, for at least 3 weeks after the last dose of ALC. In a separate experiment, daily administration of ALC (100 mg/kg; p.o.; for 10 days) to rats with established paclitaxel-induced pain produced an analgesic effect. This effect dissipated shortly after ALC treatment was withdrawn. We conclude that ALC may be useful in the prevention and treatment of chemotherapy-induced painful peripheral neuropathy.


Assuntos
Acetilcarnitina/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Paclitaxel/efeitos adversos , Dor/prevenção & controle , Doenças do Sistema Nervoso Periférico/prevenção & controle , Acetilcarnitina/administração & dosagem , Administração Oral , Animais , Masculino , Dor/induzido quimicamente , Medição da Dor , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos Sprague-Dawley
19.
Pain ; 109(1-2): 150-61, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15082137

RESUMO

Paclitaxel (Taxol) is one of the most effective and frequently used chemotherapeutics for the treatment of solid tumours. However, paclitaxel produces peripheral neurotoxicity with patients reporting sensory abnormalities and neuropathic pain during and often persisting after paclitaxel therapy. The mechanisms underlying this dose-limiting side effect are currently unknown and there are no validated drugs for its prevention or control. Male Sprague-Dawley rats received four intraperitoneal (i.p.) injections on alternate days of 2 mg/kg paclitaxel. Behavioural assessment using von Frey filaments and acetone showed that such paclitaxel treatment induced a pronounced mechanical and cold allodynia/hyperalgesia. Thus these studies aim to test potential analgesics on established paclitaxel-induced pain. Paclitaxel-induced pain appears to be relatively resistant to opioid therapy i.p. 4 mg/kg morphine was ineffective and i.p. 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia/hyperalgesia. Interestingly, a maximally tolerated dose (i.p. 0.2 mg/kg) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia/hyperalgesia suggesting that NMDA receptors have little role in paclitaxel-induced pain. Ethosuximide (i.p. 450 mg/kg) an anti-epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide (i.p. 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide (i.p. 300 mg/kg) also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain.


Assuntos
Etossuximida/uso terapêutico , Neuralgia/tratamento farmacológico , Paclitaxel/efeitos adversos , Vincristina/efeitos adversos , Animais , Comportamento Animal , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/uso terapêutico , Maleato de Dizocilpina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Etossuximida/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Neuralgia/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Estimulação Física/métodos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
20.
Eur J Pharmacol ; 484(2-3): 183-91, 2004 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-14744602

RESUMO

Interleukin-6 (IL-6) is markedly upregulated in the peripheral and central nervous systems following nerve injury; however, the functional effects of this are unclear. This study investigates the effect of peripheral interleukin-6 on nociceptive transmission in naive and neuropathic states. Using an in vitro rat skin-nerve preparation, 50 ng interleukin-6 inhibited responses of single nociceptive fibers to noxious heat. A 20-ng sample of interleukin-6 only inhibited heat responses in the presence of soluble interleukin-6 receptors. To examine in vivo effects of peripheral interleukin-6, extracellular recordings from dorsal horn neurons were made in anaesthetised naive, sham-operated and neuropathic (spinal nerve ligated) rats. Peripheral interleukin-6 (40-100 ng) markedly inhibited all naturally evoked neuronal responses in naive rats, yet only neuronal responses to heat in neuropathic rats. Behaviourally, intraplantar administration of interleukin-6 (0.01-1 microg) elicited ipsilateral thermal hypoalgesia in naive rats. Thus, interleukin-6 inhibits normal peripheral nociceptive transmission, yet such anti-nociceptive effects are attenuated following nerve injury in a modality-specific manner.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Interleucina-6/farmacologia , Medição da Dor/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/fisiopatologia , Potenciais de Ação/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/lesões , Vias Aferentes/fisiologia , Animais , Temperatura Alta/efeitos adversos , Masculino , Medição da Dor/métodos , Traumatismos dos Nervos Periféricos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/lesões , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
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