RESUMEN
Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.
Asunto(s)
Dolor Crónico/metabolismo , Umbral del Dolor , Células Receptoras Sensoriales/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Analgésicos/uso terapéutico , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Dolor Crónico/fisiopatología , Diseño de Fármacos , Humanos , Umbral del Dolor/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Transducción de Señal , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Canales de Sodio Activados por Voltaje/efectos de los fármacos , Canales de Sodio Activados por Voltaje/genéticaRESUMEN
BACKGROUND: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. METHODS: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. RESULTS: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. CONCLUSION: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.
Asunto(s)
Animales Recién Nacidos , Hormona Liberadora de Corticotropina , Glucosa , Hipocampo , Dolor , Ratas Sprague-Dawley , Receptores de Glucocorticoides , Animales , Glucosa/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Receptores de Glucocorticoides/metabolismo , Dolor/metabolismo , Dolor/etiología , Ratas , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Masculino , Umbral del Dolor/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , FemeninoRESUMEN
OBJECTIVE: Migraine, a prevalent and debilitating disease, involves complex pathophysiology possibly including inflammation and heightened pain sensitivity. The current study utilized the complete Freund's adjuvant (CFA) model of inflammation, with onabotulinumtoxinA (BoNT/A) as a treatment of interest due to its use in clinical migraine management. Using an animal model, the study sought to investigate the role of BoNT/A in modulating CFA-induced inflammation, alterations in pain sensitivity, and the regulation of calcitonin gene-related peptide (CGRP) release. Further, we aimed to assess the changes in SNAP-25 through western blot analysis to gain insights into the mechanistic action of BoNT/A. METHODS: BoNT/A or control was administered subcutaneously at the periorbital region of rats 3 days before the induction of inflammation using CFA. Periorbital mechanical sensitivity was assessed post-inflammation, and alterations in CGRP release were evaluated. Changes in SNAP-25 levels were determined using western blot analysis. RESULTS: Upon CFA-induced inflammation, there was a marked increase in periorbital mechanical sensitivity, with the inflammation side showing increased sensitivity compared to other periorbital areas. BoNT/A did decrease the withdrawal thresholds in the electronic von Frey test. Despite not being able to observe differences in pain thresholds or CGRP release, BoNT/A reduced baseline release under CFA inflamed conditions. Analysis of SNAP-25 levels in the trigeminal ganglion revealed both intact and cleaved forms that were notably elevated in BoNT/A-treated animals. These findings, derived from western blot analysis, suggest an effect on neurotransmitter release. CONCLUSION: Our investigation highlights the role of BoNT/A in reducing baseline CGRP in the context of inflammation and its involvement in SNAP-25 cleavage. In contrast, BoNT/A did not appear to alter facial pain sensitivity induced by inflammation, suggesting that mechanisms other than baseline CGRP could be implicated in the elevated thresholds in the CFA model.
Asunto(s)
Toxinas Botulínicas Tipo A , Péptido Relacionado con Gen de Calcitonina , Modelos Animales de Enfermedad , Inflamación , Trastornos Migrañosos , Ratas Sprague-Dawley , Proteína 25 Asociada a Sinaptosomas , Animales , Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas Tipo A/administración & dosificación , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Proteína 25 Asociada a Sinaptosomas/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Inflamación/tratamiento farmacológico , Ratas , Masculino , Adyuvante de Freund , Dolor/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Fármacos Neuromusculares/farmacología , Fármacos Neuromusculares/administración & dosificaciónRESUMEN
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.
Asunto(s)
Neuronas GABAérgicas , Hiperalgesia , Ratones Endogámicos C57BL , Receptores Nicotínicos , Animales , Receptores Nicotínicos/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Ratones , Porción Reticular de la Sustancia Negra/metabolismo , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Nicotina/farmacología , Analgésicos/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Capsaicina/farmacología , Acetilcolina/metabolismo , Optogenética , Umbral del Dolor/efectos de los fármacosRESUMEN
BACKGROUND: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats. METHODS: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested. RESULTS: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region. CONCLUSION: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.
Asunto(s)
Modelos Animales de Enfermedad , Proteína Potenciadora del Homólogo Zeste 2 , Neuralgia , Proteínas Proto-Oncogénicas c-myc , Ratas Sprague-Dawley , Sirtuina 3 , Animales , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Masculino , Neuralgia/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal , Ratas , Umbral del Dolor/efectos de los fármacos , Hiperalgesia/metabolismo , Hiperalgesia/genética , Infecciones por VIH/complicaciones , Infecciones por VIH/metabolismo , Histonas/metabolismo , Morfina/farmacología , Analgésicos Opioides/farmacología , Inyecciones Espinales , Indoles , Piridonas , SirtuinasRESUMEN
Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.
Asunto(s)
Capsaicina , Dolor , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Capsaicina/farmacología , Masculino , Femenino , Ratones , Dolor/metabolismo , Dolor/genética , Hormonas Esteroides Gonadales/metabolismo , Ciclo Estral/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Caracteres Sexuales , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
BACKGROUND: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets. METHODS: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST. RESULTS: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05). CONCLUSIONS: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.
Asunto(s)
Encéfalo , Modelos Animales de Enfermedad , Trastornos Migrañosos , Nitroglicerina , Animales , Nitroglicerina/toxicidad , Nitroglicerina/farmacología , Nitroglicerina/administración & dosificación , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , Ratones , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratones Endogámicos C57BL , Mapeo Encefálico , Vasodilatadores/farmacología , Vasodilatadores/administración & dosificación , Umbral del Dolor/efectos de los fármacosRESUMEN
We studied the influence of DMSO administered ad libitum with drinking water in concentrations of 0.01, 0.1, and 1% for 4 and 6 weeks on pain sensitivity, motor coordination, and myelin content in the corpus callosum of C57BL/6 mice. After 6-week administration, DMSO in all studied concentrations decreased myelin content in the corpus callosum. Moreover, 4-week administration of 0.1% DMSO and 6-week administration of 1% DMSO increased the latency to fall in the rotarod test by 3.1 (p<0.05) and 5.1 (p<0.001) times, respectively. After 4-week administration of DMSO in concentrations of 0.01 and 0.1%, the latency of the tail flick response increased by 2.1 (p<0.05) and 1.8 times (p<0.001), respectively. Administration of DMSO in concentrations of 0.01 and 1% for 6 weeks led to a decrease of this parameter by 2.7 (p<0.05) and 3.8 times (p<0.01), respectively. Thus, DMSO in all studied concentrations decreased myelin content in the corpus callosum of C57BL/6 mice and modified motor coordination and pain sensitivity of animals.
Asunto(s)
Cuerpo Calloso , Dimetilsulfóxido , Ratones Endogámicos C57BL , Vaina de Mielina , Animales , Dimetilsulfóxido/administración & dosificación , Dimetilsulfóxido/toxicidad , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/patología , Ratones , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Masculino , Prueba de Desempeño de Rotación con Aceleración Constante , Umbral del Dolor/efectos de los fármacosRESUMEN
Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENT Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.
Asunto(s)
Analgésicos/uso terapéutico , Antineoplásicos/efectos adversos , Clorhidrato de Duloxetina/uso terapéutico , Umbral del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Analgésicos/farmacología , Animales , Antineoplásicos/uso terapéutico , Corticosterona/sangre , Clorhidrato de Duloxetina/farmacología , Femenino , Masculino , Oxaliplatino/efectos adversos , Paclitaxel/efectos adversos , Manejo del Dolor , Enfermedades del Sistema Nervioso Periférico/sangre , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.
Asunto(s)
Neuronas/fisiología , Dolor/fisiopatología , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/fisiopatología , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiopatología , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Globo Pálido/efectos de los fármacos , Humanos , Hipersensibilidad , Ratones , Neuronas/efectos de los fármacos , Oxidopamina/farmacología , Dolor/complicaciones , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Enfermedad de Parkinson/complicaciones , Sustancia Negra/fisiopatología , Núcleo Subtalámico/efectos de los fármacosRESUMEN
Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the NaV1.1 channel blocker ICA-121431 and NaV1.1 protein in the ION, but no change in NaV1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain.SIGNIFICANCE STATEMENT This study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of NaV1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of NaV1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Carbamazepina/uso terapéutico , Neuralgia/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Neuralgia del Trigémino/tratamiento farmacológico , Analgésicos no Narcóticos/farmacología , Animales , Carbamazepina/farmacología , Femenino , Masculino , Canal de Sodio Activado por Voltaje NAV1.1/biosíntesis , Neuralgia/metabolismo , Dimensión del Dolor/métodos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Neuralgia del Trigémino/metabolismoRESUMEN
Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E2 (PGE2) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE2 (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4-) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE2 (100 nm) was enhanced. The sensitizing effect of 10 nm PGE2 was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed in vivo Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE2 in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.SIGNIFICANCE STATEMENT Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an in vitro model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E2 (PGE2) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE2-induced sensitization was observed in vitro, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4-)] nociceptors.
Asunto(s)
Analgésicos Opioides/toxicidad , Hiperalgesia/inducido químicamente , Nociceptores/efectos de los fármacos , Animales , Desoxiadenosinas/farmacología , Dinoprostona , Fentanilo/metabolismo , Fentanilo/farmacología , Lectinas , Masculino , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Morfina , Plasticidad Neuronal/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/agonistas , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10 females/13 males; 27 ± 7 yr; 26 ± 3 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in â¼0.4°C ice bath for 2 min) before and 5 min after drug/placebo administration (75 µg fentanyl or saline). We compared pain perception (100-mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo timepoints) using paired, two-tailed t tests. Before drug/placebo administration, perceived pain (P = 0.8287), ΔMSNA burst frequency (P = 0.7587), and Δmean BP (P = 0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, P < 0.0001), ΔMSNA burst frequency (9 vs. 17 bursts/min, P = 0.0054), and Δmean BP (7 vs. 13 mmHg, P = 0.0174) during the CPT compared with placebo. Fentanyl-induced reductions in pain perception and Δmean BP were moderately related (r = 0.40, P = 0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Sistema Cardiovascular/inervación , Fentanilo/administración & dosificación , Músculo Esquelético/inervación , Percepción del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Sistema Nervioso Simpático/efectos de los fármacos , Adulto , Analgésicos Opioides/efectos adversos , Frío , Estudios Cruzados , Femenino , Fentanilo/efectos adversos , Humanos , Inmersión , Masculino , Dolor/fisiopatología , Dolor/psicología , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Agua , Adulto JovenRESUMEN
One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.
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Enfermedades Virales del Sistema Nervioso Central/metabolismo , Interferón Tipo I/toxicidad , Nociceptores/metabolismo , Umbral del Dolor/fisiología , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Animales , Células Cultivadas , Enfermedades Virales del Sistema Nervioso Central/inducido químicamente , Enfermedades Virales del Sistema Nervioso Central/patología , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Nociceptores/efectos de los fármacos , Nociceptores/patología , Dolor/inducido químicamente , Dolor/patología , Umbral del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
Endogenous acetylcholine (ACh) is an important modulator of nociceptive sensory processing in the spinal cord. An increased level of spinal ACh induces analgesia both in humans and rodents while interfering with cholinergic signaling is allodynic, demonstrating that a basal tone of spinal ACh modulates nociceptive responses in naïve animals. The plasticity undergone by this cholinergic system in chronic pain situation is unknown, and the mere presence of this tone in neuropathic animals is controversial. We have addressed these issues in mice through behavioral experiments, histology, electrophysiology and molecular biology, in the cuff model of peripheral neuropathy. Our behavior experiments demonstrate the persistence, and even increased impact of the analgesic cholinergic tone acting through nicotinic receptors in cuff animals. The neuropathy does not affect the number or membrane properties of dorsal horn cholinergic neurons, nor specifically the frequency of their synaptic inputs. The alterations thus appear to be in the neurons receiving the cholinergic signaling, which is confirmed by the fact that subthreshold doses of acetylcholinesterase (AChE) inhibitors in sham animals become anti-allodynic in cuff mice and by the altered expression of the ß2 nicotinic receptor subunit. Our results demonstrate that endogenous cholinergic signaling can be manipulated to relieve mechanical allodynia in animal models of peripheral neuropathy. Until now, AChE inhibitors have mainly been used in the clinics in situations of acute pain (parturition, post-operative). The fact that lower doses (thus with fewer side effects) could be efficient in chronic pain conditions opens new avenues for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chronic pain continues to be the most common cause of disability that impairs the quality of life, accruing enormous and escalating socio-economic costs. A better understanding of the plasticity of spinal neuronal networks, crucially involved in nociceptive processing, could help designing new therapeutic avenues. We here demonstrate that chronic pain modifies the spinal nociceptive network in such a way that it becomes more sensitive to cholinergic modulations. The spinal cholinergic system is responsible for an analgesic tone that can be exacerbated by acetylcholinesterase inhibitors, a property used in the clinic to relief acute pain (child birth, post-op). Our results suggest that lower doses of acetylcholinesterases, with even fewer side effects, could be efficient to relieve chronic pain.
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Analgesia/métodos , Neuronas Colinérgicas/metabolismo , Modelos Animales de Enfermedad , Neuralgia/metabolismo , Umbral del Dolor/fisiología , Médula Espinal/metabolismo , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Neuronas Colinérgicas/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuralgia/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Médula Espinal/efectos de los fármacosRESUMEN
Neuropathic pain is a severe problem that is difficult to treat clinically. Reducing abnormal remodeling of dendritic spines/synapses and increasing the anti-inflammatory effects in the spinal cord dorsal horn are potential methods to treat this disease. Previous studies have reported that electroacupuncture (EA) could increase the pain threshold after peripheral nerve injury. However, the underlying mechanism is unclear. P2X7 receptors (P2X7R) mediate the activation of microglia and participate in the occurrence and development of neuropathic pain. We hypothesized that the effects of EA on relieving pain may be related to the downregulation of the P2X7R. Spinal nerve ligation (SNL) rats were used as a model in this experiment, and 2'(3')-O-(4-benzoyl)benzoyl ATP (BzATP) was used as a P2X7R agonist. We found that EA treatment decreased dendritic spine density, inhibited synaptic reconstruction and reduced inflammatory response, which is consistent with the decrease in P2X7R expression as well as the improved neurobehavioral performance. In contrast to the beneficial effects of EA, BzATP enhanced abnormal remodeling of dendritic spines/synapses and inflammation. Furthermore, the EA-mediated positive effects were reversed by BzATP, which is consistent with the increased P2X7R expression. These findings indicated that EA improves neuropathic pain by reducing abnormal dendritic spine/synaptic reconstruction and inflammation via suppressing P2X7R expression.
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Electroacupuntura , Neuralgia/metabolismo , Neuralgia/terapia , Receptores Purinérgicos P2X7/metabolismo , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Espinas Dendríticas/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Ligadura , Masculino , Modelos Biológicos , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Umbral del Dolor/efectos de los fármacos , Ratas Sprague-Dawley , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/patología , Nervios Espinales/efectos de los fármacos , Nervios Espinales/patología , Nervios Espinales/fisiopatologíaRESUMEN
Researches have shown that calcitonin gene-related peptide (CGRP) plays a pivotal role in pain modulation. Nociceptive information from the periphery is relayed from parabrachial nucleus (PBN) to brain regions implicated involved in pain. This study investigated the effects and mechanisms of CGRP and CGRP receptors in pain regulation in the PBN of naive and neuropathic pain rats. Chronic sciatic nerve ligation was used to model neuropathic pain, CGRP and CGRP 8-37 were injected into the PBN of the rats, and calcitonin receptor-like receptor (CLR), a main structure of CGRP receptor, was knocked down by lentivirus-coated CLR siRNA. The hot plate test (HPT) and the Randall Selitto Test (RST) was used to determine the latency of the rat hindpaw response. The expression of CLR was detected with RT-PCR and western blotting. We found that intra-PBN injecting of CGRP induced an obvious anti-nociceptive effect in naive and neuropathic pain rats in a dose-dependent manner, the CGRP-induced antinociception was significantly reduced after injection of CGRP 8-37, Moreover, the mRNA and protein levels of CLR, in PBN decreased significantly and the antinociception CGRP-induced was also significantly lower in neuropathic pain rats than that in naive rats. Knockdown CLR in PBN decreased the expression of CLR and the antinociception induced by CGRP was observably decreased. Our results demonstrate that CGRP induced antinociception in PBN of naive or neuropathic pain rats, CGRP receptor mediates this effect. Neuropathic pain induced decreases in the expression of CGRP receptor, as well as in CGRP-induced antinociception in PBN.
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Analgésicos/farmacología , Péptido Relacionado con Gen de Calcitonina/farmacología , Proteína Similar al Receptor de Calcitonina/agonistas , Dolor Nociceptivo/prevención & control , Umbral del Dolor/efectos de los fármacos , Núcleos Parabraquiales/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/agonistas , Ciática/prevención & control , Animales , Proteína Similar al Receptor de Calcitonina/genética , Proteína Similar al Receptor de Calcitonina/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Masculino , Dolor Nociceptivo/genética , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/fisiopatología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiopatología , Ratas Sprague-Dawley , Receptores de Péptido Relacionado con el Gen de Calcitonina/genética , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Ciática/genética , Ciática/metabolismo , Ciática/fisiopatologíaRESUMEN
Morphine is an opioid agonist and a nonselective mu, kappa and delta receptor agonist. It is a commonly used analgesic drug for the treatment of acute and chronic pain as well as cancer pain. Morphine is particularly important to address the problem of morphine tolerance. Tcf7l2, known as a risk gene for schizophrenia and autism, encodes a member of the LEF1/TCF transcription factor family. TCF7L2 is an important transcription factor that is upregulated in neuropathic pain models. However, the relationship between TCF7L2 and morphine tolerance has not been reported. In this study, we found that morphine tolerance led to the upregulation of TCF7L2 in the spinal cord, and also led to the upregulation of TCF7L2 expression in glial cells, which promoted inflammation related signal, and activated TLR4 / NF-κB/NLRP3 pathway. In addition, TCF7L2 regulated microglial cell activation induced by chronic morphine treatment. Mechanically, we found that TCF7L2 transcriptionally regulated TLR4 expression, and the depletion of TCF7L2 alleviated morphine tolerance induced by chronic morphine treatment, and further alleviated pain hypersensitivity induced by chronic morphine treatment. We therefore suggested that TCF7L2 regulates the activation of TLR4/ NF-κB/NLRP3 pathway in microglia, and is involved in the formation of morphine tolerance. Our results provide a new idea for the regulation mechanism of morphine tolerance.
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Analgésicos Opioides/toxicidad , Tolerancia a Medicamentos , Hiperalgesia/inducido químicamente , Microglía/efectos de los fármacos , Morfina/toxicidad , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Dolor Nociceptivo/prevención & control , Receptor Toll-Like 4/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Ratones , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/fisiopatología , Umbral del Dolor/efectos de los fármacos , Transducción de Señal , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/fisiopatología , Receptor Toll-Like 4/genética , Proteína 2 Similar al Factor de Transcripción 7/genética , Regulación hacia ArribaRESUMEN
High glucose (HG)-induced nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome activation leads to diabetic neuropathic pain. We recently showed that salidroside could suppress NLRP3 inflammasome activation in hepatocytes exposed to HG. The aim of this study was to evaluate the analgesic effect of salidroside on diabetic rats and to explore its underlying mechanisms. Rat models with diabetic neuropathic pain were induced by high-fat diet feeding combined with low dose streptozotocin injections. Doses of salidroside at 50 and 100 mg.kg-1.day-1 were administered by gavage to diabetic rats for 6 weeks. Mechanical allodynia test, thermal hyperalgesia test and biochemical analysis were performed to evaluate therapeutic effects. Primary dorsal root ganglion (DRG) cells exposed to HG at 45 mM were used to further study the effects of salidroside on the AMP-activated protein kinase (AMPK)-NLRP3 inflammasome axis and insulin sensitivity in vitro. Salidroside administration improved hyperglycemia, ameliorated insulin resistance, and alleviated neuropathic pain in diabetic rats. Moreover, salidroside induced AMPK activation and suppressed NLRP3 inflammasome activation in the DRGs of diabetic rats. In addition, salidroside treatment relieved oxidative stress, improved insulin sensitivity and regulated the AMPK-NLRP3 inflammasome axis in HG-treated DRGs in vitro. Furthermore, AMPK inhibition in vivo or AMPK silencing in vitro abolished the beneficial effects of salidroside on diabetic neuropathic pain. Together, these results indicate that salidroside alleviates diabetic neuropathic pain through its regulation of the AMPK-NLRP3 inflammasome axis in DRGs.
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Proteínas Quinasas Activadas por AMP/metabolismo , Analgésicos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Ganglios Espinales/efectos de los fármacos , Glucósidos/farmacología , Hipoglucemiantes/farmacología , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neuralgia/prevención & control , Fenoles/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/enzimología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Ganglios Espinales/enzimología , Ganglios Espinales/fisiopatología , Resistencia a la Insulina , Masculino , Neuralgia/enzimología , Neuralgia/etiología , Neuralgia/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
INTRODUCTION/AIMS: Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions. METHODS: Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle. RESULTS: Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers. DISCUSSION: Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.