RESUMEN
Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
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Potenciales de Acción , Ganglios Espinales , Radiculopatía , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Humanos , Masculino , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Radiculopatía/tratamiento farmacológico , Células Cultivadas , Persona de Mediana Edad , Femenino , Anciano , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14 and OSM in male and CCL1, CCL21, PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Coexpression modules revealed enrichment in members of JUN-FOS signalling in males and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.
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Neuralgia , ARN , Femenino , Humanos , Masculino , Ganglios Espinales/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , ARN/metabolismo , Transcriptoma , Factores SexualesRESUMEN
Methylene blue (MB) is an effective treatment for methemoglobinemia, ifosfamide-induced encephalopathy, cyanide poisoning, and refractory vasoplegia. However, clinical case reports and preclinical studies indicate potentially neurotoxic activity of MB at certain concentrations. The exact mechanisms of MB neurotoxicity are not known, and while the effects of MB on neuronal tissue from different brain regions and myenteric ganglia have been examined, its effects on primary afferent neurons from dorsal root ganglia (DRG) have not been studied. Mouse DRG were exposed to MB (0.3-10 µM) in vitro to assess neurite outgrowth. Increasing concentrations of MB (0.3-10 µM) were associated with neurotoxicity as shown by a substantial loss of cells with neurite formation, particularly at 10 µM. In parallel experiments, cultured rat DRG neurons were treated with MB (100 µM) to examine how MB affects electrical membrane properties of small-diameter sensory neurons. MB decreased peak inward and outward current densities, decreased action potential amplitude, overshoot, afterhyperpolarization, increased action potential rise time, and decreased action potential firing in response to current stimulation. MB induced dose-dependent toxicity in peripheral neurons, in vitro. These findings are consistent with studies in brain and myenteric ganglion neurons showing increased neuronal loss and altered membrane electrical properties after MB application. Further research is needed to parse out the toxicity profile for MB to minimize damage to neuronal structures and reduce side effects in clinical settings.
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Ganglios Espinales , Azul de Metileno , Ratas , Ratones , Animales , Azul de Metileno/farmacología , Azul de Metileno/metabolismo , Ganglios Espinales/metabolismo , Células Receptoras Sensoriales/metabolismo , Electrofisiología , Técnicas de Cultivo de Célula , Células CultivadasRESUMEN
Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.
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Nociceptores/fisiología , Animales , Dolor Crónico/fisiopatología , Humanos , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND: Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. METHODS: After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. RESULTS: A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. CONCLUSIONS: Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.
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Carcinoma de Células Escamosas , Neoplasias de la Lengua , Analgésicos Opioides/uso terapéutico , Carcinoma de Células Escamosas/cirugía , Humanos , Dolor Postoperatorio/tratamiento farmacológico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de la Lengua/cirugíaRESUMEN
Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo. Most (44 of 53) of the C-fiber nociceptors isolated from Nav1.8-ChR2+ mice were found to be responsive to blue (470 nm) light. Response characteristics, including conduction velocity and responses to mechanical stimuli, were comparable between nociceptors isolated from Nav1.8-ChR2+ and control mice. Interestingly, while none of the non-light-responsive C-fibers were sensitive to heat or cold, nearly all (77%) light-sensitive fibers were excited by mechanical and thermal stimuli, suggesting that Nav1.8 is predominantly expressed by C-fiber nociceptors that are responsive to multiple stimulus modalities. The ability to activate peripheral nociceptors with light provides a method of stimulation that is noninvasive, does not require mechanical interruption of the skin, and accesses receptive fields that might be difficult or impossible to stimulate with standard stimuli while allowing repeated stimulation without injuring the skin.NEW & NOTEWORTHY Transgenic mice that express the blue light-sensitive protein channelrhodopsin2 (ChR2) in nociceptive nerve fibers that contain voltage-gated sodium channel Nav1.8 were used to determine functional properties of these afferent fibers. Electrophysiological recordings in vivo revealed that most nociceptive fibers that possess Nav1.8 are C-fiber nociceptors that respond to multiple stimulus modalities. Furthermore, responses evoked by blue light stimulation were comparable to those elicited by noxious mechanical, heat, and cold stimuli.
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Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Fibras Nerviosas Amielínicas/metabolismo , Nociceptores/metabolismo , Piel/inervación , Potenciales de Acción , Animales , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Femenino , Miembro Posterior , Masculino , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.8/genética , Nocicepción/fisiología , Optogenética , Estimulación Física , Piel/metabolismoRESUMEN
Local field potentials (LFP) reflect the spatially weighted low-frequency activity nearest to a recording electrode. LFP recording is a window to a wide range of cellular activities and has gained increasing attention over recent years. We here review major conceptual issues related to LFP with the goal of creating a resource for non-experts considering implementing LFP into their research. We discuss the cellular activity that constitutes the local field potential; recording techniques, including recommendations and limitations; approaches to analysis of LFP data (with focus on power-banded analyses); and finally we discuss reports of the successful use of LFP in clinical applications.
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Microelectrodos , Neuronas/fisiología , Animales , Humanos , Fenómenos Fisiológicos del Sistema Nervioso , Procesamiento de Señales Asistido por ComputadorRESUMEN
Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN.
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Amidohidrolasas/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Endocannabinoides/metabolismo , Nocicepción , Nociceptores/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Amidohidrolasas/metabolismo , Animales , Benzamidas/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Carbamatos/farmacología , Cisplatino/efectos adversos , Hidrólisis , Indoles/farmacología , Masculino , Ratones , Morfolinas/farmacología , Fibras Nerviosas Amielínicas/metabolismo , Fibras Nerviosas Amielínicas/fisiología , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Pirazoles/farmacología , Piel/lesionesRESUMEN
Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers.
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Analgésicos Opioides , Dolor en Cáncer , Neoplasias , Humanos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/efectos adversos , Neoplasias/tratamiento farmacológico , Dolor en Cáncer/tratamiento farmacológico , Manejo del Dolor/métodos , Calidad de VidaRESUMEN
Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na+ and K+ channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
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The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30-150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer's and Parkinson's disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics.
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Exosomas , Biomarcadores/metabolismo , Comunicación Celular , Exosomas/metabolismo , Humanos , Nocicepción , DolorRESUMEN
Cancer is a significant public health problem worldwide. While there has been a steady decrease in the cancer death rate over the last two decades, the number of survivors has increased and, thus, cancer-related sequela. Pain affects the life of patients with cancer and survivors. Prescription opioids continue as the analgesic of choice to treat moderate-to-severe cancer-related pain. There has been controversy on whether opioids impact cancer progression by acting on cancer cells or the tumor microenvironment. The µ-opioid receptor is the site of action of prescription opioids. This receptor can participate in an important mechanism of cancer spread, such as perineural invasion. In this review, current evidence on the role of the µ-opioid receptor in cancer growth is summarized and preliminary evidence about its effect on the cross-talk between sensory neurons and malignant cells is provided.
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Neoplasias , Receptores Opioides , Analgésicos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Humanos , Dolor/tratamiento farmacológico , Receptores Opioides/fisiología , Microambiente TumoralRESUMEN
Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known. Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons. Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group. Conclusions: Pro-inflammatory substances released in cancer cell-DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.
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It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.
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Antineoplásicos/efectos adversos , Inmunidad Innata/inmunología , Neuralgia/inducido químicamente , Neuralgia/inmunología , Animales , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Neuralgia/patología , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/inmunologíaRESUMEN
The mechanisms underlying chemotherapy-induced peripheral neuropathy have yet to be fully elucidated, but primary afferent neurons have emerged as an especially vulnerable initiating pathophysiological target. An important recent study has also shown that the initial toxicity produced by paclitaxel in patients was highly predictive of long-term outcome. In this study, we therefore focused on defining the mechanisms of acute toxicity produced by paclitaxel treatment on primary sensory neurons under in vitro conditions. In primary rat dorsal root ganglion (DRG) culture with paclitaxel, an increase of pERK and pp38 was observed at 2 hours, and this was accompanied by an increase in expression and release of C-C chemokine ligand 2 (CCL2). There was no change in pJNK. The increase in pERK was sustained at 48 hours of exposure when the expression of TLR4, MyD88, and IL-6 was also increased. IL-6 and CCL2 were colocalized to TLR4-positive cells, and all these responses were prevented by coincubation with a TLR4 antagonist (LPS-RS). Whole-cell patch-clamp recordings revealed that DRG neurons developed spontaneous depolarizing fluctuations (DSFs) in membrane potential and hyperexcitability to current injection but no ectopic action potential activity at 24 and 48 hours of paclitaxel incubation. However, CCL2 applied to cultured neurons not only induced DSFs but also evoked action potentials. Evidence of oxidative stress and mitotoxicity was observed at 48 hours of exposure. These results closely parallel the responses measured in the DRG with paclitaxel exposure in vivo and so indicate that acute toxicity of paclitaxel on the DRG can be modelled using an in vitro approach.
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Antineoplásicos Fitogénicos , Enfermedades del Sistema Nervioso Periférico , Animales , Antineoplásicos Fitogénicos/toxicidad , Ganglios Espinales , Humanos , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ratas , Ratas Sprague-DawleyRESUMEN
It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express NaV1.8 voltage-gated sodium channels. These mice (NaV1.8-ChR2+) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. We assessed the effect of Lo/OMI on nociceptor activity in both naïve mice and mice treated with complete Freund's adjuvant (CFA) to induce chronic inflammation of the hind paw. Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity (SA) as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express NaV1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.
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Loperamida , Nociceptores , Animales , Hiperalgesia/tratamiento farmacológico , Inflamación , Loperamida/farmacología , Ratones , Morfolinas , Fibras Nerviosas Amielínicas , Receptores Opioides delta , Receptores Opioides muRESUMEN
BACKGROUND: Spontaneous pain after surgical incision is a significant problem for most post-operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non-opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post-operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre-operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. METHODS: The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30 min or 1 week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri-incisional tissue biopsies. RESULTS: Intraplantar administration of capsaicin 30 min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2 weeks post-incision, at a time when no recovery of epidermal innervation is observed. CONCLUSIONS: Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision-induced pain behaviours and reduced epidermal innervation around the incision site. The long-lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. SIGNIFICANCE: Pre-operative capsaicin infiltration attenuated spontaneous pain-like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long-lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre- or intra-operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post-operative pain and reduce the need for opioids during recovery.
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Capsaicina , Hiperalgesia , Animales , Capsaicina/farmacología , Desnervación , Humanos , Hiperalgesia/tratamiento farmacológico , Microscopía Confocal , Dolor Postoperatorio/tratamiento farmacológico , RatasRESUMEN
SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.
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Betacoronavirus , Infecciones por Coronavirus/metabolismo , Ganglios Espinales/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Nociceptores/metabolismo , Peptidil-Dipeptidasa A/biosíntesis , Neumonía Viral/metabolismo , Glicoproteína de la Espiga del Coronavirus/biosíntesis , Adulto , Anciano , Enzima Convertidora de Angiotensina 2 , COVID-19 , Infecciones por Coronavirus/genética , Femenino , Ganglios Espinales/virología , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/virología , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Sickle cell disease (SCD) describes a group of disorders associated with a point mutation in the beta chain of hemoglobin. The mutation leads to the creation of sickle hemoglobin (HbS) and causes distortion of erythrocytes through polymerization under low oxygen, resulting in characteristic sickle red blood cells. Vaso-occlusion episodes caused by accumulation of sRBCs results in ischemia-reperfusion injury, reduced oxygen supply to organs, oxidative stress, organ damage and severe pain that often requires hospitalization and opioid treatment. Further, many patients suffer from chronic pain, including hypersensitivity to heat and cold stimuli. Progress towards the development of novel strategies for both acute and chronic pain in patients with SCD has been impeded by a lack of understanding the mechanisms underlying pain in SCD. The purpose of this review is to highlight evidence for the contribution of peripheral and central sensitization that leads to widespread, chronic pain and hyperalgesia. Targeting the mechanisms that initiate and maintain sensitization in SCD might offer effective approaches to manage the severe and debilitating pain associated with this condition.
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Anemia de Células Falciformes/fisiopatología , Sensibilización del Sistema Nervioso Central/fisiología , Dolor Crónico/fisiopatología , Hiperalgesia/fisiopatología , Nociceptores/fisiología , Células del Asta Posterior/fisiología , Anemia de Células Falciformes/complicaciones , Animales , Dolor Crónico/complicaciones , Humanos , Hiperalgesia/complicacionesRESUMEN
Painful peripheral neuropathy is a dose-limiting side effect of cisplatin treatment. Using a murine model of cisplatin-induced hyperalgesia, we determined whether a PPARγ synthetic agonist, pioglitazone, attenuated the development of neuropathic pain and identified underlying mechanisms. Cisplatin produced mechanical and cold hyperalgesia and decreased electrical thresholds of Aδ and C fibers, which were attenuated by coadministration of pioglitazone (10 mg/kg, intraperitoneally [i.p.]) with cisplatin. Antihyperalgesic effects of pioglitazone were blocked by the PPARγ antagonist T0070907 (10 mg/kg, i.p.). We hypothesized that the ability of pioglitazone to reduce the accumulation of reactive oxygen species (ROS) in dorsal root ganglion (DRG) neurons contributed to its antihyperalgesic activity. Effects of cisplatin and pioglitazone on somatosensory neurons were studied on dissociated mouse DRG neurons after 24 hours in vitro. Incubation of DRG neurons with cisplatin (13 µM) for 24 hours increased the occurrence of depolarization-evoked calcium transients, and these were normalized by coincubation with pioglitazone (10 µM). Oxidative stress in DRG neurons was considered a significant contributor to cisplatin-evoked hyperalgesia because a ROS scavenger attenuated hyperalgesia and normalized the evoked calcium responses when cotreated with cisplatin. Pioglitazone increased the expression and activity of ROS-reducing enzymes in DRG and normalized cisplatin-evoked changes in oxidative stress and labeling of mitochondria with the dye MitoTracker Deep Red, indicating that the antihyperalgesic effects of pioglitazone were attributed to its antioxidant properties in DRG neurons. These data demonstrate clear benefits of broadening the use of the antidiabetic drug pioglitazone, or other PPARγ agonists, to minimize the development of cisplatin-induced painful neuropathy.