RESUMEN
The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100-1,000 µM) significantly inhibited capsaicin (100 nM)-induced, but not high K+ (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery.
Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación Neurogénica/tratamiento farmacológico , Pentobarbital/uso terapéutico , Nervios Periféricos/metabolismo , Sustancia P/metabolismo , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Canales de Calcio/metabolismo , Capsaicina/farmacología , Células Cultivadas , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ketamina/farmacología , Masculino , Inflamación Neurogénica/metabolismo , Pentobarbital/farmacología , Nervios Periféricos/efectos de los fármacos , Ratas , Ratas Wistar , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/metabolismoRESUMEN
Radiation-induced acute oral mucositis is associated with inflammation and pain. In other realms of pain research, nociceptors are known to be activated by inflammatory cytokines; for example, tumor necrosis factor alpha (TNF-α) can activate transient receptor potential ion channels on sensory neurons. But there is an unclear relationship between inflammatory cytokines and molecular mediators of pain in radiation-induced mucositis (RIM) and radiation-associated pain (RAP). In this prospective, analytical, experimental pilot study, a common drug (pentoxifylline [PTX]) was used with the goal of inhibiting TNF-α signaling in mice that underwent lingual irradiation to induce severe acute oral RIM/RAP. Body weight and glossitis scores were recorded daily. Eye wiping behaviors were assayed as a surrogate measure of oral discomfort (which is possible due to cross-sensitization of the mandibular and ophthalmic branches of the trigeminal nerve). Quantitative real-time reverse transcription polymerase chain reaction was performed on irradiated tongue tissue to measure changes in expression of TNF-α, its receptor, nuclear factor kappa-light-chain-enhancer of activated B cells, transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential vanilloid type 4 (TRPV4). Responsiveness of afferent sensory trigeminal neurons to TNF-α, a TRPV1 agonist (capsaicin), and a partial TRPV4 agonist (histamine) was measured via calcium imaging. Although PTX treatment did not reduce glossitis severity or mitigate weight loss in mice with RIM/RAP, it did inhibit the upregulation of TNF-α's receptor that normally accompanies RIM, and it also reduced neuronal responsiveness to each of the aforementioned chemical stimuli. These results provide provisional evidence that inhibition of TNF-α signaling with PTX treatment may serve as a useful tool for reducing pain in head and neck cancer patients.
Asunto(s)
Dolor/veterinaria , Pentoxifilina/uso terapéutico , Radioterapia/efectos adversos , Estomatitis/complicaciones , Animales , Capsaicina/farmacología , Histamina/farmacología , Ratones , Dolor/prevención & control , Proyectos Piloto , Estudios Prospectivos , Protectores contra Radiación/uso terapéutico , Fármacos del Sistema Sensorial/farmacología , Transducción de Señal/efectos de los fármacos , Estomatitis/tratamiento farmacológico , Estomatitis/etiología , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Oropharyngeal dysphagia, or difficulty in swallowing, is a major health problem that can lead to serious complications, such as pulmonary aspiration, malnutrition, dehydration, and pneumonia. The current clinical management of oropharyngeal dysphagia mainly focuses on compensatory strategies and swallowing exercises/maneuvers; however, studies have suggested their limited effectiveness for recovering swallowing physiology and for promoting neuroplasticity in swallowing-related neuronal networks. Several new and innovative strategies based on neurostimulation in peripheral and cortical swallowing-related regions have been investigated, and appear promising for the management of oropharyngeal dysphagia. The peripheral chemical neurostimulation strategy is one of the innovative strategies, and targets chemosensory ion channels expressed in peripheral swallowing-related regions. A considerable number of animal and human studies, including randomized clinical trials in patients with oropharyngeal dysphagia, have reported improvements in the efficacy, safety, and physiology of swallowing using this strategy. There is also evidence that neuroplasticity is promoted in swallowing-related neuronal networks with this strategy. The targeting of chemosensory ion channels in peripheral swallowing-related regions may therefore be a promising pharmacological treatment strategy for the management of oropharyngeal dysphagia. In this review, we focus on this strategy, including its possible neurophysiological and molecular mechanisms.
Asunto(s)
Trastornos de Deglución/tratamiento farmacológico , Canales Iónicos/metabolismo , Fármacos del Sistema Sensorial/uso terapéutico , Animales , Capsaicina/farmacología , Capsaicina/uso terapéutico , Ácido Cítrico/farmacología , Ácido Cítrico/uso terapéutico , Trastornos de Deglución/metabolismo , Humanos , Canales Iónicos/antagonistas & inhibidores , Mentol/farmacología , Mentol/uso terapéutico , Terapia Molecular Dirigida , Plasticidad Neuronal , Ensayos Clínicos Controlados Aleatorios como Asunto , Fármacos del Sistema Sensorial/farmacologíaRESUMEN
Atypical antipsychotics (AAPs) have the tendency of inducing severe metabolic alterations like obesity, diabetes mellitus, insulin resistance, dyslipidemia and cardiovascular complications. These alterations have been attributed to altered hypothalamic appetite regulation, energy sensing, insulin/leptin signaling, inflammatory reactions and active reward anticipation. Line of evidence suggests that transient receptor potential vanilloid type 1 and 3 (TRPV1 and TRPV3) channels are emerging targets in treatment of obesity, diabetes mellitus and could modulate feed intake. The present study was aimed to investigate the putative role TRPV1/TRPV3 in olanzapine-induced metabolic alterations in mice. Female BALB/c mice were treated with olanzapine for six weeks to induce metabolic alterations. Non-selective TRPV1/TRPV3 antagonist (ruthenium red) and selective TRPV1 (capsazepine) and TRPV3 antagonists (2,2-diphenyltetrahydrofuran or DPTHF) were used to investigate the involvement of TRPV1/TRPV3 in chronic olanzapine-induced metabolic alterations. These metabolic alterations were differentially reversed by ruthenium red and capsazepine, while DPTHF didn't show any significant effect. Olanzapine treatment also altered the mRNA expression of hypothalamic appetite-regulating and nutrient-sensing factors, inflammatory genes and TRPV1/TRPV3, which were reversed with ruthenium red and capsazepine treatment. Furthermore, olanzapine treatment also increased expression of TRPV1/TRPV3 in nucleus accumbens (NAc), TRPV3 expression in ventral tegmental area (VTA), which were reversed by the respective antagonists. However, DPTHF treatment showed reduced feed intake in olanzapine treated mice, which might be due to TRPV3 specific antagonism and reduced hedonic feed intake. In conclusion, our results suggested the putative role TRPV1 in hypothalamic dysregulations and TRPV3 in the mesolimbic pathway; both regulate feeding in olanzapine treated mice.
Asunto(s)
Regulación del Apetito/efectos de los fármacos , Inflamación/metabolismo , Olanzapina/farmacología , Canales Catiónicos TRPV/metabolismo , Animales , Capsaicina/administración & dosificación , Capsaicina/análogos & derivados , Capsaicina/farmacología , Colorantes/administración & dosificación , Colorantes/farmacología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Femenino , Furanos/administración & dosificación , Furanos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Hipotálamo/efectos de los fármacos , Inflamación/genética , Metformina/administración & dosificación , Metformina/farmacología , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Rojo de Rutenio/administración & dosificación , Rojo de Rutenio/farmacología , Fármacos del Sistema Sensorial/administración & dosificación , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/genéticaRESUMEN
Background Gabapentinoids are known to reduce neuropathic pain. The aim of this experimental study was to investigate whether gabapentinoids exert anti-inflammatory and/or anti-nociceptive effects at the cellular level using primary cultures of rat dorsal root ganglia (DRG). Methods Cells from rat DRG were cultured in the presence of gabapentin or pregabalin, and we tested the effects of subsequent stimulation with lipopolysaccharide (LPS) on the expression of genes (real-time polymerase chain reaction) and production of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) by specific bioassays. Using Ca2+ imaging, we further investigated in neurons the effects of gabapentinoids upon stimulation with the TRPV-1 agonist capsaicin. Results There is a small influence of gabapentinoids on the inflammatory response to LPS stimulation, namely, a significantly reduced expression of IL-6. Pregabalin and gabapentin further seem to exert a moderate inhibitory influence on capsaicin-induced Ca2+ signals in DRG neurons. Conclusions Although the single inhibitory effects of gabapentinoids on inflammatory and nociceptive responses are moderate, a combination of both effects might provide an explanation for the proposed function of these substances as an adjuvant for the reduction of neuropathic pain.
Asunto(s)
Gabapentina/farmacología , Ganglios Espinales/efectos de los fármacos , Inflamación/fisiopatología , Lipopolisacáridos/toxicidad , Neuralgia/tratamiento farmacológico , Corteza Somatosensorial/fisiopatología , Analgésicos/farmacología , Animales , Capsaicina/farmacología , Femenino , Ganglios Espinales/inmunología , Ganglios Espinales/metabolismo , Inflamación/inducido químicamente , Masculino , Neuralgia/metabolismo , Neuronas/efectos de los fármacos , Pregabalina/farmacología , Cultivo Primario de Células , Ratas , Ratas Wistar , Fármacos del Sistema Sensorial/farmacología , Corteza Somatosensorial/efectos de los fármacosRESUMEN
Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9-T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.
Asunto(s)
Capsaicina/uso terapéutico , Cardiotónicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Nocicepción , Fármacos del Sistema Sensorial/uso terapéutico , Piel/inervación , Animales , Capsaicina/farmacología , Cardiotónicos/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiología , Proteína Quinasa C/metabolismo , Receptor de Bradiquinina B2/metabolismo , Reflejo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Fármacos del Sistema Sensorial/farmacologíaRESUMEN
Transient receptor potential (TRP) vallinoid 1 (TRPV1) and ankyrin 1 (TRPA1) are two transducing channels expressed on peripheral sensory nerves involved in pain sensation. Upregulation of their expression, stimulated by inflammatory cytokines and growth factors in animal pain models, correlate with the induction of nociceptive hyper-sensitivity. Herein, we firstly demonstrate by immuno-cytochemical labelling that TNFα augments the surface content of these channels on rat cultured dorsal root ganglion (DRG) neurons which, in turn, enhances the electrophysiological and functional responses of the latter to their specific agonists. A molecular basis underlying this TNFα-dependent enhancement was unveiled by pre-treating DRGs with a recently-published chimeric protein, consisting of the protease light chain (LC) of botulinum neurotoxin (BoNT) serotype E fused to full-length BoNT/A (LC/E-BoNT/A). This cleaves synaptosomal-associated protein of Mr 25k (SNAP-25) and reported previously to exhibit anti-nociceptive activity in a rat model of neuropathic pain. Low pM concentrations of this chimera were found to prevent the TNFα-stimulated delivery of TRPV1/A1 to the neuronal plasmalemma and, accordingly, decreased their incremental functional activities relative to those of control cells, an effect accompanied by SNAP-25 cleavage. Advantageously, LC/E-BoNT/A did not reduce the basal surface contents of the two channels or their pharmacological responses. Thus, use of multiple complementary methodologies provides evidence that LC/E-BoNT/A abolishes the TNFα-dependent augmented, but not resting, surface trafficking of TRPV1/A1. As TNFα is known to induce nociceptive hyper-sensitivity in vivo, our observed inhibition by LC/E-BoNT/A of its action in vitro could contribute to its potential alleviation of pain.
Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas/farmacología , Ganglios Espinales/efectos de los fármacos , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Animales Recién Nacidos , Calcio/metabolismo , Capsaicina/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Escherichia coli , Ganglios Espinales/metabolismo , Ratas Sprague-Dawley , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Proteína 25 Asociada a Sinaptosomas/metabolismo , Canales Catiónicos TRPV/agonistasRESUMEN
Conrado de Freitas, M, Cholewa, JM, Freire, RV, Carmo, BA, Bottan, J, Bratfich, M, Della Bandeira, MP, Gonçalves, DC, Caperuto, EC, Lira, FS, and Rossi, FE. Acute capsaicin supplementation improves resistance training performance in trained men. J Strength Cond Res 32(8): 2227-2232, 2018-The purpose of this study was to investigate the acute effect of capsaicin supplementation on performance, rate of perceived exertion (RPE), and blood lactate concentrations during resistance exercise in healthy trained young men. Ten resistance-trained men (age = 22.7 ± 4.0 years, mass = 82.3 ± 9.6 kg, and height = 175 ± 0.1 cm) completed 2 randomized, double-blind trials: capsaicin condition (12 mg) or a placebo condition. Forty-five minutes after supplement consumption, subjects performed 4 sets until movement failure in the squat exercise at 70% of 1 repetition maximum with 90 seconds of rest interval between sets. The total mass lifted (total repetitions × mass lifted) was calculated. The RPE was recorded after the last set. Blood lactate was analyzed after each set of exercise, immediately postexercise, and after 3, 5, and at 30 minutes during recovery. The number of repetitions in each set decreased significantly after all sets compared with set-1 and after set-3 and set-4 in relation to set-2 (p < 0.001); however, total mass lifted was higher in capsaicin compared with placebo (3,919.4 ± 1,227.4 kg vs. 3,179.6 ± 942.4 kg, p = 0.002). Blood lactate increased significantly after each set (p < 0.001); however, there were no differences between conditions. Rate of perceived exertion was significantly less for the capsaicin condition than placebo (17.2 ± 1.0 vs. 18.3 ± 1.7, p = 0.048). In summary, acute capsaicin supplementation improves lower-body resistance training performance in trained young men.
Asunto(s)
Rendimiento Atlético/fisiología , Capsaicina/farmacología , Tolerancia al Ejercicio/efectos de los fármacos , Entrenamiento de Fuerza , Fármacos del Sistema Sensorial/farmacología , Adolescente , Adulto , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Prueba de Esfuerzo , Humanos , Ácido Láctico/sangre , Masculino , Esfuerzo Físico/efectos de los fármacos , Adulto JovenAsunto(s)
Antipruriginosos/uso terapéutico , Capsaicina/uso terapéutico , Prurito/tratamiento farmacológico , Administración Tópica , Antipruriginosos/farmacología , Capsaicina/farmacología , Enfermedad Crónica , Herpes Zóster/complicaciones , Humanos , Fibras Nerviosas/efectos de los fármacos , Prurito/etiología , Fármacos del Sistema Sensorial/farmacologíaRESUMEN
Chili pepper is used as a food, seasoning and has been revered for its medicinal and health claims. It is very popular and is the most common spice worldwide. Capsaicin (CAP) is a major pungent and bioactive phytochemical in chili peppers. CAP has been shown to improve mitochondrial biogenesis and adenosine triphosphate (ATP) production. However, there is limited evidence around the effects of CAP on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of CAP on anti-fatigue and ergogenic functions following physiological challenge. Female Institute of Cancer Research (ICR) mice from four groups (n = 8 per group) were orally administered CAP for 4 weeks at 0, 205, 410, and 1025 mg/kg/day, which were respectively designated the vehicle, CAP-1X, CAP-2X, and CAP-5X groups. The anti-fatigue activity and exercise performance was evaluated using forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, BUN (blood urea nitrogen) and creatine kinase (CK) after a 15-min swimming exercise. The grip strength and exhaustive swimming time of the CAP-5X group were significantly higher than other groups. CAP supplementation dose-dependently reduced serum lactate, ammonia, BUN and CK levels, and increased glucose concentration after the 15-min swimming test. In addition, CAP also increased hepatic glycogen content, an important energy source for exercise. The possible mechanism was relevant to energy homeostasis and the physiological modulations by CAP supplementation. Therefore, our results suggest that CAP supplementation may have a wide spectrum of bioactivities for promoting health, performance improvement and fatigue amelioration.
Asunto(s)
Capsaicina/administración & dosificación , Suplementos Dietéticos , Ejercicio Físico/fisiología , Fatiga Muscular/efectos de los fármacos , Resistencia Física/efectos de los fármacos , Fármacos del Sistema Sensorial/administración & dosificación , Amoníaco/sangre , Animales , Glucemia/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Capsaicina/farmacología , Capsicum/química , Creatina Quinasa/sangre , Femenino , Glucógeno/metabolismo , Humanos , Ácido Láctico/sangre , Hígado/metabolismo , Ratones , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Condicionamiento Físico Animal/métodos , Fármacos del Sistema Sensorial/farmacología , Natación/fisiologíaRESUMEN
Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.
Asunto(s)
Capsaicina/análogos & derivados , Capsaicina/uso terapéutico , Dolor/tratamiento farmacológico , Fármacos del Sistema Sensorial/uso terapéutico , Capsaicina/química , Capsaicina/farmacología , Capsicum/química , Capsicum/clasificación , Ensayos Clínicos como Asunto , Humanos , Estructura Molecular , Dolor/etiología , Dolor/metabolismo , Fármacos del Sistema Sensorial/química , Fármacos del Sistema Sensorial/farmacología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Administration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields. MATERIAL AND METHODS: Using electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles. RESULTS: Seven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation. DISCUSSION: This study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors' responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A's ability to act as a prophylactic.
Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Meninges/efectos de los fármacos , Trastornos Migrañosos/fisiopatología , Fármacos Neuromusculares/farmacología , Nociceptores/efectos de los fármacos , Animales , Capsaicina/farmacología , Suturas Craneales/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Planta de la Mostaza , Aceites de Plantas/farmacología , Ratas , Ratas Sprague-Dawley , Fármacos del Sistema Sensorial/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPV/agonistasRESUMEN
Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 µM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 µM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.
Asunto(s)
Neurotransmisores/farmacología , Oxazoles/farmacología , Oximas/farmacología , Fármacos del Sistema Sensorial/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Animales , Células CHO , Péptido Relacionado con Gen de Calcitonina/metabolismo , Calcio/metabolismo , Capsaicina/farmacología , Cationes Bivalentes/metabolismo , Línea Celular , Cricetulus , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isotiocianatos/farmacología , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oxazoles/síntesis química , Oxazoles/química , Oximas/síntesis química , Oximas/química , Ratas Wistar , Fármacos del Sistema Sensorial/síntesis química , Fármacos del Sistema Sensorial/química , Tráquea/inervación , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Potencial de Receptor Transitorio/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/fisiologíaRESUMEN
A sensitive response of the nervous system to changes in temperature is of predominant importance for homeotherms to maintain a stable body temperature. A number of temperature-sensitive transient receptor potential (TRP) ion channels have been studied as nociceptors that respond to extreme temperatures and harmful chemicals. Recent findings in the field of pain have established a family of six thermo-TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) that exhibit sensitivity to increases or decreases in temperature, as well as to chemical substances eliciting the respective hot or cold sensations. In this study, we used behavioral methods to investigate whether mustard oil (allyl isothiocyanate) and capsaicin affect the sensitivity to heat, innocuous and noxious cold, and mechanical stimuli in male rats. The results obtained indicate that TRPA1 and TRPV1 channels are clearly involved in pain reactions, and the TRPA1 agonist allyl isothiocyanate enhances the heat pain sensitivity, possibly by indirectly modulating TRPV1 channels coexpressed in nociceptors with TRPA1. Overall, our data support the role of thermosensitive TRPA1 and TRPV1 channels in pain modulation and show that these two thermoreceptor channels are in a synergistic and/or conditional relationship with noxious heat and cold cutaneous stimulation.
Asunto(s)
Nocicepción/fisiología , Dolor Nociceptivo/metabolismo , Canales Catiónicos TRPC/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Capsaicina/farmacología , Frío , Relación Dosis-Respuesta a Droga , Calor , Masculino , Planta de la Mostaza , Aceites de Plantas/farmacología , Ratas Wistar , Fármacos del Sistema Sensorial/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPV/agonistas , TactoRESUMEN
The capsaicin 8 % patch (QUTENZA®) is an adhesive patch containing a high concentration (8 % w/w) of synthetic capsaicin, a selective agonist of transient receptor potential vanilloid 1 channel. It is approved for treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain in the EU; it is only approved to treat postherpetic neuralgia (PHN) in the USA. In patients with painful diabetic peripheral neuropathy (PDPN), a single 30-min application of the capsaicin 8 % patch significantly improved pain relief and sleep quality compared with placebo in a 12-week double-blind trial. In a 52-week, randomized trial, up to seven consecutive 30-min treatments with the capsaicin 8 % patch (≤7 treatments each at least 8 weeks apart) plus standard of care therapy was associated with sustained pain relief and no negative neurological safety consequences compared with standard of care. In two randomized trials, a single 60-min application of the capsaicin 8 % patch reduced pain scores significantly more than a low-concentration (0.04 %) capsaicin control patch in patients with PHN. Capsaicin 8 % patch treatment was noninferior to pregabalin (optimized dosage) in a randomized trial in patients with nondiabetic peripheral neuropathic pain. Results in two trials in patients with HIV-AN were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8 % patch was associated with expected, transient, capsaicin-related application-site adverse events such as erythema and pain.
Asunto(s)
Capsaicina/administración & dosificación , Capsaicina/uso terapéutico , Neuropatías Diabéticas/tratamiento farmacológico , Neuralgia Posherpética/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Parche Transdérmico , Capsaicina/efectos adversos , Capsaicina/farmacocinética , Humanos , Manejo del Dolor , Pregabalina/uso terapéutico , Fármacos del Sistema Sensorial/efectos adversos , Fármacos del Sistema Sensorial/farmacocinética , Fármacos del Sistema Sensorial/farmacología , Fármacos del Sistema Sensorial/uso terapéutico , Parche Transdérmico/efectos adversosRESUMEN
Hyaluronan (HA) is present in the extracellular matrix of all body tissues, including synovial fluid in joints, in which it behaves as a filter that buffers transmission of mechanical forces to nociceptor nerve endings thereby reducing pain. Using recombinant systems, mouse-cultured dorsal root ganglia (DRG) neurons and in vivo experiments, we found that HA also modulates polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channels. HA diminishes heat, pH and capsaicin (CAP) responses, thus reducing the opening probability of the channel by stabilizing its closed state. Accordingly, in DRG neurons, HA decreases TRPV1-mediated impulse firing and channel sensitization by bradykinin. Moreover, subcutaneous HA injection in mice reduces heat and capsaicin nocifensive responses, whereas the intra-articular injection of HA in rats decreases capsaicin joint nociceptor fibres discharge. Collectively, these results indicate that extracellular HA reduces the excitability of the ubiquitous TRPV1 channel, thereby lowering impulse activity in the peripheral nociceptor endings underlying pain.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Ácido Hialurónico/farmacología , Neuronas/efectos de los fármacos , Dolor Nociceptivo , Nociceptores/efectos de los fármacos , Rodilla de Cuadrúpedos/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Bradiquinina/farmacología , Células CHO , Calcio/metabolismo , Capsaicina/farmacología , Línea Celular Tumoral , Cricetulus , Ganglios Espinales/citología , Células HEK293 , Calor , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Fármacos del Sistema Sensorial/farmacología , Rodilla de Cuadrúpedos/inervación , Canal Catiónico TRPA1 , Canales Catiónicos TRPM/efectos de los fármacos , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/efectos de los fármacos , Canales de Potencial de Receptor Transitorio/metabolismo , Vasodilatadores/farmacologíaRESUMEN
To gain a better understanding of the neuroplasticity of afferent neurons during postnatal ontogenesis, the distribution of neuronal nitric oxide synthase (nNOS) immunoreactivity was studied in the nodose ganglion (NG) and Th2 and L4 dorsal root ganglia (DRG) from vehicle-treated and capsaicin-treated female Wistar rats at different ages (10-day-old, 20-day-old, 30-day-old, and two-month-old). The percentage of nNOS-immunoreactive (IR) neurons decreased after capsaicin treatment in all studied ganglia in first 20 days of life, from 55.4% to 36.9% in the Th2 DRG, from 54.6% to 26.1% in the L4 DRG and from 37.1% to 15.0% in the NG. However, in the NG, the proportion of nNOS-IR neurons increased after day 20, from 11.8% to 23.9%. In the sensory ganglia of all studied rats, a high proportion of nNOS-IR neurons bound isolectin B4. Approximately 90% of the sensory nNOS-IR neurons bound to IB4 in the DRG and approximately 80% in the NG in capsaicin-treated and vehicle-treated rats. In 10-day-old rats, a large number of nNOS-IR neurons also expressed TrkA, and the proportion of nNOS(+)/TrkA(+) neurons was larger in the capsaicin-treated rats compared with the vehicle-treated animals. During development, the percentage of nNOS(+)/TrkA(+) cells decreased in the first month of life in both groups. The information provided here will also serve as a basis for future studies investigating mechanisms of sensory neuron development.
Asunto(s)
Capsaicina/farmacología , Ganglios Sensoriales/citología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Fármacos del Sistema Sensorial/farmacología , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Masculino , Lectinas de Plantas/metabolismo , Embarazo , Ratas , Ratas WistarRESUMEN
The neuronal and smooth muscle effects of a methanol extract prepared from the air-dried flowering aerial parts of Sideritis montana L. (SME) was tested in vitro on Guinea-pig ileum. The chemical composition of the investigated extract was analysed by HPLC-MS, and chrysoeriol, chlorogenic acid and caffeic acid were detected as main constituents. The isolated organ assay showed that S. montana extract caused an immediate contraction and a more slowly developing inhibitory response in the ileum. The SME-induced contractions were strongly inhibited by the acetylcholine muscarinic receptor antagonist atropine (0.5 µM), but not by either the Na+ channel blocker tetrodotoxin (TTX; 0.5 µM) or the histamine H1 receptor antagonist chloropyramine (0.5 µM). Selective desensitization of capsaicin-sensitive neurons by the sensory neuron stimulant and blocker capsaicin did not influence the contractile effect of SME. As to the spasmolytic effect, SME inhibited the effects of electrical field stimulation, exogenous acetylcholine, and histamine. These smooth muscle-relaxing effects were reversible in 40 min by repeated renewals of the bathing solution.
Asunto(s)
Íleon/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Extractos Vegetales/farmacología , Sideritis/química , Animales , Atropina/farmacología , Capsaicina/farmacología , Etilenodiaminas/farmacología , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos H1/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Parasimpatolíticos/farmacología , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Fármacos del Sistema Sensorial/farmacologíaRESUMEN
UNLABELLED: Although nonnoxious, high-frequency electrical stimulation applied segmentally (ie, conventional transcutaneous electrical nerve stimulation [TENS]) has been proposed to modulate pain, the mechanisms underlying analgesia remain poorly understood. To further elucidate how TENS modulates pain, we examined evoked responses to noxious thermal stimuli after the induction of sensitization using capsaicin in healthy volunteers. We hypothesized that sensitization caused by capsaicin application would unmask TENS analgesia, which could not be detected in the absence of sensitization. Forty-nine healthy subjects took part in a series of experiments. The experiments comprised the application of topical capsaicin (.075%) on the left hand in the C6 dermatome, varying the location of TENS (segmental, left C6 dermatome, vs extrasegmental, right shoulder), and assessing rating of perception (numeric rating scale: 0-10) and evoked potentials to noxious contact heat stimuli. The extrasegmental site was included as a control condition because previous studies indicate no analgesic effect to remote conventional TENS. Conventional TENS had no significant effect on rating or sensory evoked potentials in subjects untreated with capsaicin. However, segmental TENS applied in conjunction with capsaicin significantly reduced sensation to noxious thermal stimuli following a 60-minute period of sensitization. PERSPECTIVE: The study indicates that sensitization with capsaicin unmasks the analgesic effect of conventional TENS on perception of noxious contact heat stimuli. Our findings indicate that TENS may be interacting segmentally to modulate distinct aspects of sensitization, which in turn results in analgesia to thermal stimulation.
Asunto(s)
Capsaicina/farmacología , Hiperalgesia/terapia , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Fármacos del Sistema Sensorial/farmacología , Estimulación Eléctrica Transcutánea del Nervio , Adulto , Fenómenos Biofísicos , Estimulación Eléctrica/efectos adversos , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Potenciales Evocados Somatosensoriales/fisiología , Femenino , Calor/efectos adversos , Humanos , Hiperalgesia/etiología , Masculino , Persona de Mediana Edad , Dolor/etiología , Dolor/fisiopatología , Dimensión del Dolor , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Factores de Tiempo , Adulto JovenRESUMEN
The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.