RESUMEN
Arthroplasty is an orthopedic surgical procedure that replaces a dysfunctional joint by an orthopedic prosthesis, thereby restoring joint function. Upon the use of the joint prosthesis, a wearing process begins, which releases components such as titanium dioxide (TiO2) that trigger an immune response in the periprosthetic tissue, leading to arthritis, arthroplasty failure, and the need for revision. Flavonoids belong to a class of natural polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Hesperidin methyl chalcone's (HMC) analgesic, anti-inflammatory, and antioxidant effects have been investigated in some models, but its activity against the arthritis caused by prosthesis-wearing molecules, such as TiO2, has not been investigated. Mice were treated with HMC (100 mg/kg, intraperitoneally (i.p.)) 24 h after intra-articular injection of 3 mg/joint of TiO2, which was used to induce chronic arthritis. HMC inhibited mechanical hyperalgesia, thermal hyperalgesia, joint edema, leukocyte recruitment, and oxidative stress in the knee joint (alterations in gp91phox, GSH, superoxide anion, and lipid peroxidation) and in recruited leukocytes (total reactive oxygen species and GSH); reduced patellar proteoglycan degradation; and decreased pro-inflammatory cytokine production. HMC also reduced the activation of nociceptor-sensory TRPV1+ and TRPA1+ neurons. These effects occurred without renal, hepatic, or gastric damage. Thus, HMC reduces arthritis triggered by TiO2, a component released upon wearing of prosthesis.
Asunto(s)
Artritis , Chalconas , Hesperidina , Ratones , Animales , Nociceptores/metabolismo , Chalconas/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Artritis/tratamiento farmacológico , Estrés Oxidativo , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Hiperalgesia/tratamiento farmacológico , Citocinas/metabolismoRESUMEN
TREK2 is a member of the 2-pore domain family of K+ channels (K2P) preferentially expressed by unmyelinated, slow-conducting and non-peptidergic isolectin B4-binding (IB4+) primary sensory neurons of the dorsal root ganglia (DRG). IB4+ neurons depend on the glial-derived neurotrophic factor (GDNF) family of ligands (GFL's) to maintain their phenotype. In our previous work, we demonstrated that 7 days after spinal nerve axotomy (SNA) of the L5 DRG, TREK2 moves away from the cell membrane resulting in a more depolarised resting membrane potential (Em). Given that axotomy deprives DRG neurons from peripherally-derived GFL's, we hypothesized that they might control the expression of TREK2. Using a combination of immunohistochemistry, immunocytochemistry, western blotting, in vivo pharmacological manipulation and behavioral tests we examined the ability of the GFL's (GDNF, neurturin and artemin) and their selective receptors (GFRα1, GFRα2 and GFRα3) to regulate the expression and function of TREK2 in the DRG. We found that TREK2 correlated strongly with the three receptors normally and ipsilaterally for all GFR's after SNA. GDNF, but not NGF, neurturin or artemin up-regulated the expression of TREK2 in cultured DRG neurons. In vivo continuous, subcutaneous administration of GDNF restored the subcellular distribution of TREK2 ipsilaterally and reversed mechanical and cold allodynia 7 days after SNA. This is the first demonstration that GDNF controls the expression of a K2P channel in nociceptors. As TREK2 controls the Em of C-nociceptors affecting their excitability, our finding has therapeutic potential in the treatment of chronic pain.
Asunto(s)
Factor Neurotrófico Derivado de la Línea Celular Glial , Neuralgia , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Animales , Axotomía , Ganglios Espinales/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Neuralgia/metabolismo , Neurturina , Nociceptores/metabolismo , RatasRESUMEN
BACKGROUND AND PURPOSE: Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature. EXPERIMENTAL APPROACH: Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1ß production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy. KEY RESULTS: RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1ß production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1ß production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages. CONCLUSIONS AND IMPLICATIONS: This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1.
Asunto(s)
Artritis Gotosa , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/tratamiento farmacológico , Péptido Relacionado con Gen de Calcitonina , Ácidos Docosahexaenoicos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Inflamación/metabolismo , Activación de Macrófagos , Masculino , Ratones , Neuroinmunomodulación , Neuronas , Nociceptores/metabolismo , Dolor , Ácido Úrico/química , Ácido Úrico/farmacologíaRESUMEN
The mechanistic interactions among redox status of leukocytes, muscle, and exercise in pain regulation are still poorly understood and limit targeted treatment. Exercise benefits are numerous, including the treatment of chronic pain. However, unaccustomed exercise may be reported as undesirable as it may contribute to pain. The aim of the present review is to evaluate the relationship between oxidative metabolism and acute exercise-induced pain, and as to whether improved antioxidant capacity underpins the analgesic effects of regular exercise. Preclinical and clinical studies addressing relevant topics on mechanisms by which exercise modulates the nociceptive activity and how redox status can outline pain and analgesia are discussed, in sense of translating into refined outcomes. Emerging evidence points to the role of oxidative stress-induced signaling in sensitizing nociceptor sensory neurons. In response to acute exercise, there is an increase in oxidative metabolism, and consequently, pain. Instead, regular exercise can modulate redox status in favor of antioxidant capacity and repair mechanisms, which have consequently increased resistance to oxidative stress, damage, and pain. Data indicate that acute sessions of unaccustomed prolonged and/or intense exercise increase oxidative metabolism and regulate exercise-induced pain in the post-exercise recovery period. Further, evidence demonstrates regular exercise improves antioxidant status, indicating its therapeutic utility for chronic pain disorders. An improved comprehension of the role of redox status in exercise can provide helpful insights into immune-muscle communication during pain modulatory effects of exercise and support new therapeutic efforts and rationale for the promotion of exercise.
Asunto(s)
Analgesia/efectos adversos , Ejercicio Físico , Músculo Esquelético/patología , Nociceptores/patología , Estrés Oxidativo , Dolor/patología , Células Receptoras Sensoriales/patología , Humanos , Músculo Esquelético/metabolismo , Nociceptores/inmunología , Nociceptores/metabolismo , Oxidación-Reducción , Dolor/etiología , Dolor/metabolismo , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismoRESUMEN
A previous study has indicated that during the state of central sensitization induced by the intradermic injection of capsaicin, there is a gradual facilitation of the dorsal horn neuronal responses produced by stimulation of the high-threshold articular afferents that is counteracted by a concurrent increase of descending inhibitory actions. Since these changes occurred without significantly affecting the responses produced by stimulation of the low-threshold articular afferents, it was suggested that the capsaicin-induced descending inhibition included a preferential presynaptic modulation of the synaptic efficacy of the slow conducting nociceptive joint afferents (Ramírez-Morales et al., Exp Brain Res 237:1629-1641, 2019). The present study was aimed to investigate more directly the contribution of presynaptic mechanisms in this descending control. We found that in the barbiturate anesthetized cat, stimulation of the high-threshold myelinated afferents in the posterior articular nerve (PAN) produces primary afferent hyperpolarization (PAH) in the slow conducting (25-35 m/s) and primary afferent depolarization (PAD) in the fast conducting (40-50 m/s) articular fibers. During the state of central sensitization induced by capsaicin, there is a supraspinally mediated shift of the autogenic PAH to PAD that takes place in the slow conducting fibers, basically without affecting the autogenic PAD generated in the fast conducting afferents. It is suggested that the change of presynaptic facilitation to presynaptic inhibition induced by capsaicin on the slow articular afferents is part of an homeostatic process aimed to keep the nociceptive-induced neuronal activity within manageable limits while preserving the proprioceptive information required for proper control of movement.
Asunto(s)
Nocicepción , Células del Asta Posterior , Animales , Capsaicina/farmacología , Gatos , Estimulación Eléctrica , Neuronas Aferentes , Nociceptores , Propiocepción , Médula EspinalRESUMEN
Dipyrone (DIP), also known as metamizole, is an over-the-counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well-known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre-sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP-treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2-induced hyperalgesia in a dose-dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway.
Asunto(s)
Analgésicos/farmacología , Dipirona/farmacología , Nociceptores/efectos de los fármacos , Dolor/prevención & control , Animales , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas WistarRESUMEN
The aim of this study was to determine whether maternal diabetes induced by alloxan injection in the first gestational day of female Wistar rats interferes with the development of the nociceptive peripheral system of the offspring. Behavioral and histologic analysis was performed using the adult offspring of diabetic and control rats. It was found that the offspring of diabetic rats were more sensitive to thermal stimulation and showed an altered response to carrageenan-induced inflammatory hyperalgesia. The histological analysis showed an increased proportion of nociceptive neurons, while the population of non-nociceptive myelinated neurons was reduced. Therefore, exposition to hyperglycemia and/or hyperinsulinemia in uterus, caused by a diabetic mother, might result in altered nociceptive sensations in the offspring throughout life.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Nocicepción , Animales , Carragenina , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/patología , Femenino , Ganglios Espinales/patología , Calor , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Masculino , Neuronas/patología , Nociceptores , Dimensión del Dolor , Estimulación Física , Embarazo , Ratas , Ratas WistarRESUMEN
There are different animal models to evaluate pain among them the formalin hind paw assay which is widely used since some of its events appear to be similar to the clinical pain of humans. The assay in which a dilute solution of formalin is injected into the dorsal hindpaw of a murine produces two 'phases' of pain behavior separated by a inactive period. The early phase (Phase I) is probably due to direct activation of nociceptors and the second phase (Phase II) is due to ongoing inflammatory input and central sensitization. Mice were used to determine the potency antinociceptive of piroxicam (1,3,10,and 30 mg/kg), parecoxib (0.3, 1,3,10 and 30 mg/kg), dexketoprofen (3,10,30 and 100 mg/kg) and ketoprofen (3,10,30 and 100 mg/kg). Dose-response for each NSAIDs were created before and after 5 mg/kg of L-NAME i.p. or 5 mg/kg i.p. of 7-nitroindazole. A least-squares linear regression analysis of the log dose-response curves allowed the calculation of the dose that produced 50% of antinociception (ED50) for each drug. The ED50 demonstrated the following rank order of potency, in the phase I: piroxicam > dexketoprofen > ketoprofen > parecoxib and in the phase II: piroxicam > ketoprofen > parecoxib > dexketoprofen. Pretreatment of the mice with L-NAME or 7-nitroindazol induced a significant increase of the analgesic power of the NSAIDs, with a significant reduction of the ED50. It is suggested that NO may be involved in both phases of the trial, which means that nitric oxide regulates the bioactivity of NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Óxido Nítrico/metabolismo , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Modelos Animales de Enfermedad , Formaldehído/toxicidad , Humanos , Indazoles/administración & dosificación , Masculino , Ratones , NG-Nitroarginina Metil Éster/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Dolor/inducido químicamente , Dolor/diagnóstico , Dimensión del DolorRESUMEN
Diabetes is a chronic degenerative disease that represent a major threat to public health worldwide. Once the disease is established, one of the major concerns about the diabetes complications is the development of neuropathy. This study established an experimental model that evaluates the effect of type 1 diabetes on nociceptive challenges in the temporomandibular joint (TMJ). Streptozotocin-induced type 1 (STZ 75â¯mg/Kg) diabetes inhibited the responsiveness of C-fibers nociceptors located in the TMJ of Wistar rats since seventh day after the disease induction. Diabetes-induced hyporesponsiveness of C-fibers nociceptors was associated with significantly reduction of protein level of neuropeptides Substance P and Calcitonin Gene Related Peptide. Diabetic animals pre-treated with Protein Kinase C (PKC)-α and -ß inhibitor (GO6976) or PKC-ß inhibitor (LY333531) significantly increased capsaicin-induced nociception in the TMJ higher protein levels of Na+/K+-ATPase pump in the trigeminal ganglia. On the other hand, although diabetes inhibits formalin-induced nociception higher protein levels of pro-inflammatory cytokine IL1-ß and chemokine CINC-1/CXCL-1 were observed. Overall, the results of the present work suggest that diabetes causes a hyporesponsiveness of C-fiber and a potentialization of the inflammatory response which may result in the degenerative process of periarticular tissues without pain perception.
Asunto(s)
Nociceptores/efectos de los fármacos , Dolor/fisiopatología , Trastornos de la Articulación Temporomandibular/fisiopatología , Articulación Temporomandibular/efectos de los fármacos , Animales , Capsaicina/farmacología , Diabetes Mellitus Tipo 1/fisiopatología , Masculino , Nocicepción/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas Wistar , Estreptozocina/farmacologíaRESUMEN
Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.
Asunto(s)
Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Receptores de Dopamina D2/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Calcio/metabolismo , Calcio/fisiología , Agonistas de Dopamina/farmacología , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/fisiología , Masculino , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Nociceptores/fisiología , Pramipexol/farmacología , Quinpirol/farmacología , Ratas , Ratas Wistar , Médula Espinal/metabolismoRESUMEN
INTRODUCTION: Pain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry. METHODS AND ANALYSIS: A GWAS on genetic contributions to pain sensitivity in the naïve state and following nociceptive sensitisation will be conducted in unrelated healthy individuals of mixed ancestry. Mechanical and thermal pain sensitivity will be evaluated with a battery of quantitative sensory tests evaluating pain thresholds. In addition, variation in mechanical and thermal sensitisation following topical application of mustard oil to the skin will be evaluated. ETHICS AND DISSEMINATION: This study received ethical approval from the University College London research ethics committee (3352/001) and from the bioethics committee of the Odontology Faculty at the University of Antioquia (CONCEPTO 01-2013). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations at international conferences.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Umbral del Dolor , Dolor/genética , Colombia , Voluntarios Sanos , Humanos , Nociceptores/fisiologíaRESUMEN
Cumulating data suggests that ion channel alterations in nociceptive neurons might be involved in the development of diabetic painful neuropathy. In the present study we investigated the involvement of ATP-sensitive potassium (K+ATP) channels in the acute effect of high glucose solution in vitro and in vivo. High glucose concentrations depolarized cultured nociceptive neurons and depolarization was blocked by the K+ATP opener, diazoxide or by insulin. Glucose injection at the rat dorsal root ganglia (L5) resulted in acute mechanical hyperalgesia that was blocked by diazoxide. Mannitol injection indicates that osmolarity changes are not responsible for glucose effect. Therefore, this study suggests that K+ATP channels expressed in peripheral sensory neurons might be involved in the development of diabetic painful neuropathy. Since sulfonylureas, that act by blocking K+ATP are used for diabetes treatment, it is important to evaluate the possible side effects of such drugs at primary sensory neurons.
Asunto(s)
Hiperalgesia/etiología , Hiperglucemia/complicaciones , Hiperglucemia/fisiopatología , Canales KATP , Potenciales de la Membrana , Nociceptores , Células Receptoras Sensoriales , Animales , Diazóxido/farmacología , Diuréticos/farmacología , Ganglios Espinales/citología , Ganglios Espinales/fisiopatología , Masculino , Manitol/farmacología , Concentración Osmolar , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Cultivo Primario de Células , Ratas , Ratas WistarRESUMEN
Previous studies from our laboratory showed that in the anesthetized cat, the intradermal injection of capsaicin in the hindpaw facilitated the intraspinal field potentials (IFPs) evoked by stimulation of the intermediate and high-threshold myelinated fibers in the posterior articular nerve (PAN). The capsaicin-induced facilitation was significantly reduced 3-4 h after the injection, despite the persistence of hindpaw inflammation. Although this effect was attributed to an incremented descending inhibition acting on the spinal pathways, it was not clear if it was set in operation once the capsaicin-induced effects exceeded a certain threshold, or if it was continuously operating to keep the increased neuronal activation within manageable limits. To evaluate the changes in descending inhibition, we now examined the effects of successive reversible spinal blocks on the amplitude of the PAN IFPs evoked at different times after the intradermal injection of capsaicin. We found that after capsaicin the PAN IFPs recorded in laminae III-V by activation of high-threshold nociceptive Aδ myelinated fibers increased gradually during successive reversible spinal blocks, while the IFPs evoked by intermediate and low threshold proprioceptive Aß afferents were only slightly affected. It is concluded that during the development of the central sensitization produced by capsaicin, there is a gradual increase of descending inhibition that tends to limit the nociceptive-induced facilitation, mainly by acting on the neuronal populations receiving inputs from the capsaicin-activated afferents without significantly affecting the information on joint angle transmitted by the low threshold afferents.
Asunto(s)
Capsaicina/farmacología , Neuronas Aferentes/efectos de los fármacos , Nociceptores/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Tractos Piramidales/efectos de los fármacos , Fármacos del Sistema Sensorial/farmacología , Animales , Gatos , Femenino , Masculino , Neuronas Aferentes/fisiología , Nociceptores/fisiología , Células del Asta Posterior/fisiología , Tractos Piramidales/fisiologíaRESUMEN
Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.
Asunto(s)
Analgésicos/farmacología , Corteza Motora/fisiología , Umbral del Dolor/efectos de los fármacos , Dolor/fisiopatología , Animales , Hiperalgesia/metabolismo , Masculino , Neuralgia/terapia , Neuronas/efectos de los fármacos , Nociceptores/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Columna Vertebral/efectos de los fármacosRESUMEN
Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.
Asunto(s)
Hipersensibilidad/patología , Inflamación/patología , Nociceptores/patología , Péptidos/metabolismo , Animales , Dinoprostona/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Hipersensibilidad/complicaciones , Hipersensibilidad/fisiopatología , Inflamación/complicaciones , Inflamación/fisiopatología , Lectinas/farmacología , Masculino , Ratones Endogámicos C57BL , Fibras Nerviosas Amielínicas/metabolismo , Nocicepción/efectos de los fármacos , Nociceptores/efectos de los fármacos , Dolor/complicaciones , Dolor/fisiopatología , Saporinas/farmacologíaRESUMEN
O estudo da dor e suas particularidades é de grande importância para o tratamento de diversas patologias e para a melhora na qualidade de vida dos pacientes. A maioria das disfunções orgânicas tem a dor como um ponto importante da sua manifestação. Dessa maneira, é justificável a elaboração de conteúdo para auxiliar os profissionais da saúde no entendimento e tratamento das principais causas de dores agudas e crônicas. Este livro foi elaborado com o objetivo de servir como um guia prático para o manejo da dor por profissionais e acadêmicos de Medicina. Engloba temas como conceitos e aspectos biopsicossociais da dor, além de questões mais complexas como a fisiologia da dor e o tratamento medicamentoso com o arsenal terapêutico existente. Finalmente, também trata dos diversos tipos de dor mais prevalentes e o conhecimento básico que envolve seu manejo.
Asunto(s)
Humanos , Masculino , Femenino , Embarazo , Preescolar , Adulto , Anciano , Adulto Joven , Dolor/historia , Dolor/psicología , Dolor Postoperatorio , Examen Físico , Calidad de Vida , Dimensión del Dolor/psicología , Terapias Complementarias , Anciano , Nociceptores , Fibromialgia , Niño , Dolor Pélvico , Dolor de Parto , Quimioterapia , Percepción del Dolor/fisiología , Dolor Agudo , Dolor Musculoesquelético , Dolor Crónico , Dolor en Cáncer , Cefalea , Analgesia , AnamnesisRESUMEN
The medullary dorsal horn (MDH or Sp5c/C1 region) plays a key role modulating the nociceptive input arriving from craniofacial structures. Some reports suggest that oxytocin could play a role modulating the nociceptive input at the MDH level, but no study has properly tested this hypothesis. Using an electrophysiological and pharmacological approach, the present study aimed to determine the effect of oxytocin on the nociceptive signaling in the MDH and the receptor involved. In sevoflurane, anesthetized rats, we performed electrophysiological unitary recordings of second order neurons at the MDH region responding to peripheral nociceptive-evoked responses of the first branch (V1; ophthalmic) of the trigeminal nerve. Under this condition, we constructed dose-response curves analyzing the effect of local spinal oxytocin (0.2-20 nmol) on MDH nociceptive neuronal firing. Furthermore, we tested the role of oxytocin receptors (OTR) or vasopressin V1A receptors (V1AR) involved in the oxytocin effects. Oxytocin dose-dependently inhibits the peripheral-evoked activity in nociceptive MDH neurotransmission. This inhibition is associated with a blockade of neuronal activity of Aδ- and C-fibers. Since this antinociception was abolished by pretreatment (in the MDH) with the potent and selective OTR antagonist (L-368,899; 20 nmol) and remained unaffected after the V1AR antagonist (SR49059; 20 nmol or 200 nmol), the role of OTR is implied. This electrophysiological study demonstrates that oxytocin inhibits the peripheral-evoked neuronal activity at MDH, through OTR activation. Thus, OTR may represent a new potential drug target to treat craniofacial nociceptive dysfunction in the MDH.
Asunto(s)
Nociceptores/efectos de los fármacos , Oxitócicos/farmacología , Oxitocina/farmacología , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/metabolismo , Asta Dorsal de la Médula Espinal/citología , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Canfanos/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Indoles/farmacología , Masculino , Fibras Nerviosas/fisiología , Oxitocina/antagonistas & inhibidores , Piperazinas/farmacología , Pirrolidinas/farmacología , Ratas , Ratas WistarRESUMEN
The anterior cingulate cortex (ACC) is crucial in the modulation of the sensory, affective and cognitive aspects of nociceptive processing. Also, it participates in the planning and execution of behavioral responses evoked by nociceptive stimuli via descending projections to the brainstem. In laboratory animals nociceptive experimental tests evaluate behavioral responses that preferentially express the sensory-discriminative or affective-motivational component of pain. The objective of this study was to investigate the participation of opioid and cholinergic neurotransmission in the ACC on different nociceptive responses in guinea pigs. We used nociceptive tests of formalin and vocalization evoked by peripheral noxious stimuli (electric shock) to evaluate the behavioral expression of the sensory-discriminative and affective motivational components, respectively. We verified that the microinjection of morphine (4.4nmol) in the ACC of guinea pigs promotes antinociception in the two experimental tests investigated. This effect is blocked by prior microinjection of naloxone (2.7nmol). On the other hand, the microinjection of carbachol (2.7nmol) in the ACC induces antinociception only in the vocalization test. This effect was prevented by prior microinjection of atropine (0.7nmol) and naloxone (2.7nmol). In fact, the blockade of µ-opioids receptors with naloxone in ACC prevented the antinociceptive effect of carbachol in the vocalization test. Accordingly, we suggest that the antinociception promoted by carbachol was mediated by the activation of muscarinic receptors on local ACC opioid interneurons. The release of endogenous opioids seems to inhibited the expression of the behavioral response of vocalization. Therefore, we verified that the antinociceptive effect of morphine microinjection in ACC is broader and more robust than that promoted by carbachol.
Asunto(s)
Giro del Cíngulo/metabolismo , Nociceptores/fisiología , Receptores Opioides/metabolismo , Vocalización Animal/fisiología , Acetilcolina/farmacología , Analgésicos Opioides/farmacología , Animales , Atropina/farmacología , Carbacol/metabolismo , Carbacol/farmacología , Colinérgicos/farmacología , Cobayas , Giro del Cíngulo/efectos de los fármacos , Masculino , Microinyecciones , Morfina/metabolismo , Morfina/farmacología , Muscimol/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Nociceptores/efectos de los fármacos , Péptidos Opioides/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dolor/prevención & control , Transmisión Sináptica/efectos de los fármacos , Vocalización Animal/efectos de los fármacosRESUMEN
Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms underlying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly determined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathematical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration.SIGNIFICANCE STATEMENT This paper unveils the critical role of the brake potassium current IKD in damage-triggered cold allodynia. Using a well-known form of nerve injury and combining behavioral analysis, calcium imaging, patch clamping, and pharmacological tools, validated by mathematical modeling, we determined that the functional expression of IKD is reduced in sensory neurons in response to peripheral nerve damage. This downregulation not only enhances cold sensitivity of high-threshold cold thermoreceptors signaling cold discomfort, but it also transforms a subpopulation of polymodal nociceptors signaling pain into neurons activated by mild temperature drops. Our results suggest that cold allodynia is linked to a reduction of IKD in both high-threshold cold thermoreceptors and nociceptors expressing TRPM8, providing a general model for this form of cold-induced pain.
Asunto(s)
Frío/efectos adversos , Hiperalgesia/fisiopatología , Nociceptores/metabolismo , Traumatismos de los Nervios Periféricos/fisiopatología , Potasio/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Células Cultivadas , Enfermedad Crónica , Simulación por Computador , Hiperalgesia/diagnóstico , Hiperalgesia/etiología , Activación del Canal Iónico , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Neurológicos , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/diagnósticoRESUMEN
Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.