RESUMEN

Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRsNav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRsNav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. However, no change was observed in the ratio of AMPA to NMDA receptor-mediated components of Nav1.8-STTN EPSCs or in the amplitude of unitary EPSCs constituting Nav1.8-STTN EPSCs recorded with extracellular Ca2+ replaced by Sr2+ In addition, there was a small increase (approximately 10%) in the number of L1-STTNs showing immunoreactivity for phosphorylated extracellular signal-regulated kinases in mice after SNI compared with sham. Similarly, only a small percentage of L1-STTNs showed a lower action potential threshold after SNI. In conclusion, our results show that SNI induces presynaptic modulation at NRNav1.8 (consisting of both peptidergic and nonpeptidergic nociceptors) synapses on L1-STTNs forming the lateral spinothalamic tract.

Asunto(s)

Potenciales Postsinápticos Excitadores , Canal de Sodio Activado por Voltaje NAV1.8 , Nociceptores , Tractos Espinotalámicos , Transmisión Sináptica , Animales , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/genética , Nociceptores/metabolismo , Nociceptores/fisiología , Tractos Espinotalámicos/metabolismo , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Transmisión Sináptica/fisiología , Ratones , Optogenética , Ratones Endogámicos C57BL , Ratones Transgénicos

RESUMEN

In the mammalian somatosensory system, polymodality is defined as the competence of some neurons to respond to multiple forms of energy (e.g., mechanical and thermal). This ability is thought to be an exclusive property of nociceptive neurons (polymodal C-fiber nociceptors) and one of the pillars of nociceptive peripheral plasticity. The current study uncovered a completely different neuronal sub-population with polymodal capabilities on the opposite mechanical modality spectrum (tactile). We have observed that several tactile afferents (1/5) can respond to cold in non-nociceptive ranges. These cells' mechanical thresholds and electrical properties are similar to any low-threshold mechano-receptors (LT), conducting in a broad range of velocities (Aδ to Aß), lacking CGRP and TRPM8 receptors. Due to its density, cold-response range, speed, and response to injury (or lack thereof), we speculate on its role in controlling reflexive behaviors (wound liking and rubbing) and modulation of nociceptive spinal cord integration. Further studies are required to understand the mechanisms behind this neuron's polymodality, central architecture, and impact on pain perception.

Asunto(s)

Frío , Canales Catiónicos TRPM , Canales Catiónicos TRPM/metabolismo , Animales , Nociceptores/metabolismo , Nociceptores/fisiología , Masculino , Tacto/fisiología , Neuronas Aferentes/fisiología , Ratones , Ratones Endogámicos C57BL

RESUMEN

Sensory axons projecting to the central nervous system are organized into topographic maps that represent the locations of sensory stimuli. In some sensory systems, even adjacent sensory axons are arranged topographically, forming "fine-scale" topographic maps. Although several broad molecular gradients are known to instruct coarse topography, we know little about the molecular signaling that regulates fine-scale topography at the level of two adjacent axons. Here, we provide evidence that transsynaptic bone morphogenetic protein (BMP) signaling mediates local interneuronal communication to regulate fine-scale topography in the nociceptive system of Drosophila larvae. We first show that the topographic separation of the axon terminals of adjacent nociceptors requires their common postsynaptic target, the A08n neurons. This phenotype is recapitulated by knockdown of the BMP ligand, Decapentaplegic (Dpp), in these neurons. In addition, removing the Type 2 BMP receptors or their effector (Mad transcription factor) in single nociceptors impairs the fine-scale topography, suggesting the contribution of BMP signaling originated from A08n. This signaling is likely mediated by phospho-Mad in the presynaptic terminals of nociceptors to ensure local interneuronal communication. Finally, reducing Dpp levels in A08n reduces the nociceptor-A08n synaptic contacts. Our data support that transsynaptic BMP signaling establishes the fine-scale topography by facilitating the formation of topographically correct synapses. Local BMP signaling for synapse formation may be a developmental strategy that independently regulates neighboring axon terminals for fine-scale topography.

Asunto(s)

Proteínas Morfogenéticas Óseas , Proteínas de Drosophila , Células Receptoras Sensoriales , Transducción de Señal , Animales , Proteínas de Drosophila/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Transducción de Señal/fisiología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiología , Drosophila , Larva , Nociceptores/metabolismo , Nociceptores/fisiología , Animales Modificados Genéticamente , Sinapsis/metabolismo , Sinapsis/fisiología , Terminales Presinápticos/metabolismo , Terminales Presinápticos/fisiología , Proteínas de Unión al ADN , Factores de Transcripción

RESUMEN

Osteoarthritis (OA) pain originates in the joint by sensitization of articular nociceptors. While behavioural assessments provide valuable information regarding pain symptoms, the techniques are subjective and open to interpretation by the experimenter. This study used in vivo electrophysiological approaches to measure objectively joint nociceptor properties in three rodent models of OA. Single unit extracellular recordings of joint mechanosensitive afferents were carried out in male and female rats following either (1) transection of the medial meniscus (MMT: post-traumatic OA), (2) intra-articular injection of sodium monoiodoacetate (MIA: chemically-induced OA), or (3) intra-articular injection of lysophosphatidic acid (LPA: neuropathic OA). In naïve male control rats, the mechanical threshold of joint mechanonociceptors (23.5 ± 1.8 mNm) was significantly reduced with MMT (9.4 ± 1.1 mNm) and MIA (15.1 ± 1.6 mNm). In females, the mechanical threshold of naïve rats (23.2 ± 3.1 mNm) was reduced following induction of MMT (8.3 ± 1.0 mNm) and LPA (10.6 ± 2.2 mNm). Afferent firing frequency increased in male MMT (∼275 %), LPA (∼175 %), MIA (225 %), and female MMT (∼146 %), LPA (∼200 %), and MIA (∼192 %). Mechanical threshold and evoked firing were negatively correlated in all models for both sexes except LPA rats (male + female) and female MMT. These data indicate that MMT, MIA, and LPA induce peripheral sensitization of joint afferents thereby validating their use in OA pain studies.

Asunto(s)

Nociceptores , Osteoartritis , Animales , Masculino , Femenino , Osteoartritis/fisiopatología , Osteoartritis/inducido químicamente , Nociceptores/fisiología , Ratas , Ácido Yodoacético/toxicidad , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Lisofosfolípidos

RESUMEN

Increasing evidence suggests that activation of muscle nerve afferents may inhibit central motor drive, affecting contractile performance of remote exercising muscles. Although these effects are well documented for metaboreceptors, very little is known about the activation of mechano- and mechanonociceptive afferents on performance fatigability. Therefore, the purpose of the present study was to examine the influence of mechanoreceptors and nociceptors on performance fatigability. Eight healthy young males undertook four randomized experimental sessions on separate occasions in which the experimental knee extensors were the following: 1) resting (CTRL), 2) passively stretched (ST), 3) resting with delayed onset muscle soreness (DOMS), or 4) passively stretched with DOMS (DOMS+ST), whereas the contralateral leg performed an isometric time to task failure (TTF). Changes in maximal voluntary contraction (ΔMVC), potentiated twitch force (ΔQtw,pot), and voluntary muscle activation (ΔVA) were also assessed. TTF was reduced in DOMS+ST (-43%) and ST (-29%) compared with CTRL. DOMS+ST also showed a greater reduction of VA (-25% vs. -8%, respectively) and MVC compared with CTRL (-28% vs. -45%, respectively). Rate of perceived exertion (RPE) was significantly increased at the initial stages (20-40-60%) of the TTF in DOMS+ST compared with all conditions. These findings indicate that activation of mechanosensitive and mechanonociceptive afferents of a muscle with DOMS reduces TTF of the contralateral homologous exercising limb, in part, by reducing VA, thereby accelerating mechanisms of central fatigue.NEW & NOTEWORTHY We found that activation of mechanosensitive and nociceptive nerve afferents of a rested muscle group experiencing delayed onset muscle soreness was associated with reduced exercise performance of the homologous exercising muscles of the contralateral limb. This occurred with lower muscle voluntary activation of the exercising muscle at the point of task failure.

Asunto(s)

Mecanorreceptores , Fatiga Muscular , Músculo Esquelético , Mialgia , Nociceptores , Humanos , Masculino , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Mecanorreceptores/fisiología , Mecanorreceptores/metabolismo , Adulto Joven , Nociceptores/fisiología , Mialgia/fisiopatología , Adulto , Ejercicio Físico/fisiología , Contracción Muscular , Contracción Isométrica

RESUMEN

Efficient data processing is heavily reliant on prioritizing specific stimuli and categorizing incoming information. Within human biological systems, dorsal root ganglions (particularly nociceptors situated in the skin) perform a pivotal role in detecting external stimuli. These neurons send warnings to our brain, priming it to anticipate potential harm and prevent injury. In this study, we explore the potential of using a ferroelectric memristor device structured as a metal-ferroelectric-insulator-semiconductor as an artificial nociceptor. The aim of this device is to electrically receive external damage and interpret signals of danger. The TiN/HfAlOx (HAO)/HfSiOx (HSO)/n+ Si configuration of this device replicates the key functions of a biological nociceptor. The emulation includes crucial aspects, such as threshold reactivity, relaxation, no adaptation, and sensitization phenomena known as "allodynia" and "hyperalgesia." Moreover, we propose establishing a connection between nociceptors and synapses by training the Hebbian learning rule. This involves exposing the device to injurious stimuli and using this experience to enhance its responsiveness, replicating synaptic plasticity.

Asunto(s)

Nociceptores , Sinapsis , Sinapsis/fisiología , Nociceptores/fisiología , Humanos , Hafnio/química , Semiconductores

RESUMEN

A chemogenetic screen reveals links between nociceptors and gut immune function.

Asunto(s)

Microbioma Gastrointestinal , Tracto Gastrointestinal , Nociceptores , Linfocitos T Reguladores , Canales Catiónicos TRPV , Animales , Humanos , Ratones , Microbioma Gastrointestinal/inmunología , Tracto Gastrointestinal/inmunología , Nociceptores/fisiología , Nociceptores/inmunología , Ganglios Espinales/inmunología , Ganglios Espinales/fisiopatología , Linfocitos T Reguladores/inmunología , Canales Catiónicos TRPV/metabolismo

RESUMEN

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency Aß-mediated response, considered tactile, and a longer-latency Aδ-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to Aß tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of Aß fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current required to elicit the NWR was higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the Aß-mediated tuning fork sensation was lost while Aδ-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current, the reflex could not be evoked despite a two-fold increase in the pre-block current and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of Aß-fiber inputs in pain and reflex signaling.

Asunto(s)

Estimulación Eléctrica , Reflejo , Humanos , Masculino , Adulto , Femenino , Reflejo/fisiología , Bloqueo Nervioso , Adulto Joven , Umbral del Dolor/fisiología , Dolor/fisiopatología , Nocicepción/fisiología , Nociceptores/fisiología , Percepción del Dolor/fisiología

RESUMEN

Wide-range thermoreceptive neurons (WRT-EN) in monkey cortical area 7b that encoded innocuous and nocuous cutaneous thermal and threatening visuosensory stimulation with high fidelity were studied to identify their multisensory integrative response properties. Emphasis was given to characterizing the spatial and temporal effects of threatening visuosensory input on the thermal stimulus-response properties of these multisensory nociceptive neurons. Threatening visuosensory stimulation was most efficacious in modulating thermal evoked responses when presented as a downward ("looming"), spatially congruent, approaching and closely proximal target in relation to the somatosensory receptive field. Both temporal alignment and misalignment of spatially aligned threatening visual and thermal stimulation significantly increased mean discharge frequencies above those evoked by thermal stimulation alone, particularly at near noxious (43°C) and mildly noxious (45°C) temperatures. The enhanced multisensory discharge frequencies were equivalent to the discharge frequency evoked by overtly noxious thermal stimulation alone at 47°C (monkey pain tolerance threshold). A significant increase in behavioral mean escape frequency with shorter escape latency was evoked by multisensory stimulation at near noxious temperature (43°C), which was equivalent to that evoked by noxious stimulation alone (47°C). The remarkable concordance of elevating both neural discharge and escape frequency from a nonnociceptive and prepain level by near noxious thermal stimulation to a nociceptive and pain level by multisensory visual and near noxious thermal stimulation and integration is an elegantly designed defensive neural mechanism that in effect lowers both nociceptive response and pain thresholds to preemptively engage nocifensive behavior and, consequently, avert impending and actual injurious noxious thermal stimulation.NEW & NOTEWORTHY Multisensory nociceptive neurons in cortical area 7b are engaged in integration of threatening visuosensory and a wide range of innocuous and nocuous somatosensory (thermoreceptive) inputs. The enhancement of neuronal activity and escape behavior in monkey by multisensory integration is consistent and supportive of human psychophysical studies. The spatial features of visuosensory stimulation in peripersonal space in relation to somatic stimulation in personal space are critical to multisensory integration, nociception, nocifensive behavior, and pain.

Asunto(s)

Macaca mulatta , Nociceptores , Animales , Nociceptores/fisiología , Masculino , Nocicepción/fisiología , Calor , Percepción Visual/fisiología , Umbral del Dolor/fisiología , Estimulación Luminosa , Reacción de Fuga/fisiología , Termorreceptores/fisiología

RESUMEN

BACKGROUND: Following peripheral nerve damage, various non-neuronal cells are activated, triggering accumulation in the peripheral and central nervous systems, and communicate with neurons. Evidence suggest that neuronal and non-neuronal cell communication is a critical mechanism of neuropathic pain; however, its detailed mechanisms in contributing to neuropathic orofacial pain development remain unclear. HIGHLIGHT: Neuronal and non-neuronal cell communication in the trigeminal ganglion (TG) is believed to cause neuronal hyperactivation following trigeminal nerve damage, resulting in neuropathic orofacial pain. Trigeminal nerve damage activates and accumulates non-neuronal cells, such as satellite cells and macrophages in the TG and microglia, astrocytes, and oligodendrocytes in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). These non-neuronal cells release various molecules, contributing to the hyperactivation of TG, Vc, and C1-C2 nociceptive neurons. These hyperactive nociceptive neurons release molecules that enhance non-neuronal cell activation. This neuron and non-neuronal cell crosstalk causes hyperactivation of nociceptive neurons in the TG, Vc, and C1-C2. Here, we addressed previous and recent data on the contribution of neuronal and non-neuronal cell communication and its involvement in neuropathic orofacial pain development. CONCLUSION: Previous and recent data suggest that neuronal and non-neuronal cell communication in the TG, Vc, and C1-C2 is a key mechanism that causes neuropathic orofacial pain associated with trigeminal nerve damage.

Asunto(s)

Dolor Facial , Neuralgia , Dolor Facial/fisiopatología , Dolor Facial/patología , Neuralgia/fisiopatología , Neuralgia/patología , Humanos , Animales , Ganglio del Trigémino/patología , Comunicación Celular , Microglía/patología , Microglía/metabolismo , Astrocitos/patología , Macrófagos/metabolismo , Oligodendroglía/patología , Traumatismos del Nervio Trigémino/patología , Traumatismos del Nervio Trigémino/fisiopatología , Nociceptores/fisiología , Células Satélites Perineuronales/metabolismo

RESUMEN

Three decades ago, the first endocannabinoid, anandamide (AEA), was identified, and its analgesic effect was recognized in humans and preclinical models. However, clinical trial failures pointed out the complexity of the AEA-induced analgesia. The first synapses in the superficial laminae of the spinal cord dorsal horn represent an important modulatory site in nociceptive transmission and subsequent pain perception. The glutamatergic synaptic transmission at these synapses is strongly modulated by two primary AEA-activated receptors, cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both highly expressed on the presynaptic side formed by the endings of primary nociceptive neurons. Activation of these receptors can have predominantly inhibitory (CB1) and excitatory (TRPV1) effects that are further modulated under pathological conditions. In addition, dual AEA-mediated signaling and action may occur in primary sensory neurons and dorsal horn synapses. AEA application causes balanced inhibition and excitation of primary afferent synaptic input on superficial dorsal horn neurons in normal conditions, whereas peripheral inflammation promotes AEA-mediated inhibition. This review focuses mainly on the modulation of synaptic transmission at the spinal cord level and signaling in primary nociceptive neurons by AEA via CB1 and TRPV1 receptors. Furthermore, the spinal analgesic effect in preclinical studies and clinical aspects of AEA-mediated analgesia are considered.

Asunto(s)

Ácidos Araquidónicos , Endocannabinoides , Alcamidas Poliinsaturadas , Médula Espinal , Transmisión Sináptica , Endocannabinoides/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Animales , Humanos , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Transmisión Sináptica/fisiología , Transmisión Sináptica/efectos de los fármacos , Nocicepción/fisiología , Nocicepción/efectos de los fármacos , Nociceptores/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Receptor Cannabinoide CB1/metabolismo , Canales Catiónicos TRPV/metabolismo

RESUMEN

Peripheral neurons are heterogeneous and functionally diverse, but all share the capability to switch to a pro-regenerative state after nerve injury. Despite the assumption that the injury response is similar among neuronal subtypes, functional recovery may differ. Understanding the distinct intrinsic regenerative properties between neurons may help to improve the quality of regeneration, prioritizing the growth of axon subpopulations to their targets. Here, we present a comparative analysis of regeneration across four key peripheral neuron populations: motoneurons, proprioceptors, cutaneous mechanoreceptors, and nociceptors. Using Cre/Ai9 mice that allow fluorescent labeling of neuronal subtypes, we found that nociceptors showed the greater regeneration after a sciatic crush, followed by motoneurons, mechanoreceptors, and, finally, proprioceptors. By breeding these Cre mice with Ribotag mice, we isolated specific translatomes and defined the regenerative response of these neuronal subtypes after axotomy. Only 20% of the regulated genes were common, revealing a diverse response to injury among neurons, which was also supported by the differential influence of neurotrophins among neuron subtypes. Among differentially regulated genes, we proposed MED12 as a specific regulator of the regeneration of proprioceptors. Altogether, we demonstrate that the intrinsic regenerative capacity differs between peripheral neuron subtypes, opening the door to selectively modulate these responses.

Asunto(s)

Traumatismos de los Nervios Periféricos , Animales , Ratones , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Regeneración Nerviosa/fisiología , Neuronas Motoras/fisiología , Nociceptores/fisiología , Nociceptores/metabolismo , Análisis de Secuencia de ARN , Mecanorreceptores/fisiología , Mecanorreceptores/metabolismo , Axotomía , Masculino , Nervio Ciático/lesiones , Neuronas/fisiología

RESUMEN

Members of both the Piezo and transmembrane channel-like (TMC) families are bona fide mammalian mechanotransducers. In a recent study, Zhang, Shao et al. discovered that TMC7, a non-mechanosensitive TMC, inhibits Piezo2-dependent mechanosensation, with implications for the importance of cellular context for Piezo2 channels in normal and pathological responses to mechanical pain.

Asunto(s)

Canales Iónicos , Mecanotransducción Celular , Nociceptores , Animales , Humanos , Canales Iónicos/metabolismo , Mecanotransducción Celular/fisiología , Nociceptores/metabolismo , Nociceptores/fisiología , Dolor/metabolismo , Dolor/fisiopatología , Roedores

RESUMEN

An artificial nociceptor, as a critical and special bionic receptor, plays a key role in a bioelectronic device that detects stimuli and provides warnings. However, fully exploiting bioelectronic applications remains a major challenge due to the lack of the methods of implementing basic nociceptor functions and nociceptive blockade in a single device. In this work, we developed a Pt/LiSiOx/TiN artificial nociceptor. It had excellent stability under the 104 endurance test with pulse stimuli and exhibited a significant threshold current of 1 mA with 1 V pulse stimuli. Other functions such as relaxation, inadaptation, and sensitization were all realized in a single device. Also, the pain blockade function was first achieved in this nociceptor with over a 25% blocking degree, suggesting a self-protection function. More importantly, an obvious depression was activated by a stimulus over 1.6 V due to the cooperative effects of both lithium ions and oxygen ions in LiSiOx and the dramatic accumulation of Joule heat. The conducting channel ruptured partially under sequential potentiation, thus achieving nociceptive blockade, besides basic functions in one single nociceptor, which was rarely reported. These results provided important guidelines for constructing high-performance memristor-based artificial nociceptors and opened up an alternative approach to the realization of bioelectronic systems for artificial intelligence.

Asunto(s)

Inteligencia Artificial , Nociceptores , Humanos , Nociceptores/fisiología , Dolor , Biónica , Iones/farmacología

RESUMEN

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.g., migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence, in vivo electrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using Fluoro-Ruby) from the PVN to the WDR cells filled with Neurobiotin were observed. Moreover, colocalization between OTR and calcitonin gene-related peptide (CGRP) or OTR and GABA was found near Neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (True-Blue, TB) and infraorbital nerves (Fluoro-Gold, FG) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells.

Asunto(s)

Estimulación Eléctrica , Oxitocina , Núcleo Hipotalámico Paraventricular , Ratas Wistar , Receptores de Oxitocina , Transmisión Sináptica , Animales , Masculino , Núcleo Hipotalámico Paraventricular/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Oxitocina/metabolismo , Oxitocina/análogos & derivados , Ratas , Receptores de Oxitocina/metabolismo , Receptores de Oxitocina/antagonistas & inhibidores , Transmisión Sináptica/fisiología , Nociceptores/fisiología , Nociceptores/metabolismo , Nocicepción/fisiología , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de los fármacos , Meninges/fisiología , Inhibición Neural/fisiología

RESUMEN

ABSTRACT: Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 µg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 µg), induced persistent mechanical allodynia for >2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator.

Asunto(s)

MicroARNs , Microglía , Médula Espinal , Transmisión Sináptica , Animales , Masculino , Ratones , Potenciales Postsinápticos Excitadores/fisiología , Ganglios Espinales/metabolismo , Hiperalgesia/fisiopatología , Hiperalgesia/metabolismo , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Nociceptores/metabolismo , Nociceptores/fisiología , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/fisiopatología , Transmisión Sináptica/fisiología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/genética

RESUMEN

Recently, we showed that while atogepant-a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist-does not fully prevent activation of meningeal nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C fibres and late response probability in Aδ fibres. The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons. In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 versus 1/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 versus 5/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant's inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant' ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated Aδ fibres. Atogepant's inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation.

Asunto(s)

Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Depresión de Propagación Cortical , Trastornos Migrañosos , Ratas Sprague-Dawley , Animales , Masculino , Trastornos Migrañosos/prevención & control , Trastornos Migrañosos/tratamiento farmacológico , Ratas , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Núcleo Espinal del Trigémino/efectos de los fármacos , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología

RESUMEN

Ultraviolet B (UVB) radiation induces cutaneous inflammation, leading to thermal and mechanical hypersensitivity. Here, we examine the mechanical properties and profile of tactile and nociceptive peripheral afferents functionally disrupted by this injury and the role of oxytocin (OXT) as a modulator of this disruption. We recorded intracellularly from L4 afferents innervating the irradiated area (5.1 J/cm2) in 4-6 old week male mice (C57BL/6J) after administering OXT intraperitoneally, 6 mg/Kg. The distribution of recorded neurons was shifted by UVB radiation to a pattern observed after acute and chronic injuries and reduced mechanical thresholds of A and C- high threshold mechanoreceptors while reducing tactile sensitivity. UVB radiation did not change somatic membrane electrical properties or fiber conduction velocity. OXT systemic administration rapidly reversed these peripheral changes toward normal in both low and high-threshold mechanoreceptors and shifted recorded neuron distribution toward normal. OXT and V1aR receptors were present on the terminals of myelinated and unmyelinated afferents innervating the skin. We conclude that UVB radiation, similar to local tissue surgical injury, cancer metastasis, and peripheral nerve injury, alters the distribution of low and high threshold mechanoreceptors afferents and sensitizes nociceptors while desensitizing tactile units. Acute systemic OXT administration partially returns all of those effects to normal.

Asunto(s)

Nocicepción , Oxitocina , Ratones , Masculino , Animales , Oxitocina/farmacología , Oxitocina/uso terapéutico , Ratones Endogámicos C57BL , Tacto/fisiología , Piel/inervación , Mecanorreceptores , Nociceptores/fisiología

RESUMEN

Although in vivo local injection of quercetin into the peripheral receptive field suppresses the excitability of rat nociceptive trigeminal ganglion (TG) neurons, under inflammatory conditions, the acute effects of quercetin in vivo, particularly on nociceptive TG neurons, remain to be determined. The aim of this study was to examine whether acute local administration of quercetin into inflamed tissue attenuates the excitability of nociceptive TG neurons in response to mechanical stimulation. The mechanical escape threshold was significantly lower in complete Freund's adjuvant (CFA)-inflamed rats compared to before CFA injection. Extracellular single-unit recordings were made from TG neurons of CFA-induced inflammation in anesthetized rats in response to orofacial mechanical stimulation. The mean firing frequency of TG neurons in response to both non-noxious and noxious mechanical stimuli was reversibly inhibited by quercetin in a dose-dependent manner (1-10 mM). The mean firing frequency of inflamed TG neurons in response to mechanical stimuli was reversibly inhibited by the local anesthetic, 1% lidocaine (37 mM). The mean magnitude of inhibition on TG neuronal discharge frequency with 1 mM quercetin was significantly greater than that of 1% lidocaine. These results suggest that local injection of quercetin into inflamed tissue suppresses the excitability of nociceptive primary sensory TG neurons. PERSPECTIVE: Local administration of the phytochemical, quercetin, into inflamed tissues is a more potent local analgesic than voltage-gated sodium channel blockers as it inhibits the generation of both generator potentials and action potentials in nociceptive primary nerve terminals. As such, it contributes to the area of complementary and alternative medicines.

Asunto(s)

Lidocaína , Quercetina , Ratas , Animales , Lidocaína/farmacología , Ratas Wistar , Quercetina/farmacología , Nocicepción , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Nociceptores/fisiología , Potenciales de Acción

RESUMEN

Early life adversities influence a nervous system still in development with long-term consequences for later life. These include nociceptive circuit alterations critical to shape an adaptive pain response to protect the organism from potential damage. Adult rats with a history of neonatal maternal separation (NMS) display visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anaesthetized adult rats during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat's hindpaws. This nicely explains the hypernociceptive behaviours seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e., TRPV1, TRPM8 and TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevation of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS are associated with reduced spinal cord inhibition favouring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites, as other NMS-associated symptoms include excessive anxiety and impaired sociability.

Asunto(s)

Privación Materna , Nocicepción , Ratas , Animales , Dolor , Médula Espinal , Analgésicos , Nociceptores/fisiología