RESUMEN
C-tactile afferents form a distinct channel that encodes pleasant tactile stimulation. Prevailing views indicate they project, as with other unmyelinated afferents, in lamina I-spinothalamic pathways. However, we found that spinothalamic ablation in humans, whilst profoundly impairing pain, temperature and itch, had no effect on pleasant touch perception. Only discriminative touch deficits were seen. These findings preclude privileged C-tactile-lamina I-spinothalamic projections and imply integrated hedonic and discriminative spinal processing from the body.
Asunto(s)
Principio de Dolor-Placer , Placer/fisiología , Percepción del Tacto/fisiología , Tacto/fisiología , Vías Aferentes/fisiología , Anciano , Cordotomía , Emociones/fisiología , Femenino , Humanos , Masculino , Mecanorreceptores/metabolismo , Mecanorreceptores/fisiología , Persona de Mediana Edad , Fibras Nerviosas Amielínicas/metabolismo , Fibras Nerviosas Amielínicas/fisiología , Estimulación Física , Prurito/fisiopatología , Piel/fisiopatología , Tractos Espinotalámicos/metabolismo , Tractos Espinotalámicos/fisiologíaRESUMEN
Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal µ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-ß3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.
Asunto(s)
Antimaláricos/efectos adversos , Antipruriginosos/uso terapéutico , Cloroquina/efectos adversos , Malaria/tratamiento farmacológico , Prurito/etiología , Potenciales de Acción/efectos de los fármacos , Antipruriginosos/farmacología , Población Negra , Calcio/metabolismo , Enfermedad Crónica/tratamiento farmacológico , Combinación de Medicamentos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Perfilación de la Expresión Génica , Humanos , Medicina de Precisión/métodos , Prurito/tratamiento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Piel/efectos de los fármacos , Piel/inervación , Piel/metabolismo , Tractos Espinotalámicos/efectos de los fármacos , Tractos Espinotalámicos/metabolismo , Canal Catiónico TRPA1/metabolismo , Transcriptoma/efectos de los fármacosRESUMEN
BACKGROUND: Paracetamol's (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans. METHODS AND RESULTS: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter. CONCLUSION: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain.
Asunto(s)
Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Encéfalo/efectos de los fármacos , Dolor/tratamiento farmacológico , Adulto , Encéfalo/metabolismo , Estudios Cruzados , Método Doble Ciego , Potenciales Evocados/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Tractos Espinotalámicos/efectos de los fármacos , Tractos Espinotalámicos/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Allodynia and hyperalgesia present after surgical interventions are often a major complain of surgical patients. It is thought that both peripheral and central mechanisms contribute to these symptoms. In this study, the role of peripheral nerve fibres that express transient receptor potential vanilloid 1 (TRPV1) receptors in the activation of spinothalamic tract (STT) and postsynaptic dorsal column (PSDC) neurons was assessed in a model of surgical pain. METHODS: Spinothalamic tract and PSDC neurons retrogradely labelled from the thalamus and nucleus gracilis were used. Activation of these projection neurons was evaluated after plantar incision as expression of the early gene product, c-Fos protein, in the nuclei of these neurons. RESULTS: There was a robust increase in c-Fos immunopositivity in the STT and PSDC neurons, in the control animals after a plantar incision. This increase in c-Fos expression was significantly attenuated in animals in which a single high-concentration capsaicin injection was made intradermally at the incision site 24 h before the surgery. CONCLUSIONS: Our results suggest that activation of both STT and PSDC neurons is involved in development of pain states present after surgical incision and that TRPV1-containing peripheral nerve fibres are needed for c-Fos expression in these dorsal horn neurons after plantar incision.
Asunto(s)
Capsaicina/farmacología , Bulbo Raquídeo/metabolismo , Fibras Nerviosas , Dolor Postoperatorio , Células del Asta Posterior/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Fármacos del Sistema Sensorial/farmacología , Tractos Espinotalámicos/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Capsaicina/administración & dosificación , Modelos Animales de Enfermedad , Masculino , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Dolor Postoperatorio/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Ratas , Ratas Wistar , Fármacos del Sistema Sensorial/administración & dosificación , Tractos Espinotalámicos/efectos de los fármacosRESUMEN
Neuropathic pain is one of the most difficult consequences of spinal cord injury (SCI). The clinical correlates of the underlying mechanisms responsible for neuropathic pain are not well understood, although methods such as quantitative somatosensory testing (QST) or brain imaging have been used to further a mechanism-based understanding of pain. Our previous SCI study demonstrated a significantly lower glutamate-glutamine/myo-inositol ratio (Glx/Ins) in the anterior cingulate cortex in persons with severe neuropathic pain compared with those with less severe neuropathic pain or pain-free, able-bodied controls, suggesting that a combination of decreased glutamatergic metabolism and glial activation may contribute to the development of severe neuropathic pain after SCI. The present study aimed to determine the relationships between somatosensory function below the level of injury and low thalamic Glx/Ins in persons with intense neuropathic pain after SCI. Participants underwent QST and a 3 Tesla proton magnetic resonance spectroscopy. A cluster analysis including SCI participants resulted in 1 group (n = 19) with significantly (P < 0.001) greater pain intensity (6.43 ± 1.63; high neuropathic pain [HNP], and lower Glx/Ins [1.22 ± 0.16]) and another group (n = 35) with lower pain intensity ratings (1.59 ± 1.52, low neuropathic pain [LNP], and higher Glx/Ins [1.47 ± 0.26]). After correcting for age, QST indicated significantly greater somatosensory function in the HNP group compared with the LNP group. Our results are consistent with research suggesting that damage to, but not abolition of, the spinothalamic tract contributes to development of neuropathic pain after SCI and that secondary inflammatory processes may amplify residual spinothalamic tract signals by facilitation, disinhibition, or sensitization.
Asunto(s)
Dimensión del Dolor/métodos , Dolor/metabolismo , Fenotipo , Traumatismos de la Médula Espinal/metabolismo , Tálamo/metabolismo , Adulto , Femenino , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Dolor/etiología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/diagnóstico , Tractos Espinotalámicos/metabolismo , Adulto JovenRESUMEN
Central pain syndrome is characterized by severe and excruciating pain resulting from a lesion in the central nervous system. Previous studies have shown that estradiol decreases pain and that inhibitors of the enzyme aromatase, which synthesizes estradiol from aromatizable androgens, increases pain sensitivity. In this study we have assessed whether aromatase expression in the dorsal horns of the spinal cord is altered in a rat model of central pain syndrome, induced by the unilateral electrolytic lesion of the spinothalamic tract. Protein and mRNA levels of aromatase, as well as the protein and mRNA levels of estrogen receptors α and ß, were increased in the dorsal horn of female rats after spinothalamic tract injury, suggesting that the injury increased estradiol synthesis and signaling in the dorsal horn. To determine whether the increased aromatase expression in this pain model may participate in the control of pain, mechanical allodynia thresholds were determined in both hind paws after the intrathecal administration of letrozole, an aromatase inhibitor. Aromatase inhibition enhanced mechanical allodynia in both hind paws. Because estradiol is known to regulate gliosis we assessed whether the spinothalamic tract injury and aromatase inhibition regulated gliosis in the dorsal horn. The proportion of microglia with a reactive phenotype and the number of glial fibrillary acidic protein-immunoreactive astrocytes were increased by the injury in the dorsal horn. Aromatase inhibition enhanced the effect of the injury on gliosis. Furthermore, a significant a positive correlation of mechanical allodynia and gliosis in the dorsal horn was detected. These findings suggest that aromatase is up-regulated in the dorsal horn in a model of central pain syndrome and that aromatase activity in the spinal cord reduces mechanical allodynia by controlling reactive gliosis in the dorsal horn.
Asunto(s)
Inhibidores de la Aromatasa/efectos adversos , Aromatasa/metabolismo , Gliosis/inducido químicamente , Dolor/inducido químicamente , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Tractos Espinotalámicos/efectos de los fármacos , Tractos Espinotalámicos/lesiones , Animales , Aromatasa/genética , Progresión de la Enfermedad , Femenino , Gliosis/genética , Gliosis/metabolismo , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patología , Dolor/genética , Dolor/metabolismo , Umbral del Dolor , Ratas , Ratas Sprague-Dawley , Asta Dorsal de la Médula Espinal/metabolismo , Asta Dorsal de la Médula Espinal/patología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , Tractos Espinotalámicos/metabolismo , Tractos Espinotalámicos/patologíaRESUMEN
Targeted mutation of the Frizzled3 (Fz3) gene in mice has been shown to disrupt the growth and guidance of a subset of peripheral and central axons. Here we used conditional deletion of Fz3 to explore the forebrain territories in which Fz3 action is required for the development of the anterior commissure and the corticothalamic, corticospinal, and thalamocortical tracts. Experiments with region-specific deletion of Fz3 using a variety of Cre lines show that proper routing of corticothalamic and thalamocortical axons in the internal capsule requires Fz3 expression in the ventral telencephalon. The pattern of defects among forebrain axon tracts that are induced by conditional deletion of Fz3 conforms closely to the pattern previously observed with analogous conditional deletion of Celsr3, implying a close mechanistic link between Fz3 and Celsr3 in axon guidance. We further found that several central nervous system axon tracts require Fz3 function as early as embryonic day 11.5, and that Fz3 is required for pathfinding by dopaminergic and serotonergic axons in the brain and by a subset of optic tract axons. In addition, conditional deletion of Fz3 in all tissues caudal to the neck eliminates the spinothalamic tract and the transmission of somatosensory information from the spinal cord to the brain, as determined by neuroanatomic tracing and behavioral testing.
Asunto(s)
Axones/metabolismo , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Receptores Frizzled/metabolismo , Animales , Encéfalo/embriología , Encéfalo/patología , Catecolaminas/metabolismo , Embrión de Mamíferos/metabolismo , Receptores Frizzled/deficiencia , Silenciador del Gen , Mesencéfalo/embriología , Mesencéfalo/metabolismo , Mesencéfalo/patología , Ratones , Ratones Noqueados , Especificidad de Órganos , Serotonina/metabolismo , Médula Espinal/patología , Tractos Espinotalámicos/metabolismo , Tractos Espinotalámicos/patología , Telencéfalo/metabolismoRESUMEN
Neuropathic pain is a widespread and highly debilitating condition commonly resulting from injury to the nervous system, one main sequela of which is tactile allodynia, a pain induced by innocuous mechanical stimulation of the skin. Yet, the cellular mechanisms and neuronal substrates underlying this pathology have remained elusive. We studied this by quantifying and manipulating behavioural and neuronal nociceptive thresholds in normal and pathological pain conditions. We found that, in both control rats and those with pain hypersensitivity induced by nerve injury, the nociceptive paw withdrawal threshold matches the response threshold of nociceptive-specific deep spinothalamic tract neurons. In contrast, wide dynamic range or multimodal spinothalamic tract neurons showed no such correlation nor any change in properties after nerve injury. Disrupting Cl(-) homeostasis by blocking K(+)-Cl(-) co-transporter 2 replicated the decrease in threshold of nociceptive-specific spinothalamic tract neurons without affecting wide dynamic range spinothalamic tract cells. Accordingly, only combined blockade of both GABAA- and glycine-gated Cl(-) channels replicated the effects of nerve injury or K(+)-Cl(-) co-transporter 2 blockade to their full extent. Conversely, rescuing K(+)-Cl(-) co-transporter 2 function restored the threshold of nociceptive-specific spinothalamic tract neurons to normal values in animals with nerve injury. Thus, we unveil a tight association between tactile allodynia and abnormal sensory coding within the normally nociceptive-specific spinothalamic tract. Thus allodynia appears to result from a switch in modality specificity within normally nociceptive-specific spinal relay neurons rather than a change in gain within a multimodal ascending tract. Our findings identify a neuronal substrate and a novel cellular mechanism as targets for the treatment of pathological pain.
Asunto(s)
Hiperalgesia/fisiopatología , Transporte Iónico/fisiología , Neuronas , Nocicepción/fisiología , Tractos Espinotalámicos/fisiopatología , Animales , Modelos Animales de Enfermedad , Hiperalgesia/metabolismo , Masculino , Microelectrodos , Neuronas/citología , Neuronas/metabolismo , Dimensión del Dolor , Técnicas de Placa-Clamp , Cloruro de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/inducido químicamente , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Tractos Espinotalámicos/citología , Tractos Espinotalámicos/lesiones , Tractos Espinotalámicos/metabolismo , SimportadoresRESUMEN
Oxytocin (OT) secreted by the hypothalamo-spinal projection exerts antinociceptive effects in the dorsal horn. Electrophysiological evidence indicates that OT could exert these effects by activating OT receptors (OTR) directly on dorsal horn neurons and/or primary nociceptive afferents in the dorsal root ganglia (DRG). However, little is known about the identity of the dorsal horn and DRG neurons that express the OTR. In the dorsal horn, we found that the OTR is expressed principally in neurons cell bodies. However, neither spino-thalamic dorsal horn neurons projecting to the contralateral thalamic ventral posterolateral nucleus (VPL) and posterior nuclear group (Po) nor GABaergic dorsal horn neurons express the OTR. The OTR is not expressed in skin nociceptive terminals or in dorsal horn nociceptive fibers. In the DRG, however, the OTR is expressed predominantly in non-peptidergic C-fiber cell bodies, but not in peptidergic or mechanoreceptor afferents or in skin nociceptive terminals. Our results suggest that the antinociceptive effects of OT are mediated by direct activation of dorsal horn neurons and peripheral actions on nociceptive, non-peptidergic C-afferents in the DRG.
Asunto(s)
Ganglios Espinales/metabolismo , Neuronas/metabolismo , Nociceptores/metabolismo , Células del Asta Posterior/metabolismo , Receptores de Oxitocina/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Técnica del Anticuerpo Fluorescente , Colorantes Fluorescentes , Ganglios Espinales/citología , Procesamiento de Imagen Asistido por Computador , Interneuronas/metabolismo , Masculino , Fibras Nerviosas Amielínicas/metabolismo , Neuronas Aferentes/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Wistar , Tractos Espinotalámicos/citología , Tractos Espinotalámicos/metabolismo , Estilbamidinas , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Specific neuronal populations are known to express calcium binding proteins (CBP) such as calbindin (CB), parvalbumin (PV) and calretinin (CR). These CBP can act as calcium buffers that modify spatiotemporal characteristics of intracellular calcium transients and affect calcium homeostasis in neurons. It was recently shown that changes in neuronal CBP expression can have significant modulatory effect on synaptic transmission. Spinothalamic tract (STT) neurons form a major nociceptive pathway and they become sensitized after peripheral inflammation. In our experiments, expression of CBP in STT neurons was studied in a model of unilateral acute knee joint arthritis in rats. Altogether 377, 374 and 358 STT neurons in the segments L3-4 were evaluated for the presence of CB, PV and CR. On the contralateral (control) side 1%, 9% and 47% of the retrogradely labeled STT neurons expressed CB, PV and CR, respectively. On the ipsilateral (arthritic) side there was significantly more CB (23%) and PV (25%) expressing STT neurons, while the number of CR positive neurons (50%) did not differ. Our results show increased expression of fast (CB) and slow (PV) calcium binding proteins in STT neurons after induction of experimental arthritis. This suggests that change in CBP expression could have a significant effect on calcium homeostasis and possibly modulation of synaptic activity in STT neurons.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Inflamación/metabolismo , Neuronas/metabolismo , Tractos Espinotalámicos/metabolismo , Animales , Calbindina 2 , Calbindinas , Masculino , Parvalbúminas/metabolismo , Ratas , Ratas Wistar , Proteína G de Unión al Calcio S100/metabolismoRESUMEN
The spinothalamic tract (STT) neurons in the spinal dorsal horn play an important role in transmission and processing of nociceptive sensory information. Although transient receptor potential vanilloid type 1 (TRPV1) receptors are present in the spinal cord dorsal horn, their physiological function is not fully elucidated. In this study, we examined the role of TRPV1 in modulating neuronal activity of the STT neurons through excitatory and inhibitory synaptic inputs. Whole-cell patch-clamp recordings were performed on STT neurons labeled by a retrograde fluorescent tracer injected into the ventral posterior lateral (VPL) nucleus of the thalamus. Capsaicin (1 microM) increased the frequency of miniature excitatory postsynaptic currents (mEPSC) without changing the amplitude or decay time constant of mEPSC. In contrast, capsaicin had no distinct effect on GABAergic miniature inhibitory postsynaptic currents (mIPSC). Capsazepine (10 microM), a TRPV1 receptor antagonist, abolished the effect of capsaicin on mEPSCs. Capsazepine itself did not affect the baseline amplitude and frequency of mEPSC. The effect of capsaicin on mEPSC was also abolished by removal of external Ca(2+), but not by treatment with Cd(2+). Furthermore, capsaicin increased the firing activity of the STT neurons and this increase in neuronal activity by capsaicin was abolished in the presence of non-N-methyl-d-aspartic acid (NMDA) and NMDA receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) and (R)-amino-5-phosphonovaleric acid (APV). These data suggest that activation of TRPV1 potentiates the glutamate release from excitatory terminals of primary afferent fibers and subsequently increases the neural activity of STT neurons of the rat spinal cord deep dorsal horn.
Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Dolor/metabolismo , Células del Asta Posterior/metabolismo , Tractos Espinotalámicos/metabolismo , Transmisión Sináptica/fisiología , Canales Catiónicos TRPV/metabolismo , Animales , Canales de Calcio/metabolismo , Capsaicina/farmacología , Femenino , Ácido Glutámico/metabolismo , Técnicas In Vitro , Masculino , Potenciales Postsinápticos Miniatura/fisiología , Ratas , Ratas Sprague-Dawley , Fármacos del Sistema Sensorial/farmacología , Tractos Espinotalámicos/citología , Estadísticas no Paramétricas , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Although most projection neurons in lamina I express the neurokinin 1 receptor (NK1r), we have identified a population of large multipolar projection cells that lack the NK1r, are characterized by the high density of gephyrin puncta that coat their cell bodies and dendrites, and express the transcription factor Fos in response to noxious chemical stimulation. Here we show that these cells have a very high density of glutamatergic input from axons with strong immunoreactivity for vesicular glutamate transporter 2 that are likely to originate from excitatory interneurons. However, they receive few contacts from peptidergic primary afferents or transganglionically labeled Adelta nociceptors. Unlike most glutamatergic synapses in superficial laminas, those on the gephyrin-coated cells contain the GluR4 subunit of the AMPA receptor. A noxious heat stimulus caused Fos expression in 38% of the gephyrin-coated cells but in 85% of multipolar NK1r-immunoreactive cells. These findings are consistent with the suggestion that there is a correlation between function and morphology for lamina I neurons but indicate that there are at least two populations of multipolar neurons that differ in receptor expression, excitatory inputs, and responses to noxious stimulation. Although there are only approximately 10 gephyrin-coated cells on each side per segment in the lumbar enlargement, they constitute approximately 18% of the lamina I component of the spinothalamic tract at this level, which suggests that they play an important role in transmission of nociceptive information to the cerebral cortex. Our results also provide the first evidence that postsynaptic GluR4-containing AMPA receptors are involved in spinal nociceptive transmission.
Asunto(s)
Ácido Glutámico/metabolismo , Nociceptores/metabolismo , Células del Asta Posterior/metabolismo , Terminales Presinápticos/metabolismo , Receptores AMPA/metabolismo , Tractos Espinotalámicos/metabolismo , Animales , Proteínas Portadoras/metabolismo , Forma de la Célula/fisiología , Dendritas/metabolismo , Dendritas/ultraestructura , Inmunohistoquímica , Interneuronas/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Nociceptores/citología , Dolor/metabolismo , Dolor/fisiopatología , Estimulación Física , Células del Asta Posterior/citología , Terminales Presinápticos/ultraestructura , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Tractos Espinotalámicos/citología , Sustancia P/metabolismo , Transmisión Sináptica/fisiología , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
UNLABELLED: Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation. PERSPECTIVE: This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.
Asunto(s)
Dolor/fisiopatología , Prurito/fisiopatología , Piel/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Factor de Transcripción Activador 3/metabolismo , Análisis de Varianza , Animales , Axones/metabolismo , Axones/patología , Desnervación/efectos adversos , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Inmunohistoquímica , Masculino , Dolor/etiología , Prurito/etiología , Ácido Quiscuálico , Ratas , Ratas Long-Evans , Piel/inervación , Traumatismos de la Médula Espinal/inducido químicamente , Traumatismos de la Médula Espinal/complicaciones , Tractos Espinotalámicos/metabolismo , Tractos Espinotalámicos/patología , Tractos Espinotalámicos/fisiopatología , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Activation of the cAMP pathway is an important mediator of chronic muscle pain. This study examined phosphorylation of the transcription factor cAMP-response-element-binding protein (p-CREB) and the NR1 subunit of the NMDA receptor (p-NR1) in the spinal cord. Bilateral mechanical hyperalgesia of the paw was induced by administering two injections of acidic saline, 5 days apart, into the gastrocnemius muscle of male Sprague-Dawley rats. The proportion of spinothalamic neurons that expressed p-NR1 or p-CREB did not change in the dorsal horn 24h after the second intramuscular acid injection compared with animals that received pH 7.2 injections. This lack of change in spinothalamic neurons in the dorsal horn may be due to increases in individual spinothalamic neurons or increases in non-spinothalamic neurons. There was an increase in the proportion of spinothalamic neurons expressing p-NR1 in lamina X. These findings suggest that there are region-specific changes in spinothalamic neurons that express p-NR1 and lamina X may play an important role in the modulation of chronic muscle pain.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Músculo Esquelético/metabolismo , Neuronas/metabolismo , Dolor/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Tractos Espinotalámicos/metabolismo , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Hiperalgesia/fisiopatología , Masculino , Músculo Esquelético/patología , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
Distinct morphological types of spinothalamic tract (STT) lamina I (LI) neurons have been identified in the cat and monkey spinal dorsal horn. Because these morphological types appear to differ in functional properties and receptor expression, we examined their distribution in the rat to test how their identification relates to earlier classification schemes. LI STT cells were retrogradely labeled with cholera toxin subunit b (CTb). Three types were recognized on the basis of cell body shape and proximal dendrites in the horizontal plane: fusiform, multipolar, and pyramidal. The relative distribution of these types was: 43, 26, and 28%, respectively, similar to that observed in the cat and monkey. 3D reconstructions were used to view each cell in all three major projection planes: horizontal, parasagittal, and transverse. Most LI STT neurons appeared fusiform in the parasagittal plane even though they belonged to different types based on their appearance in the horizontal plane, except in the most lateral portion of the dorsal horn, where LI curves ventrally. The proportion of STT neurons within LI was quantified by using the optical dissector method. To label all LI neurons, we used an anti-neuron-specific nuclear protein (NeuN) antibody. We found that approximately 9% of LI neurons projected to the thalamus. We also investigated neurokinin 1 receptor (NK-1r) expression in LI STT neurons. As in the monkey, most pyramidal STT neurons did not express NK-1r. These results provide further evidence that distinct morphological types of neurons differ in phenotype but not in their projection pattern.
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Neuronas Aferentes/citología , Neuronas Aferentes/metabolismo , Receptores de Neuroquinina-1/metabolismo , Médula Espinal/metabolismo , Tractos Espinotalámicos/metabolismo , Animales , Inmunohistoquímica , Masculino , Neuronas Aferentes/clasificación , Ratas , Ratas Sprague-Dawley , Médula Espinal/citología , Tractos Espinotalámicos/citología , Distribución TisularRESUMEN
Brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in the phenomena of synaptic plasticity in the adult. It is found in terminals of nociceptive primary afferents. Following a pain-related stimulus, it is released in the spinal cord, where it activates its high-affinity receptor TrkB, leading to the phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK). A large body of evidence suggests that BDNF has a positive neuromodulatory effect on glutamate transmission in the spinal cord. However, none of these studies examined anatomically whether projection neurons known to be involved in transmission of nociceptive inputs express BDNF's receptor. Because the spinothalamic tract (STT) is a well-characterized pathway for its role in the transfer and integration of sensory and nociceptive informations, this study in rats aimed to 1) determine whether neurons of the STT pathway express the TrkB receptor, 2) establish the rostrocaudal and laminar distribution of STT-TrkB neurons in the whole spinal cord, and 3) test the potential functionality of TrkB expression in these cells by investigating the ability of BDNF to activate the MAP kinase ERK. Using tract tracing coupled to immunofluorescent labeling for TrkB, we observed that in all levels of the spinal cord most STT neurons were immunoreactive for TrkB. Furthermore, microinjections of BDNF into the spinal cord or release of endogenous BDNF by intraplantar injection of capsaicin activated ERK phosphorylation in TrkB-containing STT neurons. These data suggest an important role for BDNF in nociception as an activator of spinothalamic projection neurons.
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Factor Neurotrófico Derivado del Encéfalo/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Receptor trkB/biosíntesis , Tractos Espinotalámicos/citología , Tractos Espinotalámicos/metabolismo , Animales , Capsaicina/farmacología , Activación Enzimática/efectos de los fármacos , Colorantes Fluorescentes , Inmunohistoquímica , Ratas , Ratas Wistar , Receptor trkB/genética , Tractos Espinotalámicos/efectos de los fármacos , Técnicas Estereotáxicas , EstilbamidinasRESUMEN
Spinal cord injury (SCI) often leads to the generation of chronic intractable neuropathic pain. The mechanisms that lead to chronic central neuropathic pain (CNP) following SCI are not well understood, resulting in ineffective treatments for pain relief. Studies have demonstrated persistent hyperexcitability of dorsal horn neurons which may provide a substrate for CNP. We propose a number of similarities between CNP mechanisms and mechanisms that occur in long-term potentiation, in which hippocampal neurons are hyperexcitable. One biochemical similarity may be activation of the transcription factor, cyclic AMP response element-binding protein (CREB), via phosphorylation (pCREB). The current study was designed to examine whether tactile allodynia that develops in segments rostral to SCI (at-level pain) correlates with an increase in CREB phosphorylation in specific neurons known to be involved in allodynia, the spinothalamic tract (STT) cells. This study determined that, in animals experiencing at-level allodynia 35 days after SCI, pCREB was upregulated in the spinal cord segment rostral to the injury. In addition, pCREB was found to be upregulated specifically in STT cells in the rostral segment 35 days after SCI. These findings suggest one mechanism of maintained central neuropathic pain following SCI involves persistent upregulation of pCREB expression within STT cells.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Neuronas/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Tractos Espinotalámicos/patología , Análisis de Varianza , Animales , Conducta Animal , Western Blotting/métodos , Recuento de Células/métodos , Técnica del Anticuerpo Fluorescente/métodos , Masculino , Dimensión del Dolor/métodos , Fosforilación , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/fisiopatología , Tractos Espinotalámicos/metabolismo , Tractos Espinotalámicos/fisiopatología , Estilbamidinas/metabolismo , Regulación hacia ArribaRESUMEN
The spinothalamic tract (STT) has been classically viewed as the major ascending pathway for pain transmission while the dorsal column (DC) was thought to be involved primarily in signaling innocuous stimuli. Recent clinical studies have shown that limited midline myelotomy, which transects fibers in the DC, offers good pain relief in patients with visceral cancer pain. Experimental studies provided evidence that a DC lesion decreases the activation of thalamic neurons by visceral stimuli and suggested that this effect is due to transection of the axons of postsynaptic dorsal column (PSDC) neurons. In our study, Fos protein expression in retrogradely labeled STT and PSDC neurons in the lumbosacral enlargement in rats was used as an anatomical marker of enhanced activation to compare the role of these neurons in cutaneous and visceral pain. The noxious stimuli used were intradermal injection of capsaicin and distention of the ureter. Retrogradely labeled PSDC neurons were found in laminae III-IV and in the vicinity of the central canal. STT neurons were located in laminae I, III-VII and X. Ureter distention evoked Fos expression in PSDC and STT neurons located in all laminae in which retrogradely labeled cells were found, with the maximum in the L(2) spinal segment. The Fos-positive PSDC neurons represented a significantly higher percentage of the retrogradely labeled PSDC neurons (19.3+/-2.3% SEM) than of the STT Fos-positive neurons (13.2+/-1.5% SEM). Intradermal capsaicin injection also evoked Fos expression in both PSDC and STT neurons, but with no significant difference between these two, when expressed as a percentage of the retrogradely labeled cells (11.6+/-2.9% SEM, 10.8+/-1.1% SEM). These results show that both PSDC and STT neurons are activated by cutaneous and visceral noxious stimuli. Their particular role in transmission and modulation of painful stimuli needs to be investigated further.
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Dolor/metabolismo , Células del Asta Posterior/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Tractos Espinotalámicos/metabolismo , Animales , Regulación de la Expresión Génica/fisiología , Masculino , Dimensión del Dolor/métodos , Estimulación Física/efectos adversos , Proteínas Proto-Oncogénicas c-fos/genética , Ratas , Ratas Sprague-Dawley , Tacto/fisiologíaRESUMEN
To elucidate the organization of the ferret spinocervicothalamic pathway (SCTP), we examined the lateral cervical nucleus (LCN) and the termination of the cervicothalamic tract (CTY) in this species. In thionin-stained sections, the ferret LCN appeared as an easily delineated column of cells in the dorsolateral funiculus from about mid-C3 to the rostral end of C1, with most cells located in the C1 and C2 segments. In transverse sections, the LCN was elongated along a dorsolateral to ventromedial axis and in the rostral half of C2 and caudal half of C1 continuous with the neck of the dorsal horn. The number of ferret LCN cells was estimated to 2,500-3,700, with an average of 3,340. Substance P-like immunoreactive fibers located preferentially in the ventromedial part of the LCN, whereas serotonin-like immunoreactive fibers were found throughout the nucleus. Anterograde transport of wheat germ agglutinin-horseradish peroxidase conjugate and biotinylated dextran amine demonstrated that the ferret CTT terminates extensively in the peripheral parts of the ventral posterior lateral nucleus. Sparser termination was evident in the ventral posterior inferior nucleus, in the medial nucleus of the posterior complex, and in the medial part of the magnocellular medial geniculate nucleus. Thus, although the LCN is significantly smaller in ferrets than in cats and raccoons, the organization of the LCN and of the cervicothalamic tract is closely similar in the three species. These findings indicate a conserved general organization of the SCTP among carnivores.
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Biotina/análogos & derivados , Hurones/fisiología , Médula Espinal/fisiología , Tractos Espinotalámicos/fisiología , Animales , Recuento de Células , Colorantes , Dextranos , Colorantes Fluorescentes , Inmunohistoquímica , Fibras Nerviosas/fisiología , Fenotiazinas , Serotonina/metabolismo , Médula Espinal/anatomía & histología , Médula Espinal/metabolismo , Tractos Espinotalámicos/citología , Tractos Espinotalámicos/metabolismo , Sustancia P/metabolismo , Núcleos Talámicos/citología , Núcleos Talámicos/metabolismo , Núcleos Talámicos/fisiología , Aglutinina del Germen de Trigo-Peroxidasa de Rábano Silvestre ConjugadaRESUMEN
Spinal cord injury (SCI) leads to an increase in metabotropic glutamate receptor subtype 1 (mGluR1) immunoreactivity in the peri-lesion area. The increased expression of mGluR1 parallels the development of thermal hyperalgesia and mechanical allodynia and has been suggested to contribute to the development and maintenance of chronic central pain (CCP) syndromes resulting from SCI. However, expression of mGluR1 has not been directly shown to increase on cells in the pain pathway. Therefore, the expression of mGluR1 on spinothalamic tract (STT) neurons was quantified using confocal imaging and densiometric analysis in normal, sham, and SCI rats. Contusion SCI produced an increase in mGluR1 expression on STT cells in both the cervical enlargement and the spinal section just rostral to contusion SCI. These results suggest that mGluR1 is expressed on neurons that modulate pain transmission and expression on these cells increases following injury, supporting the hypothesis that mGluR1 contributes to CCP following SCI.