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1.
Proc Natl Acad Sci U S A ; 117(10): 5402-5408, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32102913

RESUMO

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Músculo Esquelético/lesões , Músculo Esquelético/fisiologia , Nociceptores/fisiologia , Regeneração , Linfócitos T Reguladores/imunologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Comunicação Celular , Interleucina-33/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos
2.
Nat Commun ; 10(1): 4253, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534133

RESUMO

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH.


Assuntos
Transtornos da Cefaleia Secundários/patologia , Transtornos de Enxaqueca/patologia , Canal de Sódio Disparado por Voltagem NAV1.9/metabolismo , Neurônios Aferentes/metabolismo , Óxido Nítrico/metabolismo , Triptaminas/efeitos adversos , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Degranulação Celular/fisiologia , Células Cultivadas , Feminino , Transtornos da Cefaleia Secundários/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Neurônios Aferentes/efeitos dos fármacos , Nociceptores/fisiologia , Dor/fisiopatologia , Uso Excessivo de Medicamentos Prescritos/efeitos adversos
3.
Philos Trans R Soc Lond B Biol Sci ; 374(1785): 20190277, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31544606

RESUMO

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.


Assuntos
Evolução Biológica , Aptidão Genética , Nociceptores/fisiologia , Dor/fisiopatologia , Adaptação Fisiológica , Animais , Dor/etiologia
4.
Cornea ; 38 Suppl 1: S11-S24, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31490785

RESUMO

Patients with corneal and conjunctival disorders report an array of ocular surface symptoms including stinging, foreign body sensation, and itching. The intensity and perceptual quality of these sensations and their duration, from brief intervals to long-term symptoms, also vary. We hypothesize that symptomatic differences across disorders reflect differences in the balance between ocular inflammation and nerve injury, with different conditions resulting from predominant effects of one of these, or a combined effect. This article provides an overview of corneal and conjunctival nerve cells, such as nociceptors and thermoreceptors, with descriptions of their morphological and molecular characteristics and their nerve-firing patterns and evoked sensations, as determined by earlier studies in animals and humans. Detailed descriptions of the changes in neuronal responses (such as abnormal responsiveness and spontaneous firing) due to local inflammation and nerve injury are provided, and assorted ocular surface disorders are discussed. Eye conditions in which inflammation is predominant include allergic conjunctivitis and photokeratitis, whereas nerve injury is the primary factor underlying complaints of dry eye after photorefractive keratectomy and in elderly patients. Both factors contribute substantially to dry eye disease and varicella-zoster infections. This model of the combined effects of inflammation and nerve injury serves to explain the different sensations reported in various eye surface disorders, including short-term versus chronic pain and dysesthesias, and may help to improve diagnoses and treatment methods.


Assuntos
Córnea/inervação , Síndromes do Olho Seco/diagnóstico , Dor Ocular/diagnóstico , Ceratite/diagnóstico , Nociceptores/fisiologia , Sensação/fisiologia , Termorreceptores/fisiopatologia , Síndromes do Olho Seco/fisiopatologia , Dor Ocular/etiologia , Humanos , Ceratite/fisiopatologia , Lágrimas/metabolismo
6.
Science ; 365(6454): 695-699, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31416963

RESUMO

An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.


Assuntos
Percepção da Dor/fisiologia , Células de Schwann/fisiologia , Pele/inervação , Animais , Feminino , Masculino , Mecanorreceptores/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/fisiologia , Optogenética , Limiar da Dor , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/metabolismo , Termorreceptores/fisiologia
7.
Nat Neurosci ; 22(9): 1477-1492, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358991

RESUMO

Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.


Assuntos
Tronco Encefálico/fisiologia , Vias Neurais/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia , Animais , Tronco Encefálico/citologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Vias Neurais/citologia , Nociceptores/citologia , Ocitocina , Peixe-Zebra
8.
eNeuro ; 6(4)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308053

RESUMO

Although TWIK-related spinal cord K+ (TRESK) channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), whether TRESK activity regulates trigeminal pain processing is still not established. Dominant-negative TRESK mutations are associated with migraine but not with other types of pain in humans, suggesting that genetic TRESK dysfunction preferentially affects the generation of trigeminal pain, especially headache. Using TRESK global knock-out mice as a model system, we found that loss of TRESK in all TG neurons selectively increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4-). Similarly, loss of TRESK resulted in hyper-excitation of the small IB4- dural afferent neurons but not those that bind to IB4 (IB4+). Compared with wild-type littermates, both male and female TRESK knock-out mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors, whereas their body and visceral pain responses were normal. Interestingly, neither the total persistent outward current nor the intrinsic excitability was altered in adult TRESK knock-out DRG neurons, which may explain why genetic TRESK dysfunction is not associated with body and/or visceral pain in humans. We reveal for the first time that, among all primary afferent neurons, TG nociceptors are the most vulnerable to the genetic loss of TRESK. Our findings indicate that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors. Importantly, we provide evidence that genetic loss of TRESK significantly increases the likelihood of developing headache.


Assuntos
Cefaleia/fisiopatologia , Neurônios Aferentes/fisiologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Canais de Potássio/fisiologia , Gânglio Trigeminal/fisiopatologia , Animais , Feminino , Gânglios Espinais/fisiopatologia , Masculino , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Aferentes/metabolismo , Nociceptores/fisiologia , Canais de Potássio/genética , Canais de Potássio/metabolismo , Gânglio Trigeminal/metabolismo
9.
Semin Fetal Neonatal Med ; 24(4): 101001, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31160226

RESUMO

Fetal pain is difficult to assess, because the main feature needed to spot pain, is the subject's capability of declaring it. Nonetheless, much can be affirmed about this issue. In this review we first report the epochs of the development of human nociceptive pathways; then we review since when they are functioning. We also review the latest data about the new topic of analgesia and prenatal surgery and about the scarce effect on fetal pain sentience of the natural sedatives fetuses produce. It appears that pain is a neuroadaptive phenomenon that emerges in the middle of pregnancy, at about 20-22 weeks of gestation, and becomes more and more evident for bystanders and significant for the fetus, throughout the rest of the pregnancy.


Assuntos
Feto/cirurgia , Dor/embriologia , Dor/prevenção & controle , Analgesia , Feminino , Feto/inervação , Humanos , Nociceptividade/fisiologia , Nociceptores/fisiologia , Percepção da Dor/fisiologia , Gravidez
11.
eNeuro ; 6(3)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182472

RESUMO

Neurons of the PNS are able to regenerate injured axons, a process requiring significant cellular resources to establish and maintain long-distance growth. Genetic activation of mTORC1, a potent regulator of cellular metabolism and protein translation, improves axon regeneration of peripheral neurons by an unresolved mechanism. To gain insight into this process, we activated mTORC1 signaling in mouse nociceptors via genetic deletion of its negative regulator Tsc2. Perinatal deletion of Tsc2 in nociceptors enhanced initial axon growth after sciatic nerve crush, however by 3 d post-injury axon elongation rate became similar to controls. mTORC1 inhibition prior to nerve injury was required to suppress the enhanced axon growth. Gene expression analysis in purified nociceptors revealed that Tsc2-deficient nociceptors had increased activity of regeneration-associated transcription factors (RATFs), including cJun and Atf3, in the absence of injury. Additionally, nociceptor deletion of Tsc2 activated satellite glial cells and macrophages in the dorsal root ganglia (DRG) in a similar manner to nerve injury. Surprisingly, these changes improved axon length but not percentage of initiating axons in dissociated cultures. The pro-regenerative environment in naïve DRG was recapitulated by AAV8-mediated deletion of Tsc2 in adult mice, suggesting that this phenotype does not result from a developmental effect. Consistently, AAV8-mediated Tsc2 deletion did not improve behavioral recovery after a sciatic nerve crush injury despite initially enhanced axon growth. Together, these data show that neuronal mTORC1 activation induces an incomplete pro-regenerative environment in the DRG that improves initial but not later axon growth after nerve injury.


Assuntos
Axônios/fisiologia , Gânglios Espinais/fisiopatologia , Regeneração Nervosa/fisiologia , Nociceptores/fisiologia , Animais , Axônios/metabolismo , Feminino , Gânglios Espinais/metabolismo , Expressão Gênica , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Camundongos Transgênicos , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/fisiologia
12.
Ann Anat ; 225: 28-32, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195095

RESUMO

Anterior cruciate ligament (ACL) tears is a devastating injury and one of the most common knee injuries experienced by athletes in the United States. Although patients reach maximal subjective improvement by one-year following ACL reconstruction, many patients often experience moderate to severe post-operative pain. Opioids, intra-articular injections, and regional anesthesia have been previously implemented to mediate post-operative pain. However, chronic opioid usage has become an epidemic in the United States. Alternative analgesic modalities, such as nerve blocks, have been implemented in clinical practice to provide adequate pain relief and minimize opioid usage. Periarticular injections targeted towards local neurological structures performed concomitantly with nerve blocks provides superior pain relief and satisfaction than isolated nerve blocks. Therefore, it is imperative for physicians to understand local neurological anatomy around the knee joint in order to provide adequate analgesia while minimizing opioid consumption. This purpose of this investigation is to summarize (1) neurogenic origins of pain generators and mediators in sites affected by ACL reconstruction and autograft harvest sites and (2) analgesia utilized in ACL reconstruction.


Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/anatomia & histologia , Articulação do Joelho/irrigação sanguínea , Articulação do Joelho/inervação , Dor Pós-Operatória/etiologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestesia Local , Anestésicos Locais/administração & dosagem , Ligamento Cruzado Anterior/inervação , Ligamento Cruzado Anterior/cirurgia , Autoenxertos , Canais Iônicos/metabolismo , Mecanorreceptores/fisiologia , Bloqueio Nervoso , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia
13.
Science ; 364(6443): 852-859, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31147513

RESUMO

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.


Assuntos
Evolução Molecular , Ratos-Toupeira/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Dor Nociceptiva/genética , Limiar da Dor , Canal de Cátion TRPA1/genética , Animais , Sítios de Ligação , Capsaicina/farmacologia , Ácido Clorídrico/farmacologia , Mordeduras e Picadas de Insetos/genética , Mordeduras e Picadas de Insetos/imunologia , Isotiocianatos/farmacologia , Ratos-Toupeira/genética , Ratos-Toupeira/imunologia , Dor Nociceptiva/induzido quimicamente , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Conformação Proteica , Análise de Sequência de RNA , Especificidade da Espécie , Canal de Cátion TRPA1/química
14.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137507

RESUMO

The prime task of nociceptors is the transformation of noxious stimuli into action potentials that are propagated along the neurites of nociceptive neurons from the periphery to the spinal cord. This function of nociceptors relies on the coordinated operation of a variety of ion channels. In this review, we summarize how members of nine different families of ion channels expressed in sensory neurons contribute to nociception. Furthermore, data on 35 different types of G protein coupled receptors are presented, activation of which controls the gating of the aforementioned ion channels. These receptors are not only targeted by more than 20 separate endogenous modulators, but can also be affected by pharmacotherapeutic agents. Thereby, this review provides information on how ion channel modulation via G protein coupled receptors in nociceptors can be exploited to provide improved analgesic therapy.


Assuntos
Canais Iônicos/metabolismo , Nociceptores/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Humanos , Nociceptores/fisiologia , Transdução de Sinais
15.
Pain ; 160(6): 1281-1296, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30933959

RESUMO

Endogenous inflammatory mediators contribute to the pathogenesis of pain by acting on nociceptors, specialized sensory neurons that detect noxious stimuli. Here, we describe a new factor mediating inflammatory pain. We show that platelet-derived growth factor (PDGF)-BB applied in vitro causes repetitive firing of dissociated nociceptor-like rat dorsal root ganglion neurons and decreased their threshold for action potential generation. Injection of PDGF-BB into the paw produced nocifensive behavior in rats and led to thermal and mechanical pain hypersensitivity. We further detailed the biophysical mechanisms of these PDGF-BB effects and show that PDGF receptor-induced inhibition of nociceptive M-current underlies PDGF-BB-mediated nociceptive hyperexcitability. Moreover, in vivo sequestration of PDGF or inhibition of the PDGF receptor attenuates acute formalin-induced inflammatory pain. Our discovery of a new pain-facilitating proinflammatory mediator, which by inhibiting M-current activates nociceptive neurons and thus contributes to inflammatory pain, improves our understanding of inflammatory pain pathophysiology and may have important clinical implications for pain treatment.


Assuntos
Inflamação/tratamento farmacológico , Nociceptores/fisiologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Células Receptoras Sensoriais/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Nociceptores/efeitos dos fármacos , Dor/metabolismo , Dor/fisiopatologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos
16.
Exp Brain Res ; 237(7): 1629-1641, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949729

RESUMO

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.


Assuntos
Capsaicina/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Tratos Piramidais/efeitos dos fármacos , Fármacos do Sistema Sensorial/farmacologia , Animais , Gatos , Feminino , Masculino , Neurônios Aferentes/fisiologia , Nociceptores/fisiologia , Células do Corno Posterior/fisiologia , Tratos Piramidais/fisiologia
17.
BMJ Open ; 9(4): e025530, 2019 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31005922

RESUMO

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.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Limiar da Dor , Dor/genética , Colômbia , Voluntários Saudáveis , Humanos , Nociceptores/fisiologia
18.
Methods Mol Biol ; 1987: 125-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028678

RESUMO

Patch-clamp recording combined with biophysical modeling and mutagenic perturbations provides an effective means to study structural functions of ion channels. The methodology has been successful for studying ligand- or voltage-gated channels and brought about much of the knowledge we know today on how ligand or voltage gates an ion channel. The approach, when applied to thermal channels, however, has faced unique challenges. For one problem, thermal channels can operate at high temperatures, and for these channels, prolonged temperature stimulation incurs excessive thermal stress to destabilize patches. For another problem, conventional temperature controls are slow and limit the attainment of high resolution data such as time-resolved activations of thermal channels. Due to these issues, thermal channels have been less accessible to biophysical studies at mechanistic levels. In this chapter we address the problems and demonstrate fast temperature controls enabling recording of time-resolved responses of thermal channels at high temperatures.


Assuntos
Técnicas de Patch-Clamp/métodos , Canais de Receptores Transientes de Potencial/metabolismo , Animais , Células HEK293 , Temperatura Alta , Humanos , Cinética , Camundongos , Nociceptores/fisiologia , Ratos , Termorreceptores/fisiologia
19.
Neurosci Lett ; 705: 20-26, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30995520

RESUMO

Sickle cell disease (SCD) describes a group of disorders associated with a point mutation in the beta chain of hemoglobin. The mutation leads to the creation of sickle hemoglobin (HbS) and causes distortion of erythrocytes through polymerization under low oxygen, resulting in characteristic sickle red blood cells. Vaso-occlusion episodes caused by accumulation of sRBCs results in ischemia-reperfusion injury, reduced oxygen supply to organs, oxidative stress, organ damage and severe pain that often requires hospitalization and opioid treatment. Further, many patients suffer from chronic pain, including hypersensitivity to heat and cold stimuli. Progress towards the development of novel strategies for both acute and chronic pain in patients with SCD has been impeded by a lack of understanding the mechanisms underlying pain in SCD. The purpose of this review is to highlight evidence for the contribution of peripheral and central sensitization that leads to widespread, chronic pain and hyperalgesia. Targeting the mechanisms that initiate and maintain sensitization in SCD might offer effective approaches to manage the severe and debilitating pain associated with this condition.


Assuntos
Anemia Falciforme/fisiopatologia , Sensibilização do Sistema Nervoso Central/fisiologia , Dor Crônica/fisiopatologia , Hiperalgesia/fisiopatologia , Nociceptores/fisiologia , Células do Corno Posterior/fisiologia , Anemia Falciforme/complicações , Animais , Dor Crônica/complicações , Humanos , Hiperalgesia/complicações
20.
Pain ; 160(5): 1146-1155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30920428

RESUMO

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 µm, range 16-57 µm) than immunonegative neurons (26 ± 3.4 µm, range 15-43 µm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.


Assuntos
Gânglios Espinais/patologia , Nociceptores/efeitos dos fármacos , Ocitocina/uso terapêutico , Traumatismos dos Nervos Periféricos/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Tato , Potenciais de Ação/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Mecanorreceptores/efeitos dos fármacos , Nociceptores/fisiologia , Ocitocina/farmacologia , Limiar da Dor/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Células Receptoras Sensoriais/fisiologia
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