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1.
Anesthesiology ; 135(5): 877-892, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610092

RESUMO

BACKGROUND: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. METHODS: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. RESULTS: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). CONCLUSIONS: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.


Assuntos
Anestesia Geral , Encéfalo/fisiologia , Hemodinâmica/fisiologia , Nociceptividade/fisiologia , Vigília/fisiologia , Adulto , Encéfalo/efeitos dos fármacos , Feminino , Humanos , Masculino , Espectroscopia de Luz Próxima ao Infravermelho , Adulto Jovem
3.
J Neurosci ; 41(36): 7546-7560, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34353899

RESUMO

Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain.SIGNIFICANCE STATEMENT It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of CaV2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral CaV2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of CaV2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related CaV2.1 channels. Our findings suggest that interrupting CaV2.2-dependent calcium entry in skin might reduce heat hypersensitivity that develops after noxious heat exposure and may limit the degree of heat hypersensitivity associated with certain other forms of pain.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Cálcio/metabolismo , Hiperalgesia/metabolismo , Neurônios/fisiologia , Nociceptores/fisiologia , Terminações Pré-Sinápticas/metabolismo , Pele/inervação , Corno Dorsal da Medula Espinal/metabolismo , Animais , Temperatura Alta , Camundongos , Nociceptividade/fisiologia , Estimulação Física , Pele/metabolismo , Transmissão Sináptica/fisiologia
4.
Mol Pain ; 17: 17448069211037401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34399634

RESUMO

Chronic pain is a debilitating condition affecting millions of people worldwide, and an improved understanding of the pathophysiology of chronic pain is urgently needed. Nociceptors are the sensory neurons that alert the nervous system to potentially harmful stimuli such as mechanical pressure or noxious thermal temperature. When an injury occurs, the nociceptive threshold for pain is reduced and an increased pain signal is produced. This process is called nociceptive sensitization. This sensitization normally subsides after the injury is healed. However, dysregulation can occur which results in sensitization that persists after the injury has healed. This process is thought to perpetuate chronic pain. The Hedgehog (Hh) signaling pathway has been previously implicated in nociceptive sensitization in response to injury in Drosophila melanogaster. Downstream of Hh signaling, the Bone Morphogenetic Protein (BMP) pathway has also been shown to be necessary for this process. Here, we describe a role for nuclear components of BMP's signaling pathway in the formation of injury-induced nociceptive sensitization. Brinker (Brk), and Schnurri (Shn) were suppressed in nociceptors using an RNA-interference (RNAi) "knockdown" approach. Knockdown of Brk resulted in hypersensitivity in the absence of injury, indicating that it normally acts to suppress nociceptive sensitivity. Animals in which transcriptional activator Shn was knocked down in nociceptors failed to develop normal allodynia after ultraviolet irradiation injury, indicating that Shn normally acts to promote hypersensitivity after injury. These results indicate that Brk-related transcription regulators play a crucial role in the formation of nociceptive sensitization and may therefore represent valuable new targets for pain-relieving medications.


Assuntos
Drosophila melanogaster/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica/genética , Proteínas Hedgehog/metabolismo , Nociceptores/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
5.
Biomolecules ; 11(6)2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204137

RESUMO

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of α3 subtype GlyRs and on the present state of related drug discovery programs.


Assuntos
Nociceptividade/fisiologia , Receptores de Glicina/agonistas , Receptores de Glicina/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Endocanabinoides/farmacologia , Humanos , Nociceptividade/efeitos dos fármacos , Propofol/farmacologia , Estrutura Secundária de Proteína , Receptores de Glicina/química , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Zonisamida/farmacologia
6.
Clin Neurophysiol ; 132(11): 2896-2906, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34226125

RESUMO

OBJECTIVE: Neurophysiological investigation of nociceptive pathway has so far been limited to late cortical responses. We sought to detect early components of the cortical evoked potentials possibly reflecting primary sensory activity. METHODS: The 150 IDE micropatterned electrode was used to selectively activate Aδ intraepidermic fibres of the right hand dorsum in 25 healthy subjects and 3 patients suffering from trigeminal neuralgia. Neurographic recordings were performed to assess type of stimulated fibres and check selectivity. Cortical evoked potentials were recorded from C3'-Fz and Cz-Au1. RESULTS: Neurographic recordings confirmed selective activation of Aδ fibres. Early components were detected after repetitive stimulation (0.83/s rate and 250-500 averages); the first negative component occured at 40 ms (N40) on the contralateral scalp. CONCLUSIONS: The provided data support the hypothesis that N40 could be the cortical primary response conducted by fast Aδ fibres. SIGNIFICANCE: This is the first report of early, possibly primary, cortical responses in humans by nociceptive peripheral stimulation. Although not perfected yet to allow widespread diagnostic use, this is probably the only method to allow fully objective evaluation of the nociceptive system, with important future implications in experimental and clinical neurophysiology.


Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Nociceptividade/fisiologia , Estudo de Prova de Conceito , Couro Cabeludo/fisiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/fisiopatologia
7.
J Neurosci ; 41(37): 7712-7726, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34326146

RESUMO

Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in murine dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of translation in vitro and in vivo Inflammatory cues promote local translation of Arc in the skin. Arc-deficient male mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles (EVs), we hypothesized that intercellular Arc signaling regulates the inflammatory response in skin. We found that the excessive thermal responses and vasodilation observed in Arc defective mice are rescued by injection of Arc-containing EVs into the skin. Our findings suggest that activity-dependent production of Arc in afferent fibers regulates neurogenic inflammation potentially through intercellular signaling.SIGNIFICANCE STATEMENT Nociceptors play prominent roles in pain and inflammation. We examined rapid changes in the landscape of nascent translation in cultured dorsal root ganglia (DRGs) treated with a combination of inflammatory mediators using ribosome profiling. We identified several hundred transcripts subject to rapid preferential translation. Among them is the immediate early gene (IEG) Arc. We provide evidence that Arc is translated in afferent fibers in the skin. Arc-deficient mice display several signs of exaggerated inflammation which is normalized on injection of Arc containing extracellular vesicles (EVs). Our work suggests that noxious cues can trigger Arc production by nociceptors which in turn constrains neurogenic inflammation in the skin.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Gânglios Espinais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Vasodilatação/fisiologia , Animais , Proteínas do Citoesqueleto/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Nociceptividade/fisiologia , Nociceptores/fisiologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia
8.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069553

RESUMO

Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia-neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.


Assuntos
Dor Facial/metabolismo , Dor Facial/fisiopatologia , Neuroglia/fisiologia , Animais , Dor Facial/terapia , Neoplasias de Cabeça e Pescoço/fisiopatologia , Cefaleia/fisiopatologia , Humanos , Inflamação/fisiopatologia , Microglia/fisiologia , Neurônios/fisiologia , Nociceptividade/fisiologia , Gânglio Trigeminal/fisiologia
9.
Commun Biol ; 4(1): 732, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127787

RESUMO

The central amygdala (CE) emerges as a critical node for affective processing. However, how CE local circuitry interacts with brain wide affective states is yet uncharted. Using basic nociception as proxy, we find that gene expression suggests diverging roles of the two major CE neuronal populations, protein kinase C δ-expressing (PKCδ+) and somatostatin-expressing (SST+) cells. Optogenetic (o)fMRI demonstrates that PKCδ+/SST+ circuits engage specific separable functional subnetworks to modulate global brain dynamics by a differential bottom-up vs. top-down hierarchical mesoscale mechanism. This diverging modulation impacts on nocifensive behavior and may underly CE control of affective processing.


Assuntos
Afeto/fisiologia , Tonsila do Cerebelo/fisiologia , Rede Nervosa/fisiologia , Nociceptividade/fisiologia , Tonsila do Cerebelo/citologia , Animais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-delta/fisiologia , Somatostatina/metabolismo , Somatostatina/fisiologia
10.
Sci Rep ; 11(1): 12500, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127705

RESUMO

The bed nucleus of the stria terminalis (BNST) plays an emerging role in pain regulation. Pharmacological studies have found that inhibiting corticotropin-releasing factor (CRF) signaling in the BNST can selectively mitigate the sensory and affective-motivational components of pain. However, mechanistic insight on the source of CRF that drives BNST responses to these harmful experiences remains unknown. In the present study, we used a series of genetic approaches to show that CRF in the BNST is engaged in the processing and modulation of pain. We conducted cell-type specific in vivo calcium imaging in CRF-Cre mice and found robust and synchronized recruitment of BNSTCRF neurons during acute exposures to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF neurons differed for male and female mice. We then used a viral approach in Floxed-CRF mice to selectively reduce CRF expression in the BNST and found it decreased nociceptive sensitivity for both sexes and increased paw attending for females. Together, these findings reveal that CRF in the BNST influences multiple facets of the pain experience to impact the sex-specific expression of pain-related behaviors.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Neurônios/metabolismo , Nociceptividade/fisiologia , Dor/fisiopatologia , Núcleos Septais/fisiologia , Animais , Hormônio Liberador da Corticotropina/genética , Modelos Animais de Doenças , Feminino , Temperatura Alta/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Imagem Óptica , Dor/etiologia , Núcleos Septais/citologia , Núcleos Septais/diagnóstico por imagem , Fatores Sexuais
11.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946979

RESUMO

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.


Assuntos
Colina/fisiologia , Oftalmopatias/metabolismo , Acetilcolina/biossíntese , Acetilcolina/fisiologia , Animais , Deficiência de Colina/complicações , Deficiência de Colina/fisiopatologia , Retinopatia Diabética/fisiopatologia , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/fisiopatologia , Oftalmopatias/etiologia , Oftalmopatias/fisiopatologia , Dor Ocular/fisiopatologia , Glaucoma/fisiopatologia , Glicerilfosforilcolina/uso terapêutico , Humanos , Aparelho Lacrimal/inervação , Aparelho Lacrimal/metabolismo , Cristalino/metabolismo , Nociceptividade/fisiologia , Nervo Óptico/metabolismo , Sistema Nervoso Parassimpático/fisiopatologia , Fosfatidilcolinas/biossíntese , Fosfolipídeos/metabolismo , Receptores Nicotínicos/fisiologia , Retina/crescimento & desenvolvimento , Retina/metabolismo , Vasos Retinianos/metabolismo , Lágrimas/metabolismo
12.
Nat Commun ; 12(1): 2744, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980860

RESUMO

Understanding the neurophysiology underlying neonatal responses to noxious stimulation is central to improving early life pain management. In this neonatal multimodal MRI study, we use resting-state and diffusion MRI to investigate inter-individual variability in noxious-stimulus evoked brain activity. We observe that cerebral haemodynamic responses to experimental noxious stimulation can be predicted from separately acquired resting-state brain activity (n = 18). Applying this prediction model to independent Developing Human Connectome Project data (n = 215), we identify negative associations between predicted noxious-stimulus evoked responses and white matter mean diffusivity. These associations are subsequently confirmed in the original noxious stimulation paradigm dataset, validating the prediction model. Here, we observe that noxious-stimulus evoked brain activity in healthy neonates is coupled to resting-state activity and white matter microstructure, that neural features can be used to predict responses to noxious stimulation, and that the dHCP dataset could be utilised for future exploratory research of early life pain system neurophysiology.


Assuntos
Encéfalo/fisiologia , Nociceptividade/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Conectoma , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Rede Nervosa , Acoplamento Neurovascular , Dor/fisiopatologia , Descanso/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologia
13.
PLoS One ; 16(5): e0251356, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33956879

RESUMO

Elucidating the mechanisms underlying human pain sensation requires the establishment of an in vitro model of pain reception comprising human cells expressing pain-sensing receptors and function properly as neurons. Human dental pulp stem cells (hDPSCs) are mesenchymal stem cells and a promising candidate for producing human neuronal cells, however, the functional properties of differentiated hDPSCs have not yet been fully characterized. In this study, we demonstrated neuronal differentiation of hDPSCs via both their expression of neuronal marker proteins and their neuronal function examined using Ca2+ imaging. Moreover, to confirm the ability of nociception, Ca2+ responses in differentiated hDPSCs were compared to those of rat dorsal root ganglion (DRG) neurons. Those cells showed similar responses to glutamate, ATP and agonists of transient receptor potential (TRP) channels. Since TRP channels are implicated in nociception, differentiated hDPSCs provide a useful in vitro model of human peripheral neuron response to stimuli interpreted as pain.


Assuntos
Polpa Dentária/citologia , Células-Tronco Mesenquimais/fisiologia , Neurônios/citologia , Animais , Cálcio/metabolismo , Diferenciação Celular , Células Cultivadas , Polpa Dentária/crescimento & desenvolvimento , Polpa Dentária/fisiologia , Imunofluorescência , Hipocampo/citologia , Humanos , Microscopia Confocal , Neurônios/fisiologia , Nociceptividade/fisiologia , Ratos , Ratos Wistar
14.
J Bone Joint Surg Am ; 103(15): 1374-1382, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34014863

RESUMO

BACKGROUND: To our knowledge, it is still unknown if central sensitization (CS) influences the magnitude of the minimal clinically important difference (MCID) for patient-reported outcome measures after total knee arthroplasty (TKA). The purpose of this study was to determine the influence of CS on the MCID for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score in patients who underwent TKA for knee osteoarthritis. METHODS: A total of 422 patients who underwent unilateral TKA and completed a 2-year follow-up were enrolled in this study. CS was measured using the Central Sensitization Inventory (CSI). The WOMAC score was used to evaluate preoperative and postoperative patient-reported outcomes. The measurement of the MCID was performed separately for patients with and without CS using both the anchor-based method and the distribution method. The change difference method defined the MCID as the difference in preoperative-to-postoperative change between the minimal-improvement group and the no-change group. In addition, the MCID was calculated using receiver operating characteristic (ROC) curve analysis. The percentage of MCID achievement in each group was also compared. RESULTS: According to the change difference method, the MCID for the WOMAC total score was 23.4 points for patients with CS and 14.7 points for patients without CS. The MCID using the ROC cutoff value for the WOMAC total score was 29.5 points for the patients with CS and 26.5 points for the patients without CS. MCID achievement rates in WOMAC pain, function, and total scores were all found to be significantly higher in the patients without CS through the change difference method and the ROC method (all p < 0.05). CONCLUSIONS: The MCID for the WOMAC score of patients with CS after TKA was greater than that for patients without CS. Furthermore, by applying the calculated MCID to the group to which the patients belonged (with or without CS), we determined that patients with CS showed a lower MCID achievement rate than patients without CS. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Artralgia/cirurgia , Artroplastia do Joelho/estatística & dados numéricos , Sensibilização do Sistema Nervoso Central/fisiologia , Nociceptividade/fisiologia , Osteoartrite do Joelho/cirurgia , Idoso , Artralgia/diagnóstico , Artralgia/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Diferença Mínima Clinicamente Importante , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/diagnóstico , Medição da Dor/estatística & dados numéricos , Medidas de Resultados Relatados pelo Paciente , Curva ROC , Resultado do Tratamento
15.
Int J Biochem Cell Biol ; 135: 105981, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895353

RESUMO

The airways receive a dense supply of sensory nerve fibers that are responsive to damaging or potentially injurious stimuli. These airway nociceptors are mainly derived from the jugular and nodose vagal ganglia, and when activated they induce a range of reflexes and sensations that play an essential role in airway protection. Jugular nociceptors differ from nodose nociceptors in their embryonic origins, molecular profile and termination patterns in the airways and the brain, and recent discoveries suggest that excessive activity in jugular nociceptors may be central to the development of chronic cough. For these reasons, targeting jugular airway nociceptor signaling processes at different levels of the neuraxis may be a promising target for therapeutic development. In this focused review, we present the current understanding of jugular ganglia nociceptors, how they may contribute to chronic cough and mechanisms that could be targeted to bring about cough suppression.


Assuntos
Tosse/terapia , Gânglios/fisiologia , Veias Jugulares/fisiologia , Neurônios/fisiologia , Nociceptividade/fisiologia , Nociceptores/metabolismo , Mucosa Respiratória/fisiologia , Nervo Vago/fisiologia , Animais , Humanos
16.
J Neurosci ; 41(20): 4410-4427, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33888610

RESUMO

A number of cellular systems work in concert to modulate nociceptive processing in the periphery, but the mechanisms that regulate neonatal nociception may be distinct compared with adults. Our previous work indicated a relationship between neonatal hypersensitivity and growth hormone (GH) signaling. Here, we explored the peripheral mechanisms by which GH modulated neonatal nociception under normal and injury conditions (incision) in male and female mice. We found that GH receptor (GHr) signaling in primary afferents maintains a tonic inhibition of peripheral hypersensitivity. After injury, a macrophage dependent displacement of injury-site GH was found to modulate neuronal transcription at least in part via serum response factor (SRF) regulation. A single GH injection into the injured hindpaw muscle effectively restored available GH signaling to neurons and prevented acute pain-like behaviors, primary afferent sensitization, and neuronal gene expression changes. GH treatment also inhibited long-term somatosensory changes observed after repeated peripheral insult. Results may indicate a novel mechanism of neonatal nociception.SIGNIFICANCE STATEMENT Although it is noted that mechanisms of pain development in early life are unique compared with adults, little research focuses on neonatal-specific peripheral mechanisms of nociception. This gap is evident in the lack of specialized care for infants following an injury including surgeries. This report evaluates how distinct cellular systems in the periphery including the endocrine, immune and nervous systems work together to modulate neonatal-specific nociception. We uncovered a novel mechanism by which muscle injury induces a macrophage-dependent sequestration of peripheral growth hormone (GH) that effectively removes its normal tonic inhibition of neonatal nociceptors to promote acute pain-like behaviors. Results indicate a possible new strategy for treatment of neonatal postsurgical pain.


Assuntos
Hormônio do Crescimento/metabolismo , Macrófagos/metabolismo , Nociceptividade/fisiologia , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Nociceptores/metabolismo , Receptores da Somatotropina/metabolismo
17.
Mol Pain ; 17: 17448069211013633, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33906493

RESUMO

Mouse behavioral assays have proven useful for the study of thermosensation, helping to identify receptors and circuits responsible for the transduction of thermal stimuli and information relay to the brain. However, these methods typically rely on observation of behavioral responses to various temperature stimuli to infer sensory ability and are often unable to disambiguate innocuous thermosensation from thermal nociception or to study thermosensory circuitry which do not produce easily detectable innate behavioral responses. Here we demonstrate a new testing apparatus capable of delivering small, rapid temperature change stimuli to the mouse's skin, permitting the use of operant conditioning to train mice to recognize and report temperature change. Using this assay, mice that were trained to detect a large temperature change were found to generalize this learning to distinguish much smaller temperature changes across the entire range of innocuous temperatures tested. Mice with ablated TRPV1 and TRPM8 neuronal populations had reduced ability to discriminate temperature differences in the warm (>35°C) and cool (<30°C) ranges, respectively. Furthermore, mice that were trained to recognize temperature changes in only the cool, TRPM8-mediated temperature range did not generalize this learning in the warm, TRPV1-mediated range (and vice versa), suggesting that thermosensory information from the TRPM8- and TRPV1-neuronal populations are perceptually distinct.


Assuntos
Condicionamento Operante/fisiologia , Discriminação Psicológica/fisiologia , Nociceptividade/fisiologia , Sensação Térmica/fisiologia , Animais , Feminino , Masculino , Camundongos , Pele , Temperatura
18.
Neuron ; 109(8): 1274-1282.e6, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33667343

RESUMO

Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1+ spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1+ spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.


Assuntos
Hiperalgesia/metabolismo , Macrófagos/fisiologia , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Camundongos , Nociceptividade/fisiologia , Medição da Dor
19.
Neuron ; 109(9): 1513-1526.e11, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33770505

RESUMO

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.


Assuntos
Encéfalo/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Catalepsia/induzido quimicamente , Membrana Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
20.
Nat Commun ; 12(1): 1401, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658516

RESUMO

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPM/metabolismo , Fator 4 Ativador da Transcrição/genética , Animais , Membrana Celular/metabolismo , Quimiocina CXCL12/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Células HEK293 , Temperatura Alta , Humanos , Injeções Espinhais , Cinesina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Técnicas de Patch-Clamp , Transporte Proteico , Receptores CXCR4/metabolismo , Canais de Cátion TRPM/genética
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