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1.
PLoS One ; 15(9): e0239094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915912

RESUMO

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a µ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.


Assuntos
Analgésicos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Nociceptividade/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Substância Gelatinosa/efeitos dos fármacos , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Injeções Espinhais , Masculino , Modelos Animais , Naloxona/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/fisiologia , Técnicas de Patch-Clamp , Compostos de Fenilureia/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Substância Gelatinosa/citologia , Substância Gelatinosa/fisiologia
2.
Nat Commun ; 11(1): 3935, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769979

RESUMO

GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl- load. Under high Cl- load or heightened synaptic drive, lower Cl- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Cloretos/metabolismo , Plasticidade Neuronal/fisiologia , Nociceptividade/fisiologia , Células do Corno Posterior/fisiologia , Animais , Células Cultivadas , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Camundongos , Modelos Neurológicos , Optogenética , Cultura Primária de Células , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Simportadores/metabolismo
3.
Neuron ; 107(5): 909-923.e6, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649865

RESUMO

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.


Assuntos
Vias Aferentes , Lateralidade Funcional/fisiologia , Núcleos Intralaminares do Tálamo , Nociceptividade/fisiologia , Núcleos Parabraquiais , Vias Aferentes/citologia , Vias Aferentes/fisiologia , Tonsila do Cerebelo , Animais , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/fisiologia , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia
4.
PLoS One ; 15(6): e0233858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479547

RESUMO

PURPOSE: Low back pain (LBP) is a common ailment in most developed countries. Because most cases of LBP are known as 'non-specific', it has been challenging to develop experimental pain models of LBP which reproduce patients' clinical pain. In addition, previous models have limited applicability in a steady-pain-state neuroimaging environment. Thus, this study aims to devise a low back pain model with a simple methodology to induce experimental LBP, which has similar pain properties to patients' clinical pain, and to apply the model in a steady-pain-state neuroimaging study. METHODS: Our low back extension (LBE) pain model was tested on 217 LBP patients outside the magnetic resonance imaging (MRI) scanner to determine the reproducibility of endogenous pain and the similarity to their own clinical pain (STUDY1), and applied in a steady-pain-state functional MRI study (47 LBP patients and 23 healthy controls) to determine its applicability (induced head motions and brain functional connectivity changes; STUDY2). RESULTS: By the LBE pain model, 68.2% of the LBP patients reported increased LBP with high similarity of sensations to their own clinical pain (STUDY1), and the head motions were statistically similar to and correlated with those in resting state (STUDY2). Furthermore, the LBE model altered brain functional connectivity by decreasing the default-mode and the sensorimotor networks, and increasing the salience network, which was significantly associated with the intensity of the induced pain. Conversely, the healthy controls showed increased somatosensory network (but not of the cognitive pain processing). CONCLUSION: Our investigations suggest that our LBE pain model, which increased LBP with high similarity to the LBP patients' own pain sensation and induced patient-specific brain responses with acceptable head motion, could be applied to neuroimaging studies investigating brain responses to different levels of endogenous LBP.


Assuntos
Encéfalo/fisiopatologia , Dor Lombar/fisiopatologia , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Nociceptividade/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Feminino , Humanos , Dor Lombar/diagnóstico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medição da Dor , Reprodutibilidade dos Testes
5.
Neuron ; 107(3): 538-551.e7, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502461

RESUMO

Pain is a source of substantial discomfort. Abnormal activity in both the zona incerta (ZI) and posterior complex of the thalamus (Po) are implicated in neuropathic pain, but their exact roles remain unclear. In particular, the precise cell types and molecular mechanisms of the ZI-Po circuit that regulate nociception are largely uncharacterized. Here, we found that parvalbumin (PV)-positive neuronal projections from the ventral ZI (ZIv) to the Po (ZIv-Po) are critical for promoting nocifensive behaviors, whereas selectively inhibiting ZIv-Po activity reduces nocifensive withdrawal responses. Furthermore, cannabinoid type 1 receptors (CB1Rs) are expressed specifically at ZIv-Po axon terminals in this circuit, and cannabinoids attenuate nocifensive responses through presynaptic inhibition. Selective inhibition of the ZIv-Po circuit or administration of cannabinoids into the Po are sufficient to ameliorate pathological pain. These findings identify the critical role of the ZIv-Po circuit and its modulation by endocannabinoids in controlling nocifensive behaviors.


Assuntos
Neurônios/fisiologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Núcleos Posteriores do Tálamo/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Zona Incerta/fisiologia , Animais , Comportamento Animal , Endocanabinoides , Camundongos , Inibição Neural , Vias Neurais , Neurônios/metabolismo , Dor/metabolismo , Parvalbuminas , Núcleos Posteriores do Tálamo/citologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Zona Incerta/citologia
6.
Plast Reconstr Surg ; 146(3): 664-675, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32459730

RESUMO

BACKGROUND: Common peroneal neuropathy shares the same pathophysiology as carpal tunnel syndrome. However, management is often delayed because of the traditional misconception of recognizing foot drop as the defining symptom for diagnosis. The authors believe recognizing common peroneal neuropathy before foot drop can relieve pain and help improve quality of life. METHODS: One hundred eighty-five patients who underwent surgical common peroneal neuropathy decompression between 2011 and 2017 were included. The mean follow-up time was 249 ± 28 days. Patients were classified into two stages of severity based on clinical presentation: pre-foot drop and overt foot drop. Demographics, presenting symptoms, clinical signs, electrodiagnostic studies and response to surgery were compared between these two groups. Multivariate regression analysis was used to identify variables that predicted outcome following surgery. RESULTS: Overt foot drop patients presented with significantly lower preoperative motor function (percentage of patients with Medical Research Council grade ≤ 1: overt foot drop, 90 percent; pre-foot drop, 0 percent; p < 0.001). Pre-foot drop patients presented with a significantly higher preoperative pain visual analogue scale score (pre-foot drop, 6.2 ± 0.2; overt foot drop, 4.6 ± 0.3; p < 0.001) and normal electrodiagnostic studies (pre-foot drop, 31.4 percent; overt foot drop, 0.1 percent). Postoperatively, both groups of patients showed significant improvement in quality-of-life score (pre-foot drop, 2.6 ± 0.3; overt foot drop, 2.7 ± 0.3). Patients with obesity or a traumatic cause for common peroneal neuropathy were less likely to have improvements in quality of life after surgical decompression. CONCLUSION: Increased recognition of common peroneal neuropathy can aid early management, relieve pain, and improve quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.


Assuntos
Descompressão Cirúrgica/métodos , Nociceptividade/fisiologia , Neuropatias Fibulares/diagnóstico , Qualidade de Vida , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neuropatias Fibulares/fisiopatologia , Neuropatias Fibulares/cirurgia , Estudos Retrospectivos , Fatores de Tempo
7.
J Headache Pain ; 21(1): 30, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228453

RESUMO

BACKGROUND: Task-free imaging approaches using PET have shown the posterior hypothalamus to be specifically activated during but not outside cluster headache attacks. Evidence from task related functional imaging approaches however is scarce. METHODS: Twenty-one inactive cluster headache patients (episodic cluster headache out of bout), 16 active cluster headache patients (10 episodic cluster headache in bout, 6 chronic cluster headache) and 18 control participants underwent high resolution brainstem functional magnetic resonance imaging of trigeminal nociception using gaseous ammonia as a painful stimulus. RESULTS: Following trigeminonociceptive stimulation with ammonia there was a significantly stronger activation within the posterior hypothalamus in episodic cluster headache patients out of bout when compared to controls. When contrasting estimates of the pain contrast, active cluster headache patients where in between the two other groups but did not differ significantly from either. CONCLUSION: The posterior hypothalamus might thus be hyperexcitable in cluster headache patients outside the bout while excitability to external nociceptive stimuli decreases during in bout periods, probably due to frequent hypothalamic activation and possible neurotransmitter exhaustion during cluster attacks.


Assuntos
Cefaleia Histamínica/fisiopatologia , Hipotálamo/fisiopatologia , Adulto , Tronco Encefálico/fisiopatologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nociceptividade/fisiologia , Dor/fisiopatologia
8.
J Neurosci ; 40(17): 3478-3490, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32241836

RESUMO

Gamma-band oscillations (GBOs) elicited by transient nociceptive stimuli are one of the most promising biomarkers of pain across species. Still, whether these GBOs reflect stimulus encoding in the primary somatosensory cortex (S1) or nocifensive behavior in the primary motor cortex (M1) is debated. Here we recorded neural activity simultaneously from the brain surface as well as at different depths of the bilateral S1/M1 in freely-moving male rats receiving nociceptive stimulation. GBOs measured from superficial layers of S1 contralateral to the stimulated paw not only had the largest magnitude, but also showed the strongest temporal and phase coupling with epidural GBOs. Also, spiking of superficial S1 interneurons had the strongest phase coherence with epidural GBOs. These results provide the first direct demonstration that scalp GBOs, one of the most promising pain biomarkers, reflect neural activity strongly coupled with the fast spiking of interneurons in the superficial layers of the S1 contralateral to the stimulated side.SIGNIFICANCE STATEMENT Nociceptive-induced gamma-band oscillations (GBOs) measured at population level are one of the most promising biomarkers of pain perception. Our results provide the direct demonstration that these GBOs reflect neural activity coupled with the spike firing of interneurons in the superficial layers of the primary somatosensory cortex (S1) contralateral to the side of nociceptive stimulation. These results address the ongoing debate about whether nociceptive-induced GBOs recorded with scalp EEG or epidurally reflect stimulus encoding in the S1 or nocifensive behavior in the primary motor cortex (M1), and will therefore influence how experiments in pain neuroscience will be designed and interpreted.


Assuntos
Ritmo Gama/fisiologia , Córtex Motor/fisiopatologia , Nociceptividade/fisiologia , Dor/fisiopatologia , Córtex Somatossensorial/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Potenciais Somatossensoriais Evocados/fisiologia , Interneurônios/fisiologia , Masculino , Percepção da Dor/fisiologia , Ratos
9.
Neuron ; 106(6): 927-939.e5, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32289251

RESUMO

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.


Assuntos
Aprendizagem da Esquiva/fisiologia , Reação de Fuga/fisiologia , Nociceptividade/fisiologia , Núcleos Parabraquiais/fisiologia , Animais , Núcleo Central da Amígdala/fisiologia , Camundongos , Vias Neurais/fisiologia , Neurônios Eferentes/fisiologia , Optogenética , Dor , Substância Cinzenta Periaquedutal/fisiologia , Núcleos Septais/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia
10.
Neuron ; 106(6): 940-951.e4, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32298640

RESUMO

Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that express the chloroquine receptor MrgprA3. Using optogenetics, chemogenetics, and pharmacology, we assessed the behavioral effects of their selective stimulation in a wide variety of conditions. We show that metabotropic Gq-linked stimulation of these C-afferents, through activation of native MrgprA3 receptors or DREADDs, evokes stereotypical pruriceptive rather than nocifensive behaviors. In contrast, fast ionotropic stimulation of these same neurons through light-gated cation channels or native ATP-gated P2X3 channels predominantly evokes nocifensive rather than pruriceptive responses. We conclude that C-afferents display intrinsic multimodality, and we provide evidence that optogenetic and chemogenetic interventions on the same neuronal populations can drive distinct behavioral outputs.


Assuntos
Channelrhodopsins/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Neurônios Aferentes/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Prurido/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Trifosfato de Adenosina , Animais , Cloroquina , Gânglios Espinais/metabolismo , Peptídeo Liberador de Gastrina/metabolismo , Luz , Camundongos , Neurônios Aferentes/fisiologia , Optogenética , Receptores Opioides/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo
11.
Neuron ; 106(5): 830-841.e3, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32208171

RESUMO

Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3-/- triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.


Assuntos
Fibras Nervosas Amielínicas/fisiologia , Nociceptividade/fisiologia , Percepção/fisiologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPV/genética , Sensação Térmica/genética , Animais , Camundongos , Camundongos Knockout , Mutação , Limiar Sensorial , Sensação Térmica/fisiologia , Extremidade Superior
12.
Biochem Pharmacol ; 175: 113903, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156658

RESUMO

As recently described, the administration of extremely low doses (pg/kg) of CCL4 (Macrophage inflammatory protein 1ß, MIP-1ß) can induce antinociceptive effects in mice (García-Domínguez et al., 2019b). We describe here that hydrodynamic delivery of a plasmid containing CCL4 cDNA provokes a biphasic response consisting in an initial thermal hyperalgesic reaction for 8 days followed by analgesia at days 10-12, being both responses blocked after the administration of the CCR5 antagonist DAPTA. Both the luminiscence evoked in liver after the administration of a plasmid containing CCL4 and luciferase cDNAs and the hepatic concentration of CCL4 measured by ELISA were maximal 4 days after plasmid administration and markedly diminished at day 10. A dose-effect curve including a wide dose range of exogenous CCL4 revealed thermal analgesia after the administration of 10-100 pg/kg whereas 1000 times higher doses (30-100 ng/kg) induced, instead, thermal hyperalgesia inhibited by DAPTA. This hyperalgesia was absent in mice with reduced white blood cells after cyclophosphamide treatment, thus supporting the involvement of circulating leukocytes. A multiarray bioluminescent assay revealed increased plasma levels of IL-1α, CCL2, CXCL1, CXCL13, IL-16 and TIMP-1 in mice treated with 100 ng/kg of CCL4. The hyperalgesic response evoked by CCL4 was prevented by IL-1R, CXCR2 or CCR2 antagonists or by the neutralization of CXCL13 or IL-16, but not TIMP-1, with selective antibodies. The administration of the anti-IL-16 antibody was the unique treatment able to convert hyperalgesia evoked by 100 ng/kg of CCL4 in an analgesic effect. The ability of IL-16 to evoke hypernociception was confirmed by studying the response to its exogenous administration (10-30 ng/kg). In summary, the present results demonstrate that CCL4 induces a dual modulation of nociception and describe some mechanisms involved in the hyperalgesic response evoked by this chemokine.


Assuntos
Quimiocina CCL4/administração & dosagem , Técnicas de Transferência de Genes , Temperatura Alta/efeitos adversos , Hiperalgesia/tratamento farmacológico , Nociceptividade/fisiologia , Animais , Quimiocina CCL4/genética , Relação Dose-Resposta a Droga , Hiperalgesia/genética , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos
13.
Ann Neurol ; 87(4): 646-651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32031707

RESUMO

OBJECTIVE: Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. METHODS: Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. RESULTS: Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. INTERPRETATION: Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.


Assuntos
Hipotálamo/diagnóstico por imagem , Transtornos de Enxaqueca/diagnóstico por imagem , Sintomas Prodrômicos , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Neuroimagem Funcional , Humanos , Hipotálamo/fisiopatologia , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Transtornos de Enxaqueca/fisiopatologia , Nociceptividade/fisiologia , Estimulação Luminosa , Estimulação Física , Fatores de Tempo , Nervo Trigêmeo , Adulto Jovem
14.
Plast Reconstr Surg ; 145(3): 629e-636e, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32097334

RESUMO

Pain is an unpleasant experience resulting from either tissue damage or insults to the somatosensory system. Approaches to pain management evolve as we better understand both pain pathways and the tools available to interrupt these. The interest surrounding botulinum neurotoxin as a chemodenervating agent has expanded to include its potential applications in painful pathologies, both within and beyond the confines of plastic surgery. In this article, the authors discuss botulinum neurotoxin's mechanism of action as it pertains to both muscular paralysis and its interplay in the modulation of proinflammatory pain mediators. In addition, the authors review evidence supporting the use of botulinum neurotoxin in common painful conditions, in order to prepare the readership to aptly provide their patients with evidence-based recommendations. After reading this article, the participant should be able to discuss both mechanism of action and common applications of botulinum neurotoxin in painful conditions.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Neurotoxinas/farmacologia , Nociceptividade/efeitos dos fármacos , Manejo da Dor/métodos , Dor/fisiopatologia , Toxinas Botulínicas Tipo A/uso terapêutico , Medicina Baseada em Evidências/métodos , Humanos , Neurotoxinas/uso terapêutico , Nociceptividade/fisiologia
15.
Psychopharmacology (Berl) ; 237(5): 1435-1446, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32025776

RESUMO

RATIONALE: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. OBJECTIVES: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. METHODS: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. RESULTS: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). CONCLUSIONS: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.


Assuntos
Analgésicos/administração & dosagem , Dibenzazepinas/administração & dosagem , Dor/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Doenças do Nervo Trigêmeo/tratamento farmacológico , Acetaminofen/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Masculino , Metoclopramida/administração & dosagem , Camundongos , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor/psicologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos Sprague-Dawley , Estresse Psicológico/psicologia , Doenças do Nervo Trigêmeo/psicologia
16.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973098

RESUMO

Recently discovered mechanosensitive Piezo channels emerged as the main molecular detectors of mechanical forces. The functions of Piezo channels range from detection of touch and pain, to control of the plastic changes in different organs. Recent studies suggested the role of Piezo channels in migraine pain, which is supposed to originate from the trigeminovascular nociceptive system in meninges. Interestingly, migraine pain is associated with such phenomenon as mechanical hypersensitivity, suggesting enhanced mechanotransduction. In the current review, we present the data that propose the implication of Piezo channels in migraine pain, which has a distinctive pulsatile character. These data include: (i) distribution of Piezo channels in the key elements of the trigeminovascular nociceptive system; (ii) the prolonged functional activity of Piezo channels in meningeal afferents providing a mechanistical basis for mechanotransduction in nociceptive nerve terminals; (iii) potential activation of Piezo channels by shear stress and pulsating blood flow; and (iv) modulation of these channels by emerging chemical agonists and modulators, including pro-nociceptive compounds. Achievements in this quickly expanding field should open a new road for efficient control of Piezo-related diseases including migraine and chronic pain.


Assuntos
Canais Iônicos/metabolismo , Mecanotransdução Celular/fisiologia , Transtornos de Enxaqueca/metabolismo , Dor/metabolismo , Potenciais de Ação , Animais , Humanos , Meninges/metabolismo , Nociceptividade/fisiologia
17.
Biol Sex Differ ; 11(1): 2, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918752

RESUMO

Estrogen plays substantial roles in pain modulation; however, studies concerning sex hormones and nociception often yield confusing results. The discrepancy could be a result of lack of consensus to regard estrogen as a variable when working with animal models; thus, the influence of hormones' fluctuations on nociception has continually been neglected. In the present study, we designed a novel hormone substitution model to aid us to evaluate the effects of estrogen's long-term alterations on ovariectomy (OVX)-induced mechanical hyperalgesia and the expression of estrogen receptors(ERs). OVX rats were implanted with slow-release estrogen pellets at differently arranged time points and doses, such that a gradual elevation or decrease of serum estrogen levels following a relatively stable period of estrogen replacement was achieved in rats. Our results demonstrated that gradual estrogen depletion rather than elevation following the stable period of estrogen substitution in OVX rats alleviated OVX-induced mechanical hyperalgesia in a dose-independent manner, and the opposite estrogen increase or decrease paradigms differently regulate the expression of spinal ERs. Specifically, in rats rendered to continuously increased serum estrogen, the early phase estrogen-induced anti-nociception effect in OVX rats was eliminated, which was accompanied by an over-activation of ERα and a strong depression of ERß, while in the OVX rats subject to gradual decrease of estrogen replacement, both ERα and ERß increased modestly compared with the OVX group. Thus, the present study demonstrated that estrogen increase or decrease modulate nociception differently through change of spinal ERs.


Assuntos
Estradiol/administração & dosagem , Estrogênios/fisiologia , Hiperalgesia/fisiopatologia , Nociceptividade/fisiologia , Percepção da Dor/fisiologia , Animais , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Estrogênios/sangue , Feminino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/efeitos dos fármacos , Ovariectomia , Percepção da Dor/efeitos dos fármacos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
18.
J Neuroinflammation ; 17(1): 30, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969159

RESUMO

Arachidonic acid-derived prostaglandins not only contribute to the development of inflammation as intercellular pro-inflammatory mediators, but also promote the excitability of the peripheral somatosensory system, contributing to pain exacerbation. Peripheral tissues undergo many forms of diseases that are frequently accompanied by inflammation. The somatosensory nerves innervating the inflamed areas experience heightened excitability and generate and transmit pain signals. Extensive studies have been carried out to elucidate how prostaglandins play their roles for such signaling at the cellular and molecular levels. Here, we briefly summarize the roles of arachidonic acid-derived prostaglandins, focusing on four prostaglandins and one thromboxane, particularly in terms of their actions on afferent nociceptors. We discuss the biosynthesis of the prostaglandins, their specific action sites, the pathological alteration of the expression levels of related proteins, the neuronal outcomes of receptor stimulation, their correlation with behavioral nociception, and the pharmacological efficacy of their regulators. This overview will help to a better understanding of the pathological roles that prostaglandins play in the somatosensory system and to a finding of critical molecular contributors to normalizing pain.


Assuntos
Ácido Araquidônico/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Prostaglandinas/metabolismo , Animais , Humanos
19.
J Surg Res ; 249: 13-17, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31918325

RESUMO

BACKGROUND: Preoperative anxiety is a common psychological state in cancer patients before surgery, inducing stress responses after surgery. Associations between preoperative anxiety and intraoperative nociception, however, have not been evaluated well. In the present study, we investigated the relationship in patients with lung cancer undergoing thoracic surgery. MATERIALS AND METHODS: In this prospective study, 27 adult patients were enrolled. Intraoperative nociception during surgery was calculated as mean values of the nociceptive response (NR) throughout surgery. Associations between intraoperative nociception and preoperative patient characteristics including anxiety in addition to intraoperative variables were analyzed using univariate and multivariate regression analyses. RESULTS: Multiple linear regression analysis revealed that mean NR values during surgery showed a negative correlation with preoperative anxiety (ß = -0.353; P = 0.041) after adjustment for body mass index, depression, and total amount of fentanyl used during surgery. Body mass index was a confounder positively associated with mean NR during surgery. CONCLUSIONS: Intraoperative nociception is likely associated with preoperative patient characteristics, having an inverse relationship with preoperative anxiety.


Assuntos
Ansiedade/epidemiologia , Neoplasias Pulmonares/cirurgia , Nociceptividade/fisiologia , Dor Pós-Operatória/diagnóstico , Cirurgia Torácica Vídeoassistida/psicologia , Idoso , Ansiedade/fisiopatologia , Ansiedade/psicologia , Pressão Sanguínea/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/psicologia , Período Pré-Operatório , Estudos Prospectivos , Cirurgia Torácica Vídeoassistida/efeitos adversos
20.
Anesthesiology ; 132(2): 357-372, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31939851

RESUMO

BACKGROUND: Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development. METHODS: The authors used a male mouse model of bone cancer pain. The control mice were intrathecally injected with tumor necrosis factor-α (TNF-α) and lipopolysaccharide, the bone cancer pain mice were intrathecally injected with the endoplasmic reticulum stress inhibitors 4-PBA and GSK2606414. The nociceptive behaviors, endoplasmic reticulum stress markers, and inflammatory mediators were assessed. RESULTS: Increased expression of the p-RNA-dependent protein kinase-like endoplasmic reticulum kinase and p-eukaryotic initiation factor 2α were found in the spinal neurons during bone cancer pain, along with upregulation of inflammatory mediators (TNF-α, interleukin 1ß, and interleukin 6). Intrathecal administration of TNF-α or lipopolysaccharide increased the expression of endoplasmic reticulum stress markers in control mice. Inhibition of endoplasmic reticulum stress by intrathecal administration of 4-PBA (baseline vs. 3 h: 0.34 ± 0.16 g vs. 1.65 ± 0.40 g in paw withdrawal mechanical threshold, 8.00 ± 1.20 times per 2 min vs. 0.88 ± 0.64 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) or GSK2606414 (baseline vs. 3 h: 0.37 ± 0.08 g vs. 1.38 ± 0.11 g in paw withdrawal mechanical threshold, 8.00 ± 0.93 times per 2 min vs. 3.25 ± 1.04 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) showed time- and dose-dependent antinociception. Meanwhile, decreased expression of inflammatory mediators (TNF-α, interleukin 1ß, and interleukin 6), as well as decreased activation of astrocytes in the spinal cord, were found after 4-PBA or GSK2606414 treatment. CONCLUSIONS: Inhibition of inflammatory mediator-triggered endoplasmic reticulum stress in spinal neurons attenuates bone cancer pain via modulation of neuroinflammation, which suggests new approaches to pain relief.


Assuntos
Neoplasias Ósseas/metabolismo , Dor do Câncer/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Mediadores da Inflamação/metabolismo , Nociceptividade/fisiologia , Animais , Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Gravidez
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