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1.
Molecules ; 26(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800730

RESUMO

Rosacea is a skin inflammatory condition that is accompanied by not only redness and flushing but also unseen symptoms, such as burning, stinging, and itching. TRPV1 expression in UVB-exposed skin can lead to a painful burning sensation. Upregulated TRPV1 expression helps release neuropeptides, including calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide, which can activate macrophage and inflammatory molecules. In this study, we found that radiofrequency (RF) irradiation reduced TRPV1 activation and neuropeptide expression in a UVB-exposed in vivo model and UVB- or heat-treated in an in vitro model. RF irradiation attenuated neuropeptide-induced macrophage activation and inflammatory molecule expression. Interestingly, the burning sensation in the skin of UVB-exposed mice and patients with rosacea was significantly decreased by RF irradiation. These results can provide experimental and molecular evidence on the effective use of RF irradiation for the burning sensation in patients with rosacea.


Assuntos
Hipertermia Induzida/métodos , Inflamação/prevenção & controle , Dor/prevenção & controle , Rosácea/complicações , Pele/patologia , Canais de Cátion TRPV/metabolismo , Terapia Ultravioleta/métodos , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Neuropeptídeos/toxicidade , Dor/etiologia , Dor/metabolismo , Dor/patologia , Pele/metabolismo , Pele/efeitos da radiação , Canais de Cátion TRPV/genética
2.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806698

RESUMO

Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.


Assuntos
Formaldeído/farmacologia , Inflamação/metabolismo , Dor/induzido quimicamente , Dor/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Medição da Dor/métodos , Ratos , Medula Espinal/metabolismo , Regulação para Cima/fisiologia
3.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669046

RESUMO

The phosphorylation of serine 10 in histone 3 (p-S10H3) has recently been demonstrated to participate in spinal nociceptive processing. However, superficial dorsal horn (SDH) neurons involved in p-S10H3-mediated nociception have not been fully characterized. In the present work, we combined immunohistochemistry, in situ hybridization with the retrograde labeling of projection neurons to reveal the subset of dorsal horn neurons presenting an elevated level of p-S10H3 in response to noxious heat (60 °C), causing burn injury. Projection neurons only represented a small percentage (5%) of p-S10H3-positive cells, while the greater part of them belonged to excitatory SDH interneurons. The combined immunolabeling of p-S10H3 with markers of already established interneuronal classes of the SDH revealed that the largest subset of neurons with burn injury-induced p-S10H3 expression was dynorphin immunopositive in mice. Furthermore, the majority of p-S10H3-expressing dynorphinergic neurons proved to be excitatory, as they lacked Pax-2 and showed Lmx1b-immunopositivity. Thus, we showed that neurochemically heterogeneous SDH neurons exhibit the upregulation of p-S10H3 shortly after noxious heat-induced burn injury and consequential tissue damage, and that a dedicated subset of excitatory dynorphinergic neurons is likely a key player in the development of central sensitization via the p-S10H3 mediated pathway.


Assuntos
Queimaduras/metabolismo , Histonas/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Células do Corno Posterior/metabolismo , Serina/metabolismo , Medula Espinal/metabolismo , Animais , Epigênese Genética , Feminino , Imuno-Histoquímica , Hibridização In Situ , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX2/metabolismo , Fosforilação , Ratos , Ratos Wistar , Medula Espinal/citologia , Medula Espinal/fisiologia , Fatores de Transcrição/metabolismo
4.
AAPS PharmSciTech ; 22(3): 104, 2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33718986

RESUMO

Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.


Assuntos
Analgesia/métodos , Levobupivacaína/administração & dosagem , Levobupivacaína/farmacocinética , Dor/tratamento farmacológico , Dor/metabolismo , Animais , Bovinos , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/metabolismo , Géis , Humanos , Lipossomos , Masculino , Camundongos , Células NIH 3T3 , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia
5.
Psychopharmacology (Berl) ; 238(3): 725-734, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33410983

RESUMO

RATIONALE: Mu opioid receptor agonists are indispensable for the treatment of pain, but clinical use carries the inherent risk of transition from effective treatment to abuse. Abuse potential appears to increase rapidly during periods of initial opioid exposure in humans, and this increase in opioid reward during initial opioid exposure can be modeled in rats using an intracranial self-stimulation (ICSS) procedure. OBJECTIVES: The goal of the present study was to examine temporal parameters of this phenomenon. METHODS: Adult male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure. In the first experiment, rats received daily morphine injections for 6 days, and morphine effects on ICSS were re-determined 1 day, 1 week, or 1 month after the repeated morphine treatment regimen to evaluate the persistence of enhanced opioid reward. In the second experiment, rats received six repeated morphine injections with different interdose intervals (two per day, one per day, every other day, every fourth day), and morphine effects were re-determined 1 day after the last dose to determine dosing frequencies sufficient to produce enhanced opioid reward. RESULTS: Results of the first experiment indicated that enhanced opioid reward was greatest 1 day after the morphine treatment regimen and completely dissipated after 4 weeks. The second experiment indicated that all dosing frequencies tested were sufficient to produce enhanced reward. CONCLUSIONS: Taken together, these results suggest that enhancement of opioid reward after initial opioid exposure is relatively transient but can be produced by a range of different dosing frequencies.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Receptores Opioides mu/agonistas , Recompensa , Autoestimulação/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estimulação Elétrica , Masculino , Morfina/administração & dosagem , Dor/tratamento farmacológico , Dor/metabolismo , Dor/psicologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
6.
Neurosci Lett ; 744: 135544, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33421487

RESUMO

Owing to their functional diversity, the Mas-related G-protein-coupled receptor (Mrgpr) family has a role in both itch and pain modulation. While primarily linked to pruritis, Mrgprs were originally characterized in small-diameter nociceptive neurons of dorsal root ganglia (DRG) and trigeminal ganglia. This review will focus on the role Mrgpr's have in pain physiology, discussing recent discoveries as well as how Mrgpr's may provide a new target for the treatment of pathological pain.


Assuntos
Nociceptores/metabolismo , Dor/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Mastócitos/metabolismo , Nociceptores/patologia , Dor/diagnóstico , Manejo da Dor/métodos , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia
7.
Nature ; 591(7849): 275-280, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33442058

RESUMO

The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.


Assuntos
Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Células Receptoras Sensoriais/metabolismo , Analgesia , Animais , Feminino , Humanos , Interferon Tipo I/deficiência , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Macaca mulatta , Masculino , Proteínas de Membrana/agonistas , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Nociceptividade/efeitos dos fármacos , Transdução de Sinais
8.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401784

RESUMO

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.


Assuntos
Neurônios GABAérgicos/metabolismo , Neurônios Aferentes/metabolismo , Dor/metabolismo , Receptores de GABA/metabolismo , Corno Dorsal da Medula Espinal/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/metabolismo , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/fisiologia , Dor/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos
9.
PLoS One ; 15(12): e0243566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33351799

RESUMO

Children with severe motor and intellectual disabilities experience chronic pain but cannot communicate verbally. However, no Japanese tool currently exists for assessing pain in this population. This study aimed to develop and evaluate the reliability and validity of a Japanese version of the Paediatric Pain Profile, which is a behavioral rating scale to assess pain in children with severe neurological disabilities. The sample comprised 30 children with severe motor and intellectual disabilities at three hospitals in Japan. Three specialist nurses rated low and high pain video scenes of the children (twice at 1-week intervals) using the Face, Legs, Activity, Cry, Consolability behavioral scale and a translated Japanese version of the Paediatric Pain Profile. On the basis of their ratings, we calculated the internal consistency, test-retest reliability, and intra- and inter-observer reliabilities of the Paediatric Pain Profile. Additionally, we assessed concurrent validity using the Face, Legs, Activity, Cry, Consolability behavioral scale and construct validity using low versus high pain scenes. Both internal consistency (low pain: alpha = 0.735; high pain: alpha = 0.928) and test-retest reliability (r = 0.846) of the Japanese version of the Paediatric Pain Profile were good. Intra-observer reliability was substantial (r = 0.748), whereas inter-observer reliability was only moderate (r = 0.529). However, the concurrent validity with Face, Legs, Activity, Cry, Consolability scores was good (r = 0.629) and construct validity was confirmed (p < 0.001). We confirmed the validity of the Japanese version of the Paediatric Pain Profile, but reliable pain assessment may require repeated ratings by the same person. To accurately assess pain in children with severe motor and intellectual disabilities, healthcare staff must be properly trained and become more skilled in using the Japanese version of the Paediatric Pain Profile.


Assuntos
Escala de Avaliação Comportamental/normas , Medição da Dor/métodos , Psicometria/métodos , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual , Japão , Masculino , Transtornos Motores , Variações Dependentes do Observador , Dor/metabolismo , Reprodutibilidade dos Testes , Inquéritos e Questionários , Tradução
10.
Mol Pharmacol ; 98(4): 433-444, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958571

RESUMO

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.


Assuntos
Analgésicos Opioides/farmacologia , Transtornos de Enxaqueca/metabolismo , Transtornos Relacionados ao Uso de Opioides/microbiologia , Dor/metabolismo , Receptores Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Motivação , Transtornos Relacionados ao Uso de Opioides/metabolismo , Dor/tratamento farmacológico , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 117(26): 15281-15292, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32546520

RESUMO

Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/o and ß-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.


Assuntos
Leucina Encefalina-2-Alanina/farmacologia , Inflamação/complicações , Dor/tratamento farmacológico , Dor/metabolismo , Receptores Opioides delta/agonistas , Animais , Colo/inervação , Leucina Encefalina-2-Alanina/administração & dosagem , Células HEK293 , Humanos , Camundongos , Nanopartículas/administração & dosagem , Neurônios , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
12.
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
13.
Psychopharmacology (Berl) ; 237(7): 2201-2212, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32382785

RESUMO

RATIONALE: Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks. OBJECTIVES: The present study compared antinociceptive effects produced by repeated treatment with monoamine transporter inhibitors in a preclinical assay of pain-related depression of positively reinforced operant responding. METHODS: Adult Sprague-Dawley rats equipped with microelectrodes targeting a brain-reward area responded for pulses of electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus that repeatedly depressed ICSS and also produced weight loss during 7 days of repeated acid administration. RESULTS: Acid-induced depression of both ICSS and body weight were completely blocked by repeated pretreatment with the nonsteroidal anti-inflammatory drug ketorolac. The DAT-selective inhibitor bupropion also fully blocked acid-induced ICSS depression and weight loss throughout all 7 days of treatment. The NET-selective inhibitor nortriptyline and the SERT-selective inhibitor citalopram were generally less effective, but both drugs blocked acid-induced ICSS depression by the end of the 7-day treatment. Acid-induced depression of ICSS and body weight were not blocked by the kappa opioid receptor (KOR) agonist U69593 or the KOR antagonist norbinaltorphimine. CONCLUSIONS: These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce significant but less reliable effects.


Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Depressão/tratamento farmacológico , Inibidores da Captação de Dopamina/administração & dosagem , Dor/tratamento farmacológico , Autoestimulação/efeitos dos fármacos , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Animais , Depressão/metabolismo , Estimulação Elétrica/métodos , Eletrodos Implantados , Feminino , Masculino , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Autoestimulação/fisiologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
15.
J Neurosci ; 40(18): 3517-3532, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245829

RESUMO

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.


Assuntos
Viroses do Sistema Nervoso Central/metabolismo , Interferon Tipo I/toxicidade , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Células Cultivadas , Viroses do Sistema Nervoso Central/induzido quimicamente , Viroses do Sistema Nervoso Central/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
16.
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
17.
Psychopharmacology (Berl) ; 237(6): 1681-1689, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125484

RESUMO

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.


Assuntos
Analgésicos Opioides/administração & dosagem , Compostos Aza/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores da Captação de Dopamina/uso terapêutico , Norepinefrina/antagonistas & inibidores , Remifentanil/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Animais , Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Nicotina/administração & dosagem , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Estereoisomerismo
18.
Pain Res Manag ; 2020: 4807674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190166

RESUMO

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund's adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Adjuvante de Freund/farmacologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Neurônios/metabolismo , Dor/etiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Medula Espinal/metabolismo
19.
J Pharmacol Exp Ther ; 373(3): 438-444, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32169839

RESUMO

Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the µ-opioid receptors in the enteric nervous system. Peripherally acting µ-opioid receptor antagonists (PAMORAs) can reverse OIC by inhibiting the peripheral action of opioids without affecting centrally mediated analgesia. Naldemedine is a PAMORA with potent antagonist activity against µ-, δ-, and κ-opioid receptors. In this study, the pharmacological profiles of naldemedine, compared with those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a noncompetitive antagonist of µ-opioid receptors, whereas other compounds were competitive antagonists. Also, naldemedine showed slower association and dissociation kinetics than the other compounds. In vivo, naldemedine dose-dependently ameliorated morphine-induced inhibition of small intestinal transit (SIT). The dose-response curve was not shifted at 1 and 3 mg/kg morphine. On the contrary, that of naloxegol was significantly shifted to the right from 1 to 3 mg/kg morphine. In morphine-dependent rats, naldemedine caused peripheral withdrawal symptoms (diarrhea) at doses higher than 1 mg/kg, whereas the dose that produced half the maximal preventive effect (ED50) against constipation was 0.03 mg/kg. Naldemedine showed slower onset and a lesser severity of diarrhea than the other compounds at close to the ED50 value in the SIT model. Our results reveal that naldemedine has different pharmacological profiles (type of antagonism and binding kinetics) to the other compounds. This might explain the differential inhibition of morphine-induced SIT and withdrawal symptoms among the three antagonist compounds. SIGNIFICANCE STATEMENT: Naldemedine is a novel peripherally acting µ-opioid receptor antagonist with potent antagonist activity against µ-, δ-, and κ-opioid receptors. Naldemedine showed a noncompetitive antagonism and slower association and dissociation kinetics against µ-opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced inhibition and lower and slower peripheral withdrawal symptoms (diarrhea) than the other compounds. Therefore, naldemedine has a different pharmacological profile (the type of antagonism and binding kinetics) to the other compounds.


Assuntos
Analgésicos Opioides/farmacologia , Morfinanos/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Polietilenoglicóis/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Animais , Constipação Intestinal/induzido quimicamente , Masculino , Morfina/farmacologia , Naltrexona/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Manejo da Dor/métodos , Ratos , Ratos Wistar , Receptores Opioides kappa/metabolismo
20.
Nat Commun ; 11(1): 1397, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170060

RESUMO

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.


Assuntos
Peptídeo Liberador de Gastrina/genética , Peptídeo Liberador de Gastrina/metabolismo , Dor/metabolismo , Prurido/metabolismo , Células Receptoras Sensoriais/metabolismo , Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Histamina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurotransmissores , Dor/patologia , Prurido/patologia , Células Receptoras Sensoriais/patologia , Pele/metabolismo , Pele/patologia , Transcriptoma
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