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1.
J Clin Invest ; 134(9)2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38690737

RESUMO

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.


Assuntos
Proteínas de Membrana , Nociceptores , Animais , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nociceptores/metabolismo , Gânglios Espinais/metabolismo , Interferon beta/genética , Interferon beta/metabolismo , Inflamação/genética , Inflamação/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Dor/metabolismo , Dor/genética , Transdução de Sinais , Masculino
3.
J Exp Med ; 220(10)2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37462672

RESUMO

Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue-type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify seven MC subsets (MC1-7) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the bladder, MC2 in the lungs, and MC4, MC6, and MC7 in the skin. Conversely, MC3 and MC5 are shared by most organs but not skin. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.


Assuntos
Mastócitos , Mucosa , Humanos , Camundongos , Animais , Transcriptoma/genética
4.
Sci Adv ; 9(23): eadf9491, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37285432

RESUMO

Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. We introduce MANTIS (Multiplex Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically designed for spatially resolved immune phenotyping of the skin in experimental or clinical samples. On the basis of phenotype attribution matrices coupled to α-shape algorithms, MANTIS projects a representative digital immune landscape while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome, or COVID-19-associated skin manifestations share common quantitative immune features while displaying a nonrandom distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.


Assuntos
COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , COVID-19/patologia , Pele
5.
J Clin Invest ; 132(12)2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35608912

RESUMO

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Citocinas/metabolismo , Neoplasias Pulmonares , Animais , Humanos , Hiperalgesia/metabolismo , Inflamação/patologia , Ligantes , Camundongos , Dor/tratamento farmacológico , Receptores Proteína Tirosina Quinases , Células Receptoras Sensoriais/metabolismo , Corno Dorsal da Medula Espinal/patologia
6.
Curr Opin Immunol ; 77: 102213, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35605523

RESUMO

The peripheral nervous system and the immune system are virtually distributed in all organs in mouse and human. They act in concert to constitute an exceptional sensory system capable of sensing threatening stimuli, including allergens, and triggering appropriate biological responses. Recent advances in the field have revealed that tissue-resident mast cells and nearby sensory neurons could form functional neuroimmune clusters driven by bidirectional interactions and predisposed to significantly influence major allergic conditions. In this review, we highlight recent discoveries that paved the way toward a better understanding of how mast cells and sensory neurons can communicate to regulate basic features of allergic disorders in different organs.


Assuntos
Hipersensibilidade , Mastócitos , Alérgenos , Animais , Humanos , Sistema Imunitário , Camundongos , Neurônios
7.
J Neuroinflammation ; 19(1): 7, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991641

RESUMO

BACKGROUND: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. METHODS: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. CONCLUSION: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.


Assuntos
Colite/metabolismo , Mucosa Intestinal/metabolismo , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Dor Visceral/metabolismo , Analgesia , Animais , Colite/genética , Modelos Animais de Doenças , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Receptores Opioides delta/genética , Dor Visceral/genética
8.
Neurosci Lett ; 749: 135724, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600909

RESUMO

Interplay between physiological systems in the body plays a prominent role in health and disease. At the cellular level, such interplay is orchestrated through the binding of specific ligands to their receptors expressed on cell surface. G protein-coupled receptors (GPCR) are seven-transmembrane domain receptors that initiate various cellular responses and regulate homeostasis. In this review, we focus on particular GPCRs named Mas-related G protein-coupled receptors (Mrgprs) mainly expressed by sensory neurons and specialized immune cells. We describe the different subfamilies of Mrgprs and their specific ligands, as well as recent advances in the field that illustrate the role played by these receptors in neuro-immune biological processes, including itch, pain and inflammation in diverse organs.


Assuntos
Neuroimunomodulação/fisiologia , Dor/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Proteínas de Ligação ao GTP/metabolismo , Gânglios Espinais/metabolismo , Humanos
9.
Front Pain Res (Lausanne) ; 2: 642706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35295433

RESUMO

Current analgesic treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) are limited. Here, we propose a novel antinociceptive strategy exploiting the opioid-mediated analgesic properties of T lymphocytes to relieve from bladder pain. In a chronic model of IC/BPS in rats, we show that a secondary T cell response against intravesically administered ovalbumin prevents from visceral pain in OVA-primed animals. The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist. Similarly, intravesical instillation of BCG or tetanus toxoid antigens in vaccinated rats protects from pain in the same model. We show opioid-dependent analgesic properties of local vaccine antigen recall in a preclinical rat model of chronic cystitis. Since BCG bladder instillation is regularly used in humans (as anticancer therapy), our results open it as a new therapeutic positioning for a pain management indication for IC/BPS patients.

10.
Front Pain Res (Lausanne) ; 2: 613187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35295482

RESUMO

Background: Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain. Methods: EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists. Results: A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors. Conclusions: This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis.

11.
Mol Brain ; 13(1): 61, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32290846

RESUMO

Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCß), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCß-mediated reduction of TRPM8 desensitization. This MOR-PKCß dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCß as important targets for opioid-induced cold hypersensitivity.


Assuntos
Morfina/farmacologia , Proteína Quinase C beta/metabolismo , Receptores Opioides mu/metabolismo , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Animais , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Hiperalgesia/patologia , Masculino , Mentol , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Cell Mol Gastroenterol Hepatol ; 10(2): 225-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32289500

RESUMO

BACKGROUND & AIMS: Despite achieving endoscopic remission, more than 20% of inflammatory bowel disease patients experience chronic abdominal pain. These patients have increased rectal transient receptor potential vanilloid-1 receptor (TRPV1) expression, a key transducer of inflammatory pain. Because inflammatory bowel disease patients in remission exhibit dysbiosis and microbial manipulation alters TRPV1 function, our goal was to examine whether microbial perturbation modulated transient receptor potential function in a mouse model. METHODS: Mice were given dextran sodium sulfate (DSS) to induce colitis and were allowed to recover. The microbiome was perturbed by using antibiotics as well as fecal microbial transplant (FMT). Visceral and somatic sensitivity were assessed by recording visceromotor responses to colorectal distention and using hot plate/automated Von Frey tests, respectively. Calcium imaging of isolated dorsal root ganglia neurons was used as an in vitro correlate of nociception. The microbiome composition was evaluated via 16S rRNA gene variable region V4 amplicon sequencing, whereas fecal short-chain fatty acids (SCFAs) were assessed by using targeted mass spectrometry. RESULTS: Postinflammatory DSS mice developed visceral and somatic hyperalgesia. Antibiotic administration during DSS recovery induced visceral, but not somatic, hyperalgesia independent of inflammation. FMT of postinflammatory DSS stool into antibiotic-treated mice increased visceral hypersensitivity, whereas FMT of control stool reversed antibiotics' sensitizing effects. Postinflammatory mice exhibited both increased SCFA-producing species and fecal acetate/butyrate content compared with controls. Capsaicin-evoked calcium responses were increased in naive dorsal root ganglion neurons incubated with both sodium butyrate/propionate alone and with colonic supernatants derived from postinflammatory mice. CONCLUSIONS: The microbiome plays a central role in postinflammatory visceral hypersensitivity. Microbial-derived SCFAs can sensitize nociceptive neurons and may contribute to the pathogenesis of postinflammatory visceral pain.


Assuntos
Colite Ulcerativa/complicações , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Dor Visceral/imunologia , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/microbiologia , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Fezes/microbiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Nociceptividade , Nociceptores/imunologia , Nociceptores/metabolismo , Canais de Cátion TRPV/metabolismo , Dor Visceral/microbiologia
13.
Trends Neurosci ; 43(3): 130-132, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014258

RESUMO

Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch.


Assuntos
Mastócitos , Nociceptores , Homeostase , Humanos , Dor , Pele
14.
Neurogastroenterol Motil ; 32(2): e13743, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31588671

RESUMO

BACKGROUND: The opioid-mediated analgesic activity of mucosal CD4+ T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4+ T lymphocytes alleviate from inflammation-induced abdominal pain in mice with defective immune regulation. METHODS: Endogenous control of visceral pain by opioids locally produced in inflamed mucosa was assessed in IL-10-deficient mice. KEY RESULTS: CD4+ T lymphocytes but not F4/80+ macrophages isolated from the lamina propria of IL-10-deficient mice with colitis express enkephalin-containing opioid peptides as assessed by cytofluorometry. Colitis in IL-10-/- mice was not associated with abdominal pain. Intraperitoneal injection of naloxone-methiodide, a peripheral opioid receptor antagonist, induced abdominal hypersensitivity in IL-10-/- mice with colitis. CONCLUSION AND INFERENCES: Opioid-mediated analgesic activity of mucosal T lymphocytes remains operating in IL-10-/- mice with impaired immune regulation. The data suggest that endogenous T cell-derived opioids might reduce inflammation-induced abdominal pain in inflammatory bowel diseases associated with homozygous "loss of function mutations" in interleukin-10.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-10/deficiência , Mucosa Intestinal/imunologia , Peptídeos Opioides/imunologia , Dor Visceral/imunologia , Animais , Colite/complicações , Colite/imunologia , Inflamação/complicações , Inflamação/imunologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor Visceral/etiologia
15.
Nat Immunol ; 20(11): 1435-1443, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591569

RESUMO

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.


Assuntos
Alérgenos/imunologia , Dermatite Atópica/imunologia , Mastócitos/imunologia , Nociceptores/imunologia , Pyroglyphidae/imunologia , Animais , Comunicação Celular/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Mastócitos/metabolismo , Camundongos Knockout , Nociceptores/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Pele/citologia , Pele/imunologia , Canais de Cátion TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
16.
Eur J Immunol ; 49(11): 1984-1997, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31327163

RESUMO

The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response such as withdrawal to avoid tissue injury or scratching to remove irritating molecules. More recently, breakthrough articles have shown that, on top of their primary function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) could directly sense environmental alarms and consequently regulate the development of various type of immune responses through the release of neuropeptides or growth factors. In this review, we discuss recent advances in the neural regulation of the immune response, both in physiological and pathological contexts by taking into account the type of organs (lungs, skin and gut), subtypes of peripheral neurons (sympathetic, nociceptive and intrinsic gut neurons) or immune cells and strains of pathogens studied. We also highlight future challenges in the field and potential therapeutic innovations targeting neuro-immune interactions.


Assuntos
Trato Gastrointestinal/imunologia , Imunidade nas Mucosas , Sistema Nervoso Periférico/imunologia , Células Receptoras Sensoriais/imunologia , Pele/imunologia , Transmissão Sináptica/imunologia , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Encéfalo/imunologia , Encéfalo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Trato Gastrointestinal/metabolismo , Humanos , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Neuropeptídeos/imunologia , Neuropeptídeos/metabolismo , Nociceptividade/fisiologia , Sistema Nervoso Periférico/metabolismo , Células Receptoras Sensoriais/metabolismo , Pele/metabolismo , Medula Espinal/imunologia , Medula Espinal/metabolismo
17.
iScience ; 16: 12-21, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31146128

RESUMO

Many patients with visceral inflammation develop pain and psychiatric comorbidities such as major depressive disorder, worsening the quality of life and increasing the risk of suicide. Here we show that neuroimmune activation in mice with dextran sodium sulfate-induced colitis is accompanied by the development of pain and depressive behaviors. Importantly, treatment with the flavonoid luteolin prevented both neuroimmune responses and behavioral abnormalities, suggesting a new potential therapeutic approach for patients with inflammatory bowel diseases.

18.
Sci Signal ; 12(575)2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940767

RESUMO

Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein ß-arrestin2 to the nucleus. The nuclear translocation of ß-arrestin2 in turn prevented its recruitment to the µ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund's adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of ß-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1-ß-arrestin2 axis may thus contribute to the transition from acute to chronic pain.


Assuntos
Dor Aguda/metabolismo , Analgésicos Opioides/farmacologia , Dor Crônica/metabolismo , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Dor Aguda/induzido quimicamente , Dor Aguda/tratamento farmacológico , Dor Aguda/genética , Analgesia , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Modelos Animais de Doenças , Adjuvante de Freund/efeitos adversos , Adjuvante de Freund/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Naloxona/farmacologia , Compostos de Amônio Quaternário/farmacologia , Transdução de Sinais/genética , Canais de Cátion TRPV/genética , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
19.
Brain Behav Immun ; 80: 179-192, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30872090

RESUMO

The accumulation of adverse events in utero and during childhood differentially increases the vulnerability to psychiatric diseases in men and women. Gut microbiota is highly sensitive to the early environment and has been recently hypothesized to affect brain development. However, the impact of early-life adversity on gut microbiota, notably with regards to sex differences, remains to be explored. We examined the effects of multifactorial early-life adversity on behavior and microbiota composition in C3H/HeN mice of both sexes exposed to a combination of maternal immune activation (lipopolysaccharide injection on embryonic day 17, 120 µg/kg, i.p.), maternal separation (3hr per day from postnatal day (PND)2 to PND14) and maternal unpredictable chronic mild stress. At adulthood, offspring exposed to multi-hit early adversity showed sex-specific behavioral phenotypes with males exhibiting deficits in social behavior and females showing increased anxiety in the elevated plus maze and increased compulsive behavior in the marble burying test. Early adversity also differentially regulated gene expression in the medial prefrontal cortex (mPFC) according to sex. Interestingly, several genes such as Arc, Btg2, Fosb, Egr4 or Klf2 were oppositely regulated by early adversity in males versus females. Finally, 16S-based microbiota profiling revealed sex-dependent gut dysbiosis. In males, abundance of taxa belonging to Lachnospiraceae and Porphyromonadaceae families or other unclassified Firmicutes, but also Bacteroides, Lactobacillus and Alloprevotella genera was regulated by early adversity. In females, the effects of early adversity were limited and mainly restricted to Lactobacillus and Mucispirillum genera. Our work reveals marked sex differences in a multifactorial model of early-life adversity, both on emotional behaviors and gut microbiota, suggesting that sex should systematically be considered in preclinical studies both in neurogastroenterology and psychiatric research.


Assuntos
Microbioma Gastrointestinal/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/microbiologia , Animais , Animais Recém-Nascidos , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Disbiose/metabolismo , Feminino , Masculino , Privação Materna , Camundongos , Camundongos Endogâmicos C3H , Microbiota , Córtex Pré-Frontal/metabolismo , Fatores Sexuais , Comportamento Social
20.
Sci Rep ; 9(1): 3710, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842618

RESUMO

Immune activation may underlie the pathogenesis of irritable bowel syndrome (IBS), but the evidence is conflicting. We examined whether peripheral CD4+ T-cells from IBS patients demonstrated immune activation and changes in cytokine production. To gain mechanistic insight, we examined whether immune activation correlated with psychological stress and changing symptoms over time. IBS patients (n = 29) and healthy volunteers (HV; n = 29) completed symptom and psychological questionnaires. IBS patients had a significant increase in CD4+ T-cells expressing the gut homing marker integrin ß7 (p = 0.023) and lymphoid marker CD62L (p = 0.026) compared to HV. Furthermore, phytohaemagglutinin stimulated CD4+ T-cells from IBS-D patients demonstrated increased TNFα secretion when compared to HV (p = 0.044). Increased psychological scores in IBS did not correlate with TNFα production, while stress hormones inhibited cytokine secretion from CD4+ T-cells of HV in vitro. IBS symptoms, but not markers of immune activation, decreased over time. CD4+ T-cells from IBS-D patients exhibit immune activation, but this did not appear to correlate with psychological stress measurements or changing symptoms over time. This could suggest that immune activation is a surrogate of an initial trigger and/or ongoing parallel peripheral mechanisms.


Assuntos
Linfócitos T CD4-Positivos/patologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/patologia , Adulto , Idoso , Linfócitos T CD4-Positivos/metabolismo , Citocinas/imunologia , Feminino , Trato Gastrointestinal/patologia , Humanos , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/patologia , Selectina L/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/imunologia
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