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1.
Cell ; 180(5): 956-967.e17, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084332

RESUMO

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.


Assuntos
Canais Iônicos/fisiologia , Mecanotransdução Celular/genética , Nociceptores/metabolismo , Dor/genética , Tato/genética , Animais , Regulação da Expressão Gênica/genética , Humanos , Canais Iônicos/genética , Lipídeos/genética , Camundongos , Camundongos Knockout , Dor/fisiopatologia , Técnicas de Patch-Clamp , Estresse Mecânico , Tato/fisiologia
2.
Pain Rep ; 8(5): e1090, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38225957

RESUMO

Introduction: Stings from the lionfish (Pterois volitans) constitute one of the most painful wounds in the ocean. This species has invaded the Atlantic coast of the United States, Gulf of Mexico, Caribbean, and Mediterranean Sea. In addition to its ecological impact on local fish populations, stings from the lionfish pose a medical problem because of the debilitating nature of the pain they produce. However, there are no studies examining the human pain experience of lionfish stings. Objective: To characterize the various aspects of the pain experience following a lionfish sting. Methods: We developed a pain questionnaire that includes validated scales used with patients having acute or chronic pain to understand the pain variability, as well as the use of health care resources and treatments. Results: We provide the first study of the pain experience from lionfish stings. Here, we show that the pain is intense from the start and peaks approximately 1 hour later, resolving itself in 7 days for most victims. Furthermore, pain intensity can be influenced by several factors, including (1) age of the victim, where older victims experience significantly higher pain intensities, (2) the number of spines involved, (3) and whether infection occurred at the injury site. However, pain intensity was not different between male and female participants. Conclusion: These findings will inform the medical community on the pain experience and can be used by local authorities to better appreciate the impact of lionfish envenomations to develop programs aimed at curtailing the expansion of the lionfish.

3.
Neurobiol Pain ; 13: 100120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36816616

RESUMO

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firing in pain conditions. We designed a recombinant AAV vector expressing cargos whose expression was driven by a portion of the SCN10A (NaV1.8) promoter, which is predominantly active in nociceptors. We validated its specificity for nociceptors in mouse and human dorsal root ganglia and showed that it can drive the expression of functional proteins. Our viral vector and promoter package drove the expression of both excitatory or inhibitory DREADDs in primary human DRG cultures and in whole cell electrophysiology experiments, increased or decreased neuronal firing, respectively. Taken together, we present a novel viral tool that drives expression of cargo specifically in human nociceptors. This will allow for future specific studies of human nociceptor properties as well as pave the way for potential future gene therapies for chronic pain.

4.
Toxins (Basel) ; 13(2)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669432

RESUMO

Nature's library of venoms is a vast and untapped resource that has the potential of becoming the source of a wide variety of new drugs and therapeutics. The discovery of these valuable molecules, hidden in diverse collections of different venoms, requires highly specific genetic and proteomic sequencing techniques. These have been used to sequence a variety of venom glands from species ranging from snakes to scorpions, and some marine species. In addition to identifying toxin sequences, these techniques have paved the way for identifying various novel evolutionary links between species that were previously thought to be unrelated. Furthermore, proteomics-based techniques have allowed researchers to discover how specific toxins have evolved within related species, and in the context of environmental pressures. These techniques allow groups to discover novel proteins, identify mutations of interest, and discover new ways to modify toxins for biomimetic purposes and for the development of new therapeutics.


Assuntos
Evolução Molecular , Perfilação da Expressão Gênica , Proteoma , Proteômica , Transcriptoma , Peçonhas/genética , Peçonhas/metabolismo , Animais , Filogenia , Especificidade da Espécie
5.
Pain ; 161(11): 2619-2628, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32569089

RESUMO

Children diagnosed with Christianson syndrome (CS), a rare X-linked neurodevelopmental disorder characterized by intellectual disability, epilepsy, ataxia, and mutism, also suffer from hyposensitivity to pain. This places them at risk of sustaining serious injuries that often go unattended. Christianson syndrome is caused by mutations in the alkali cation/proton exchanger SLC9A6/NHE6 that regulates recycling endosomal pH homeostasis and trafficking. Yet, it remains unclear how defects in this transporter lead to altered somatosensory functions. In this study, we validated a Nhe6 knockout (KO) mouse as a model of CS and used it to identify the cellular mechanisms underlying the elevated pain tolerance observed in CS patients. Within the central nervous system, NHE6 immunolabelling is detected in a small percentage of cortical neurons involved in pain processing, including those within the primary somatosensory and the anterior cingulate cortices as well as the periaqueductal gray. Interestingly, it is expressed in a larger percentage of nociceptors. Behaviourally, Nhe6 KO mice have decreased nocifensive responses to acute noxious thermal, mechanical, and chemical (ie, capsaicin) stimuli. The reduced capsaicin sensitivity in the KO mice correlates with a decreased expression of the transient receptor potential channel TRPV1 at the plasma membrane and capsaicin-induced Ca influx in primary cultures of nociceptors. These data indicate that NHE6 is a significant determinant of nociceptor function and pain behaviours, vital sensory processes that are impaired in CS.


Assuntos
Ataxia , Epilepsia , Doenças Genéticas Ligadas ao Cromossomo X , Deficiência Intelectual , Microcefalia , Transtornos da Motilidade Ocular , Animais , Capsaicina , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Nociceptores , Trocadores de Sódio-Hidrogênio , Canais de Cátion TRPV
6.
Pain ; 159(11): 2255-2266, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29965829

RESUMO

The lionfish (Pterois volitans) is a venomous invasive species found in the Caribbean and Northwestern Atlantic. It poses a growing health problem because of the increase in frequency of painful stings, for which no treatment or antidote exists, and the long-term disability caused by the pain. Understanding the venom's algogenic properties can help identify better treatment for these envenomations. In this study, we provide the first characterization of the pain and inflammation caused by lionfish venom and examine the mechanisms through which it causes pain using a combination of in vivo and in vitro approaches including behavioral, physiological, calcium imaging, and electrophysiological testing. Intraplantar injections of the venom produce a significant increase in pain behavior, as well as a marked increase in mechanical sensitivity for up to 24 hours after injection. The algogenic substance(s) are heat-labile peptides that cause neurogenic inflammation at the site of injection and induction of Fos and microglia activation in the superficial layers of the dorsal horn. Finally, calcium imaging and electrophysiology experiments show that the venom acts predominantly on nonpeptidergic, TRPV1-negative, nociceptors, a subset of neurons implicated in sensing mechanical pain. These data provide the first characterization of the pain and inflammation caused by lionfish venom, as well as the first insight into its possible cellular mechanism of action.


Assuntos
Venenos de Peixe/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Dor/induzido quimicamente , Dor/metabolismo , Canais de Cátion TRPV/metabolismo , Acrilamidas/uso terapêutico , Análise de Variância , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Capsaicina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Gânglios Espinais/citologia , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Hiperalgesia/fisiopatologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Inflamação Neurogênica/induzido quimicamente , Proteínas Oncogênicas v-fos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/genética , Fatores de Tempo , Tato
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