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1.
Sci Adv ; 7(24)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34117054

RESUMEN

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.


Asunto(s)
Endorfinas , Trastornos Relacionados con Opioides , Deficiencia de Vitamina D , Analgésicos Opioides/farmacología , Animales , Humanos , Ratones , Vitamina D/farmacología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , Vitaminas
2.
Sci Adv ; 7(14)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33811065

RESUMEN

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.


Asunto(s)
Analgésicos Opioides , Nocicepción , Animales , Cabello , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Receptor de Melanocortina Tipo 1/genética , Receptor de Melanocortina Tipo 4/genética
3.
Cell ; 157(7): 1527-34, 2014 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-24949966

RESUMEN

UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, ß-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in ß-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of ß-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans.


Asunto(s)
Conducta Adictiva , Piel/efectos de la radiación , betaendorfina/metabolismo , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Piel/metabolismo , Rayos Ultravioleta , betaendorfina/genética
4.
JAMA Intern Med ; 174(6): 964-70, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24710960

RESUMEN

IMPORTANCE: The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk. OBJECTIVE: To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States. DESIGN, SETTING, AND PARTICIPANTS: Our study is a prospective cohort study. In 2000, participants in the Health Professionals' Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25,848 men remained in the analysis. MAIN OUTCOMES AND MEASURES: The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed. RESULTS: We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04-3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95% CI, 1.14-3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use. CONCLUSIONS AND RELEVANCE: Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.


Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Melanoma/inducido químicamente , Inhibidores de Fosfodiesterasa 5/efectos adversos , Piperazinas/efectos adversos , Neoplasias Cutáneas/inducido químicamente , Sulfonas/efectos adversos , Anciano , Carcinoma Basocelular/inducido químicamente , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/epidemiología , Estudios de Seguimiento , Humanos , Masculino , Melanoma/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Purinas/efectos adversos , Citrato de Sildenafil , Neoplasias Cutáneas/epidemiología , Estados Unidos/epidemiología
5.
Commun Integr Biol ; 7(5)2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26842945

RESUMEN

While few people would deny the appeal of a day in the sun there are some who seem to take it too far. In recent years the concept of 'tanning addiction' has become popular and several studies have supported the notion of viewing exposure to UV radiation as a form of substance abuse. In this article we will review some of the literature on sun seeking behavior.

6.
Cell ; 155(5): 1022-33, 2013 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-24267888

RESUMEN

Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.


Asunto(s)
Factores Reguladores del Interferón/metabolismo , Polimorfismo de Nucleótido Simple , Animales , Secuencia de Bases , Elementos de Facilitación Genéticos , Humanos , Factores Reguladores del Interferón/química , Factores Reguladores del Interferón/genética , Melanocitos/metabolismo , Ratones , Datos de Secuencia Molecular , Pigmentación , Transducción de Señal , Factor de Transcripción AP-2/química , Factor de Transcripción AP-2/metabolismo , Pez Cebra
7.
Nature ; 491(7424): 449-53, 2012 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-23123854

RESUMEN

People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.


Asunto(s)
Color del Cabello/genética , Melanoma/genética , Pigmentación de la Piel/genética , Rayos Ultravioleta , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Indoles/farmacología , Melaninas/metabolismo , Ratones , Ratones Endogámicos C57BL , Monofenol Monooxigenasa/genética , Peroxidasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Receptor de Melanocortina Tipo 1/genética , Sulfonamidas/farmacología , Análisis de Supervivencia , Células Tumorales Cultivadas
9.
Cell ; 141(6): 994-1005, 2010 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-20550935

RESUMEN

DICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression--an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17 approximately 92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.


Asunto(s)
Regulación de la Expresión Génica , Melanocitos/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Ribonucleasa III/metabolismo , Transcripción Genética , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Diferenciación Celular , Supervivencia Celular , Células Cultivadas , Células Epidérmicas , Técnicas de Silenciamiento del Gen , Folículo Piloso/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , Regulación hacia Arriba
10.
Semin Cell Dev Biol ; 20(1): 111-6, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19124082

RESUMEN

The melanocyte stem cells of the hair follicle provide an attractive system for the study of stem cells. The stem cells exist in an anatomically defined niche clearly separated from their differentiated progeny, differentiated progeny can be selected against by treatment with an inhibitor of Stem Cell Factor signaling, perturbations which affect survival and differentiation have clearly visible pigmentation phenotypes, and genetic mutations can impair or completely abolish this lineage without lethality. In mice several coat color mutants have been shown to have impaired specification or survival of melanocyte stem cells. Furthermore understanding of the normal regulation and behaviors of melanocytes and melanocyte stem cells will allow development of better strategies for cancer treatment. This article will review the discovery and behaviors of melanoctye stem cells as well as some aspects of melanocyte biology.


Asunto(s)
Diferenciación Celular , Melanocitos/citología , Células Madre/citología , Animales , Folículo Piloso/citología , Queratinocitos/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Células Madre/metabolismo
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