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BACKGROUND: Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. OBJECTIVES: To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. METHODS: Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10â min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. RESULTS: The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. CONCLUSIONS: The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.
Managing itching and the effects of histamine can be difficult for people with allergies. Cooling the skin or applying menthol provides some relief from itch, but the way they work is not fully understood. Cooling agents interact with a protein called TRPM8 (also known as the 'cold and menthol receptor') and have shown potential for the management of itch. However, much of the research has been done on animals and has limitations when compared with human studies. Antihistamine medications can help with histamine-induced itching, but they may not work for other causes of itch. This study investigated the effects of a specific TRPM8 agonist (a chemical that activates a receptor to produce a biologic response) gel called cryosim-1 on itch in human skin. To do this, we conducted tests on 30 healthy people using five different substances that cause itching. Participants rated the itch intensity and pain using a scale and we measured various aspects of their skin. The results showed that all substances caused significant itching compared to a control substance, but itchiness gradually decreased over time. Histamine and compound 48/80 also caused pain. However, when participants applied the TRPM8 activator gel before exposure, they experienced less itching and lower itch intensity versus the gel without the activator. There were no significant differences in pain between the TRPM8 activator and the gel without it. In summary, our findings showed that activating TRPM8 receptors with a specific substance effectively relieved itching caused by various irritants on human skin. This suggests its potential as a treatment for itch-related conditions. Further research is needed to understand its mechanisms better and evaluate its effectiveness in real-life situations.
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Histamina , Prurido , Canais de Cátion TRPM , Humanos , Prurido/tratamento farmacológico , Prurido/induzido quimicamente , Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/antagonistas & inibidores , Adulto , Masculino , Histamina/administração & dosagem , Histamina/efeitos adversos , Feminino , Adulto Jovem , Géis , Pessoa de Meia-Idade , Antipruriginosos/administração & dosagem , Antipruriginosos/farmacologia , Antipruriginosos/efeitos adversos , Método Duplo-Cego , Administração CutâneaRESUMO
Removing water from wet fur or feathers is important for thermoregulation in warm-blooded animals. The "wet dog shake" (WDS) behavior has been largely characterized in mammals but to a much lesser extent in birds. Although it is known that TRPM8 is the main molecular transducer of low temperature in mammals, it is not clear if wetness-induced shaking in furred and feathered animals is dependent on TRPM8. Here, we show that a novel TRPM8 agonist induces WDS in rodents and, importantly, in birds, similar to the shaking behavior evoked by water-spraying. Furthermore, the WDS onset depends on TRPM8, as we show in water-sprayed mice. Overall, our results provide multiple evidence for a TRPM8 dependence of WDS behaviors in all tested species. These suggest that a convergent evolution selected similar shaking behaviors to expel water from fur and feathers, with TRPM8 being involved in wetness sensing in both mammals and birds.
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BACKGROUND: Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP. METHODS: We conducted a prospective pilot study of 15 patients with DE-associated NOP. These patients applied topical C3 to their eyelid, 4 times/day for 1 month. The patients underwent clinical examinations. They also completed the Ocular Pain Assessment Survey (OPAS), which is a validated questionnaire for NOP, at baseline, 1 week, and 1 month after treatment. RESULT: At 1 week, the OPAS scores of eye pain intensity, quality of life (driving/watching TV, general activity, sleep, and enjoying life/relations with other people), and associated factors (burning sensation, light sensitivity, and tearing) improved. The total OPAS scores of eye pain intensity, quality of life, and associated factors remained improved at 1 month. The Schirmer test scores also improved at 1 month. CONCLUSION: TRPM8 agonist (C3) could be a novel agent for treating patients with DE-associated NOP who are unresponsive to conventional treatments.
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Heat impairs human learning and work output when environmental temperatures increase from 18 °C â 25+°C. The hypothesis here is that if the localized, ambient milieu around the upper eyelid margin is perceived as being ~15 °C in coolness, then the adverse effects of heat can be attenuated. This is achieved by topical wipe of a solution to the closed eyelid skin above the eyelashes. The receptor target is TRPM8, an integral membrane protein that transduces the sense of coolness/cold to the central nervous system. The wipe solution contains a TRPM8 agonist called cryosim-3 (1-diisopropylphosphorylnonane) at 1-3 mg/mL in water and designed for delivery to the eyelid margin. Other sensory systems negatively affected by heat, such as the surfaces of the nasal cavity, can also be treated with the TRPM8 agonist as an adjunct to relieve discomfort from the heat.
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Canais de Cátion TRPM , Encéfalo/metabolismo , Temperatura Baixa , Pálpebras , Temperatura Alta , Humanos , Proteínas de Membrana , Canais de Cátion TRPM/metabolismoRESUMO
Proopiomelanocortin (POMC) can be processed to ACTH and melanocortin peptides. However, processing is incomplete in some tissues, leading to POMC precursor release from cells. This study examined POMC processing in human skin and the effect of POMC on the melanocortin-1 receptor (MC-1R) and melanocyte regulation. POMC was secreted by both human epidermal keratinocytes (from 5 healthy donors) and matched epidermal melanocytes in culture. Much lower levels of alpha-MSH were secreted and only by the keratinocytes. Neither cell type released ACTH. Cell extracts contained significantly more ACTH than POMC, and alpha-MSH was detected only in keratinocytes. Nevertheless, the POMC processing components, prohormone convertases 1, 2 and regulatory protein 7B2, were detected in melanocytes and keratinocytes. In contrast, hair follicle melanocytes secreted both POMC and alpha-MSH, and this was enhanced in response to corticotrophin-releasing hormone (CRH) acting primarily through the CRH receptor 1. In cells stably transfected with the MC-1R, POMC stimulated cAMP, albeit with a lower potency than ACTH, alpha-MSH, and beta-MSH. POMC also increased melanogenesis and dendricity in human pigment cells. This release of POMC from skin cells and its functional activity at the MC-1R highlight the importance of POMC processing as a key regulatory event in the skin.
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Queratinócitos/metabolismo , Melanócitos/citologia , Melanócitos/metabolismo , Pró-Opiomelanocortina/metabolismo , Pele/citologia , Hormônio Adrenocorticotrópico/análise , Células Cultivadas , Humanos , Queratinócitos/química , Melanocortinas/análise , Melanócitos/química , Pró-Opiomelanocortina/fisiologia , Receptor Tipo 1 de Melanocortina , alfa-MSH/análiseRESUMO
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist.
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Human skin is a local source of corticotropin-releasing hormone (CRH) and expresses CRH and CRH receptors (CRH-R) at mRNA and protein levels. Epidermal melanocytes respond to CRH by induction of cAMP with up-regulation of pro-opiomelanocortin gene expression and subsequent production of adrenocorticotropin hormone. However, the role of CRH/CRH-R in melanocyte biology is complicated by the significant heterogeneity of cutaneous melanocyte subpopulations, from continuously active and UV-responsive melanocytes in epidermis to UV nonresponsive, hair growth cycle-coupled melanogenesis in hair follicles. In the present study we report that normal human scalp hair follicle melanocytes express CRH at the mRNA level. Furthermore, CRH, urocortin and CRH-R 1 and 2 were differentially expressed in follicular melanocytes, fibroblasts, and keratinocytes depending on anatomic location and differentiation status in situ and in vitro. Stimulation of follicular melanocytes with CRH and CRH peptides, modified for selectivity for CRH-R1 and/or CRH-R2, variably induced cell melanogenesis, dendricity, and proliferation. CRH-peptides also stimulated the expression and activity of Tyrosinase, and expression of Tyrosinase-related protein-1 and-2. However, a modified urocortin peptide highly selective for CRH-R2 down-regulated melanocyte differentiation phenotype. This study indicates that CRH peptides can differentially influence hair follicle melanocyte behavior not only via CRH-R1 signaling but also by complex cross-talk between CRH-R1 and CRH-R2.
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Hormônio Liberador da Corticotropina/metabolismo , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Melanócitos/metabolismo , Adulto , Proliferação de Células , Feminino , Regulação da Expressão Gênica , Folículo Piloso/enzimologia , Humanos , Oxirredutases Intramoleculares/metabolismo , Masculino , Melaninas/metabolismo , Glicoproteínas de Membrana/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/metabolismo , Fenótipo , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Regulação para Cima , UrocortinasRESUMO
Hyaluronan and its associated water of hydration are the basis of the swelling and edema of acute inflammation. Mystixins are small, synthetic peptides that suppress the acute inflammatory response. Mystixin-7, a prototype of these peptides, has the structure p-anisoyl-Arg-Lys-Leu-Leu-D-Thi-Ile-D-Leu-NH(2). As shown previously by this laboratory, the mystixin-7 peptide inhibits edema formation in vivo following intravenous administration at doses of less than 1.0 mg/kg. Mechanisms by which this peptide might suppress edema were examined here in vitro using cultured cells. Normal human dermal fibroblasts normally secrete large quantities of hyaluronan in response to inflammatory stimuli. Mystixin-7 reduced hyaluronan deposition by up to 80% in such cultures. Stimulation of hyaluronidase activity was observed. Mystixins represent a novel class of anti-inflammatory peptides that suppress the edema associated with inflammation. We propose that stimulation of hyaluronidase activity, with a decrease in net hyaluronan deposition and its associated water of hydration, is among the mechanisms of the anti-inflammatory effect of mystixin peptides.
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Anti-Inflamatórios não Esteroides/farmacologia , Edema/tratamento farmacológico , Edema/metabolismo , Ácido Hialurônico/metabolismo , Oligopeptídeos/farmacologia , Animais , Células Cultivadas , Edema/etiologia , Fibroblastos/metabolismo , Membro Posterior , Temperatura Alta/efeitos adversos , Humanos , Hialuronoglucosaminidase/metabolismo , Imuno-Histoquímica , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
CRH cutaneous expression is significantly enhanced after exposure to various stimuli (Physiol Rev 2000, 80;979-1020). We evaluated the effect of CRH on cytokine production in HaCaT keratinocytes, a cell line shown to express CRH receptors coupled to cAMP activation and calcium-dependent transmission pathways. It is demonstrated for the first time that exogenously added CRH stimulates production of IL-6 and IL-11. It also inhibits production of IL-1beta and does not affect TNF-alpha production. Our results indicate that CRH function(s) during cutaneous stress may be mediated by differential effects on cytokine production.
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Hormônio Liberador da Corticotropina/farmacologia , Citocinas/biossíntese , Queratinócitos/efeitos dos fármacos , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Escherichia coli/imunologia , Humanos , Queratinócitos/metabolismo , Lipopolissacarídeos/farmacologiaRESUMO
Injury to soft tissue results in the lowering of interstitial fluid pressure (P(if)), plasma protein extravasation, and increased total tissue volume. In this study, the effects of N-acetyl neurotensin(8-13) [AcNT(8-13)] on P(if) in rat trachea were examined after electrical stimulation (ES) of the vagus nerve. P(if) was measured with glass capillaries connected to a servocontrolled counterpressure system. In pentobarbital-anesthetized female Wistar rats, the P(if) after intravenous saline was -1.8 +/- 0.3 mmHg (means +/- SD) and decreased to -5.0 +/- 0.6 mmHg (P < 0.01, n = 9) after ES. AcNT(8-13) (10 microg/kg) blocked the fall in P(if) after ES (-2.5 +/- 2.3 mmHg, P < 0.01, n = 8). In tracheal tissue from animals pretreated with AcNT(8-13) at the same dose and immersed in phosphate-buffered saline (0.15 M, pH 7.4), the rate of fluid accumulation in excised tissues was significantly reduced after 2 h. The ability of AcNT(8-13) to modulate the fluid mechanics of tracheal interstitium after inflammation suggests that it may be a useful tool for studying cell adhesion and related factors that maintain structural integrity of connective tissue after injury.