RESUMEN
TRPV1 channels are polymodal cation channels located predominantly on primary afferent neurons that are activated by inflammatory mediators, capsaicin (the active component in chili peppers), and noxious heat. TRPV1 channel antagonists are potential new analgesic agents, but their development has been hindered by the finding that they also produce loss of thermal homeostasis and response to noxious heat. Results from recent studies of the TRPV1 channel indicate that it might be possible to develop TRPV1 channel antagonists that inhibit pain without affecting noxious heat sensation. TRPV1 channels are also present in the central nervous system (CNS) and have been implicated in learning, memory, and behaviour. TRPV1 channel modulators have been proposed to have possible therapeutic potential in the treatment of neurological and psychiatric conditions. However, further understanding of the role of TRPV1 channels in the CNS is required before therapeutic advances in the treatment of neuropsychiatric conditions with TRPV1 channel modulators can be made.
RESUMEN
Depression and schizophrenia are major psychiatric disorders that cause much human suffering. Current treatments have major limitations and new drug targets are eagerly sought. Study of transient receptor potential (TRP) channels in these disorders is at an early stage and the potential of agents that activate or inhibit these channels remains speculative. The findings that TRPC6 channels promote dendritic growth and are selectively activated by hyperforin, the key constitutent of St John's wort, suggest that TRPC6 channels might prove to be a new target for antidepressant drug development. There is now considerable evidence that TRPV1 antagonists have anxiolytic activity but there is no direct evidence that they have antidepressant activity. There is also no direct evidence that TRP channels play a role in schizophrenia. However, the findings that TRPC channels are involved in neuronal development and fundamental synaptic mechanisms, and that TRPV1 channels play a role in central dopaminergic and cannabinoid mechanisms is suggestive of potential roles of these channels in schizophrenia. Investigation of TRP channels in psychiatric disorders holds the promise of yielding further understanding of the aetiology of psychiatric disorders and the development of new drug treatments.
Asunto(s)
Trastornos Mentales/fisiopatología , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Encéfalo/fisiopatología , HumanosRESUMEN
The World Health Organization (WHO) has declared COVID-19 a pandemic. We review and reduce the clinical literature on diagnosis of COVID-19 through symptoms that might be remotely detected as of early May 2020. Vital signs associated with respiratory distress and fever, coughing, and visible infections have been reported. Fever screening by temperature monitoring is currently popular. However, improved noncontact detection is sought. Vital signs including heart rate and respiratory rate are affected by the condition. Cough, fatigue, and visible infections are also reported as common symptoms. There are non-contact methods for measuring vital signs remotely that have been shown to have acceptable accuracy, reliability, and practicality in some settings. Each has its pros and cons and may perform well in some challenges but be inadequate in others. Our review shows that visible spectrum and thermal spectrum cameras offer the best options for truly noncontact sensing of those studied to date, thermal cameras due to their potential to measure all likely symptoms on a single camera, especially temperature, and video cameras due to their availability, cost, adaptability, and compatibility. Substantial supply chain disruptions during the pandemic and the widespread nature of the problem means that cost-effectiveness and availability are important considerations.
RESUMEN
Schizophrenia is a chronic psychiatric disorder the cause of which is unknown. It is considered to be a neurodevelopmental disorder that results from an interaction of genetic and environmental factors. Direct evidence for links between schizophrenia and TRP channels is lacking. However, several aspects of the pathophysiology of the disorder point to a possible involvement of TRP channels. In this review evidence for links between TRP channels and schizophrenia with respect to neurodevelopment, dopaminergic and cannabinoid systems, thermoregulation, and sensory processes, is discussed. Investigation of these links holds the prospect of a new understanding of schizophrenia with resultant therapeutic advances.
Asunto(s)
Esquizofrenia/etiología , Esquizofrenia/fisiopatología , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Regulación de la Temperatura Corporal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Capsaicina/farmacología , Humanos , Neuronas Aferentes/fisiología , Ratas , Receptores de Cannabinoides/metabolismo , Receptores de Cannabinoides/fisiología , Receptores Dopaminérgicos/metabolismo , Receptores Dopaminérgicos/fisiología , Esquizofrenia/genética , Sinapsis/fisiología , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
The classical tachykinins, substance P, neurokinin A and neurokinin B are predominantly found in the nervous system where they act as neurotransmitters and neuromodulators. Their respective preferred receptors are NK1, NK2, and NK3 receptors. The presence of substance P in nociceptive primary afferent neurons, electrophysiological studies showing that it activated neurons in the dorsal horn of the spinal cord, and behavioral studies in animals, supported the concept that substance P was an important transmitter in the nociceptive pathway. It was therefore surprising that non-peptide NK1 receptor antagonists were ineffective as analgesics in clinical pain conditions. Nevertheless, the discovery that NK1 receptor antagonists had antidepressant activity led to renewed interest in these antagonists. It is disappointing that clinical trials of MK869 (aprepitant) for depression were suspended. The future of NK1 receptor antagonists as antidepressant drugs will depend on the outcome of clinical trials with other NK1 receptor antagonists. NK1 receptor antagonists were also found to be effective antiemetics, and aprepitant has recently become available for the treatment of chemotherapy induced emesis. Although less is known of the potential of NK2 and NK3 receptor antagonists, recent trials of NK3 receptor antagonists have shown efficacy in schizophrenia. The discovery of a new family of tachykinins, the hemokinins and endokinins, which acts on NK1 receptors and has potent effects on immune cells, has implications for the clinical use of NK1 receptor antagonists. Thus specific therapeutic strategies may be required to enable NK1 receptor antagonists to be introduced for treatment of neuropsychiatric disorders.
Asunto(s)
Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Taquicininas/metabolismo , Animales , Antidepresivos/metabolismo , Antidepresivos/uso terapéutico , Antipsicóticos/química , Antipsicóticos/uso terapéutico , HumanosRESUMEN
The amygdala has a role in the modulation of moods and emotion, processes that are known to be affected in people with psychiatric disorders such as schizophrenia and depression. The tachykinin NK(1) receptor is known to be expressed in the amygdala. However to date, there is limited knowledge of the distribution of the NK(1) receptor in this region. This study used immunohistochemistry to analyse the distribution of the NK(1) receptor in fixed human amygdala tissue in control subjects with no history of psychiatric illness and matched subjects with a diagnosis of schizophrenia (n=4 pairs). The NK(1) receptor was observed sparsely distributed in cell bodies in all amygdaloid nuclei with the basolateral and lateral having a greater relative density of NK(1) receptor-immunoreactive cell bodies than the other nuclei. Double labelling with antibodies to microtubule associated protein and the NK(1) receptor revealed that the NK(1) receptor is expressed by large pyramidal, small stellate and large bipolar neurons. Interestingly, the basal nucleus of Meynert, which is just dorsal to the amygdala, was observed to have a significantly higher relative density of NK(1) receptor-immunoreactive cell bodies compared to any of the amygdaloid nuclei. Preliminary analysis of the density of NK(1) receptor-immunoreactive cell bodies in the major amygdaloid nuclei and the basal nucleus of Meynert revealed no significant differences between schizophrenia and control subjects. Real-time PCR showed that the mRNA for both the short and long isoforms of the NK(1) receptor was expressed at low levels in fresh frozen human amygdala tissue from control subjects and that this was not different in matched subjects with schizophrenia (n=11 pairs). In conclusion, this study has demonstrated that the NK(1) receptor is widely distributed in the amygdala, and has shown for the first time a high relative density of NK(1) receptor-immunoreactive cell bodies in the basal nucleus of Meynert.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Receptores de Neuroquinina-1/metabolismo , Esquizofrenia/patología , Adulto , Amígdala del Cerebelo/patología , Análisis de Varianza , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patología , Recuento de Células/métodos , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Microtúbulos/metabolismo , Persona de Mediana Edad , Neuronas/metabolismo , Cambios Post Mortem , Receptores de Neuroquinina-1/clasificación , Receptores de Neuroquinina-1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Esquizofrenia/metabolismoRESUMEN
Schizophrenia is considered to be a neurodevelopmental disorder with origins in the prenatal or neonatal period. Brains from subjects with schizophrenia have enlarged ventricles, reduced cortical thickness (CT) and increased neuronal density in the prefrontal cortex compared with those from normal subjects. Subjects with schizophrenia have reduced pain sensitivity and niacin skin flare responses, suggesting that capsaicin-sensitive primary afferent neurons might be abnormal in schizophrenia. This study tested the hypothesis that intrinsic somatosensory deprivation, induced by neonatal capsaicin treatment, causes changes in the brains of rats similar to those found in schizophrenia. Wistar rats were treated with capsaicin, 50 mg kg(-1) subcutaneously, or vehicle (control) at 24-36 h of life. At 5-7 weeks behavioural observations were made, and brains removed, fixed and sectioned. The mean body weight of capsaicin-treated rats was not significantly different from control, but the mean brain weight of male, but not female, rats, was significantly lower than control. Capsaicin-treated rats were hyperactive compared with controls. The hyperactivity was abolished by haloperidol. Coronal brain sections of capsaicin-treated rats had smaller cross-sectional areas, reduced CT, larger ventricles and aqueduct, smaller hippocampal area and reduced corpus callosum thickness, than brain sections from control rats. Neuronal density was increased in several cortical areas and the caudate putamen, but not in the visual cortex. It is concluded that neonatal capsaicin treatment of rats produces brain changes that are similar to those found in brains of subjects with schizophrenia.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Capsaicina/farmacología , Esquizofrenia , Privación Sensorial , Animales , Animales Recién Nacidos , Encéfalo/patología , Recuento de Células , Femenino , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Factores Sexuales , Cola (estructura animal)/efectos de los fármacos , Cola (estructura animal)/crecimiento & desarrolloRESUMEN
The aim of this study was to determine whether sensitization occurred to morphine withdrawal. Guinea-pigs were treated twice daily with increasing doses of morphine (10-100 mg/kg s.c.) for 3 days followed by injection of morphine 100 mg/kg on the fourth day. Sixty min after the last morphine injection, animals were withdrawn from morphine with naltrexone, 15 mg/kg s.c., and locomotor activity and all other behaviours scored over 90 min. Animals were then rested for 3 days. This procedure was repeated twice over the next 2 weeks. Control animals were treated with saline for the first two treatment cycles. Guinea-pigs subjected to three cycles of morphine withdrawal showed a significant increase in the total number of withdrawal behaviour counts over the 90-min observation period following the third cycle of withdrawal compared with the first and second withdrawal cycles. However, locomotor activity, a major sign of morphine withdrawal in guinea-pigs, was not significantly increased. Fos-LI was markedly increased in the repeatedly withdrawn animals in several brain regions, including amygdala, dorsal striatum, thalamus, ventral tegmental area, and ventrolateral periaqueductal gray area. It is concluded that sensitization to morphine withdrawal occurs in guinea-pigs.
Asunto(s)
Analgésicos Opioides/farmacología , Morfina/farmacología , Síndrome de Abstinencia a Sustancias/fisiopatología , Amígdala del Cerebelo/química , Amígdala del Cerebelo/efectos de los fármacos , Analgésicos Opioides/administración & dosificación , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Cobayas , Hipocampo/química , Hipocampo/efectos de los fármacos , Hipotálamo/química , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Masculino , Morfina/administración & dosificación , Actividad Motora/efectos de los fármacos , Naltrexona/administración & dosificación , Proteínas Proto-Oncogénicas c-fos/análisis , Ratas , Síndrome de Abstinencia a Sustancias/etiología , Telencéfalo/química , Telencéfalo/efectos de los fármacos , Factores de TiempoRESUMEN
Previous studies have observed increased tachykinin NK(1) receptor immunoreactivity (NK(1)-IR) in the prefrontal cortex in subjects with schizophrenia. Since the subjects were medicated the possibility of a treatment effect could not be excluded. Thus, the present study was undertaken to determine the effect of chronic treatment with the antipsychotic drug, haloperidol, on the distribution of NK(1)-IR neurons in the guinea-pig brain. Guinea pigs were treated each day for 21 days with either haloperidol (1mg/kg) or vehicle and the brains were then processed for immunohistochemistry using an NK(1) receptor-specific polyclonal antibody. NK(1)-IR neurons and fibres were abundant in the forebrain cortex and caudate putamen and more sparsely distributed in a number of other brain regions. The relative density of NK(1)-IR neurons was significantly increased in the forebrain cortex, but not in the caudate putamen in guinea pigs treated with haloperidol. This study has shown that haloperidol causes region-specific changes to the density of NK(1)-IR neurons. Whether these changes are related to the therapeutic effects or to the side effects of haloperidol in individuals with schizophrenia, remains to be determined.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/citología , Haloperidol/farmacología , Neuronas/efectos de los fármacos , Receptores de Neuroquinina-1/metabolismo , Animales , Encéfalo/efectos de los fármacos , Recuento de Células/métodos , Agonistas de Dopamina/farmacología , Interacciones Farmacológicas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Cobayas , Inmunohistoquímica/métodos , Masculino , Neuronas/metabolismo , Quinpirol/farmacología , Distribución Tisular/efectos de los fármacosRESUMEN
Increased neuronal density, cortical thinning, and alterations of GABAergic interneurons in the prefrontal cortex have been associated with the pathophysiology of schizophrenia. This study used antibodies directed against the calcium-binding proteins, calretinin (CR), parvalbumin (PV), and calbindin (CB) to compare the relative density of subpopulations of GABAergic interneurons in BA9 of the prefrontal cortex from six subjects with schizophrenia and six control subjects matched for age, gender, and postmortem interval. The relative density of interneurons expressing CR, PV, or CB did not differ significantly between subjects with schizophrenia and control subjects. In addition, no change in somal size of immunoreactive (IR) neurons or cortical thickness was observed between the two groups. This study supports previous reports consistently demonstrating no change in the relative density of interneurons expressing CR in the dorsolateral prefrontal cortex in schizophrenia but does not support previous inconsistent findings that the relative density of interneurons expressing PV and CB might be altered in this disorder.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Neuronas/metabolismo , Corteza Prefrontal/patología , Esquizofrenia/metabolismo , Adulto , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Recuento de Células/métodos , Tamaño de la Célula , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Esquizofrenia/patología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Rapid opioid withdrawal induced by naltrexone is now used as a treatment for heroin addiction. The alpha2-adrenoceptor agonist, clonidine, is currently used in clinical practice to reduce opioid withdrawal in humans. However, few studies have been reported on its effectiveness for this purpose. Guinea-pigs were made dependent and tolerant to morphine using a 3-day chronic morphine regimen (total 410 mg kg(-1) morphine base), and injected with either clonidine (0.1 mg kg(-1), s.c.) or saline, 1 h before induction of withdrawal with naltrexone (15 mg kg(-1), s.c.). Withdrawal behaviours were measured for 90 min and animals were then euthanased and the brains removed. The presence of the immediate early gene protein product, c-Fos, was detected using immunohistochemical techniques. Clonidine reduced the number of head/body shakes, but had no effect on the total withdrawal behaviour score. In the CNS, clonidine increased the number of Fos-LI neurons in the central amygdala. In conclusion, the modest effect of clonidine in the present experiments suggests that the efficacy of clonidine in humans undergoing naltrexone-induced opioid withdrawal requires further investigation.
Asunto(s)
Agonistas alfa-Adrenérgicos/uso terapéutico , Encéfalo/efectos de los fármacos , Clonidina/uso terapéutico , Dependencia de Morfina/tratamiento farmacológico , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Animales , Encéfalo/metabolismo , Femenino , Genes fos/efectos de los fármacos , Cobayas , MasculinoRESUMEN
Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5-7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5-7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16-18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Capsaicina/toxicidad , Neurotransmisores/toxicidad , Canales Catiónicos TRPV/agonistas , Estimulación Acústica , Animales , Animales Recién Nacidos , Percepción Auditiva/efectos de los fármacos , Percepción Auditiva/fisiología , Encéfalo/patología , Encéfalo/fisiopatología , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Niacina , Ácidos Nicotínicos , Tamaño de los Órganos , Inhibición Prepulso/efectos de los fármacos , Inhibición Prepulso/fisiología , Prostaglandina D2/administración & dosificación , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Fenómenos Fisiológicos de la Piel/efectos de los fármacos , Canales Catiónicos TRPV/metabolismoRESUMEN
The effects of subchronic subcutaneous treatment with tachykinin receptor antagonists over nine days on the repeated mild stress response induced by daily subcutaneous injections and on the severe acute stress induced by morphine withdrawal were investigated in guinea-pigs. The NK(1) receptor antagonist, L733,060, 0.25mg/kg, significantly increased locomotor activity of guinea-pigs compared with animals subjected to repeated injection of the inactive enantiomer, but inhibited Fos-like immunoreactivity (Fos-LI) in the hypothalamus. In animals subjected to the acute severe stress of naltrexone-induced morphine withdrawal, treatment with the NK(1) antagonist, L733,060, produced reductions in Fos-LI in the spinal dorsal horn, whereas those treated with the NK(3) antagonist, SSR146,977, 0.3mg/kg, had reduced Fos-LI in the dorsal horn, adrenal medulla, nucleus accumbens, ventral tegmental area and periaqueductal grey. Those animals treated with both NK(1) and NK(3) antagonists also had reduced Fos-LI in the amygdala and paraventricular nucleus of the thalamus. It was concluded that the NK(1) antagonist reduced the hypothalamic response to mild stress but the NK(3) antagonist was more effective in reducing the severe stress response to morphine withdrawal. Furthermore, combination of NK(1) and NK(3) antagonists was more effective than either antagonist in reducing the Fos-LI response to morphine withdrawal.
Asunto(s)
Compuestos de Metilurea/administración & dosificación , Compuestos de Metilurea/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Receptores de Taquicininas/antagonistas & inhibidores , Estrés Fisiológico/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Infusiones Subcutáneas , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Capsaicin, the hot chemical in chillies, administered to neonatal rats, causes destruction of polymodal nociceptive primary afferent neurons by acting on TRPV1 receptors causing intrinsic somatosensory deprivation. Although the effects of neonatal capsaicin treatment in the periphery have been extensively investigated, less is known about the brain networks to which the capsaicin sensory neurons are relayed. In the present study the effect of neonatal capsaicin treatment on brain receptors that have been shown to interact with TRPV1 was examined. Wistar rats were treated on neonatal day 2 with capsaicin and at 15-16 weeks of age, brains were processed to measure levels of muscarinic M(1)/M(2) and M(2)/M(4), serotonin 5HT(2A), cannabinoid CB(1), dopamine D(1), D(2) receptors and dopamine transporter. Overall increases in levels of muscarinic M(1)/M(4) (F=8.219, df=1, p=0.005), muscarinic M(2)/M(4) (F=99.759, df=1, p<0.0001), serotonin 5HT(2A) (F=28.892, df=1, p<0.0001), dopamine D(1) (F=8.726, df=1, p=0.008) and cannabinoid CB(1) (F=25.084, df=1, p<0.0001) receptors were found in the brains of capsaicin-treated rats, although significant regional changes occurred only in muscarinic M(2)/M(4) and serotonin 5HT(2A) receptors. The results of the present study suggest that neonatal intrinsic somatosensory deprivation may have a significant impact on substrates at the central nervous system that manifest as changes in central cholinergic, monaminergic and cannabinoid systems in the adult animal.