Resumen de Insomnio, estrés y canabinoides

Oscar Prospéro García, Mónica Méndez Díaz, Alejandra Ruiz Contreras, Ilia Alvarado Capuleño, León Rosenthal

• español

  El sueño es una actividad fundamental para el bienestar y la preservación del la salud. El no dormir resulta en consecuencias potencialmente letales. Por ejemplo, ratas experimentalmente privadas de sueño total (o de sueño MOR) mueren al cabo de algunas semanas de experimentación. Asimismo, en humanos, la privación de tan solo una noche de sueño conlleva consecuencias importantes.

  Hipersomnolencia y disminución de las habilidades cognoscitivas son consecuencias de la privación de sueño. El individuo privado de sueño corre el riesgo de cometer errores que potencialmente pueden poner en riesgo su vida o integridad física, así como la de otros.

  Se ha sugerido que el sueño cumple con la muy importante tarea de ofrecer las condiciones para que se lleven a cabo diversos procesos de restauración y de reorganización neuronal así como el procesamiento de información y consolidación de la memoria. La ausencia de sueño interfiere con estos procesos con el consecuente deterioro de la conducta adaptativa del sujeto.

  El insomnio es un trastorno que deteriora de manera importante la calidad de vida de las personas que lo padecen. Afecta aproximadamente al 10% de la población. El insomnio se presenta en diversas formas. La clasificación internacional de los trastornos del dormir considera 11 tipos de insomnio. Entre ellos, el insomnio psicofisiológico representa el tipo de insomnio que más frecuentemente se manifiesta en la población. Se trata de un padecimiento donde el paciente desarrolla una aversión a dormir y a todo lo que se relacione con ello. Este tipo de insomnio tiene un componente de estrés que precipita la aparición del insomnio y puede contribuir a los elementos que ayudan a perpetuarlo (insomnio crónico). Se han desarrollado diversos modelos animales para el estudio del estrés y sus consecuencias. Por ejemplo, el estrés temprano inducido por privación del cuidado maternal. Asimismo, por inducción de estrés en la madre (rata) gestante. Sin embargo, se han explotado poco para evaluar el insomnio y mejor aún, para ensayar fármacos que puedan beneficiar al paciente insomne. A pesar de contar con una gran variedad de medicamentos hipnóticos, en la actualidad no existe un hipnótico ideal. Los tratamientos más efectivos con los que contamos conllevan riesgos importantes de tolerancia, adicción y potencialmente efectos colaterales. Por ello, la búsqueda de nuevos fármacos con propiedades inductoras de sueño es inaplazable. Especialmente de fármacos que sean capaces de inducir las fases de sueño delta y sueño MOR sin causar sonambulismo, somnolencia residual y/o efectos negativos en la memoria. En este contexto se discute el potencial uso terapéutico de los endocanabinoides (eCBs), ya que son ansiolíticos e inductores de las fases profundas de sueño (delta y sueño MOR). Los eCBs son moléculas endógenas que tienen una actividad semejante a la de la mariguana. Esto es debido a que tanto la mariguana como los eCBs afectan a un mismo receptor, que es el receptor canabinoide 1 (CB1).

  Los eCBs tienen un potencial terapéutico que hasta ahora no se ha explotado en beneficio de los pacientes que sufren de insomnio y/o ansiedad. Por ello, en esta revisión se analiza el insomnio desde el punto de vista clínico, se detallan sus características para que el médico clínico no experto pueda reconocerlo y potencialmente tratarlo; también se persigue subrayar la influencia potencial del estrés en la fisiopatogénesis de este trastorno. A pesar de que hay cada vez más información acerca de la síntesis y degradación de los eCBs (lo que es muy importante porque estos mecanismos pueden ser afectados por fármacos que inhiban la degradación o la faciliten, dependiendo de las necesidades terapéuticas) no discutiremos estos temas que se vuelven más especializados. Sin embargo, es importante que se conozca y se discuta su posible uso para beneficio del paciente.

  Esta revisión se centra en discutir los potenciales beneficios causados por la activación del receptor CB1 en el paciente insomne para reducir su dolencia de mal dormir.

• English

  Sleep is a universal experience and a necessary ingredient to life. Young adult humans benefit from spending 8 h a day, every day, sleeping. While the function(s) of sleep is not completely understood, it is known that sleep is critical to the survival of the species. In humans, it restores alertness, helps consolidate memory and «recharge» cognitive abilities which are impaired at the end of the activity-phase of the cycle. Humans who do not pay their toll to sleep, for one night, for example, experience difficulties maintaining wakefulness the next day. This condition may put in danger their lives, particularly if they work in the transportation industry (i. e. taxi cabs, truck or trailers-drivers, pilots and/or operating heavy machinery among many other activities). In the past, when humans were more exposed to predators, to be sleepy in the savannah was synonymous with dying. Interestingly enough, the maladaptive strategies exhibited by a sleepy subject (which put at risk his life), are reversed by sleep. It is widely believed that sleep has a restorative function. However, what precisely is being restored during sleep remains a topic of speculation and on-going research. Sleep deprivation in humans results in cognitive deterioration and increased sleepiness, which might compromise survival as aforementioned. It is known that in rats prolonged sleep deprivation leads to death. In humans, it results in sleepiness, decreased attention, compromises memory and learning skills, and may affect motor control. The negative effects of sleep loss are reversed by recovery sleep, which may show features of delta and/or REM-sleep rebound. In this context, insomnia is a condition with known negative consequences to the health of the affected individual and frequently conveys negative effects to the family nucleus and to society in general. It has been estimated that 9% to 15% of the adult population suffers from chronic insomnia. Psychophysiologic insomnia (or primary insomnia) is likely the most prevalent type of insomnia. The patient with insomnia frequently develops an aversive response to sleep and to all aspects related to this activity. The manifestations of insomnia may include difficulty falling (and staying) asleep, frequent awakenings, early morning awakenings and/or un-refreshing quality of sleep. As a result, affected individuals frequently complain of daytime consequences such as decreased concentration, negative effects on memory (and learning), and daytime fatigue. They may also complain of headaches, fuzziness (or grogginess) and might experience manifestations of excessive sleepiness (which might represent a hazard when driving and/or operating machinery). Stress and anxiety frequently represent precipitating and/or perpetuating factors in the development of insomnia.

  In regards to stress, the role of the hypothalamus-pituitary-adrenal (HPA) axis in preserving homeostasis has been amply studied. The HPA axis involves the participation of peptides such as corticotropin-releasing hormone (CRH), corticotropin itself and cortisol. The autonomic nervous system activates the amygdaloid complex further enhancing the stress response. When patients are unable to control their stress response, the magnified response may be manifested as an anxiety disorder. According to the DSM-IV, the diagnosis of generalized anxiety disorder (GAD) is based on persistent symptoms of excessive anxiety and worry. Patients with GAD as well as those suffering from other anxiety disorders such as PTSD and panic attacks may manifest symptoms of insomnia. Several models of stress have been proposed to better understand these conditions. For example, prenatal stress has been suggested to increase vulnerability to life events and some reports have suggested impaired sleep among some of the animal models that have been studied. Specifically, it has been reported that rats who are deprived of maternal care suffer from dysregulation of the orexinergic system. Consequently, affected rats may have manifestations of sleep-wake dysregulation. There is more. Rats born to a low care maternal provider (which induces an early stress response) have been found to have methylated the gene that encodes the glucocorticoid receptors, which is reflected in a low expression of receptors. As a result, these animals release more corticosterone in response to stressful situations and are less efficient in managing stress. Furthermore, they have a lower expression of the CB1 receptor in several areas of the brain, thus suggesting that the systems responsible for reducing excitability of the brain (and consequently reducing the subjective sensation of fear and anxiety) are shattered.

  Models of insomnia evaluating the possible role of an inadequate stress-response have not been thoroughly studied. Potential pharmacologic interventions using such a theoretical framework have not been systematically studied and thus offer a venue for novel pharmacological interventions. The addition of new therapies would be particularly useful as the clinical management of patients with chronic insomnia remains a challenging area in medical practice. This despite the availability of multiple approved hypnotic medications in the physician's armamentarium. To date there is no hypnotic medication which can be considered ideal for the treatment of chronic insomnia. Issues of tolerance and dependence remain relevant concerns for those hypnotic medications, which are considered most effective in the treatment of this condition. Research identifying new compounds based on molecules whose physiologic action is to induce sleep may render safer, more efficient pharmacological interventions to treat insomnia. Following this line of thinking, we have tested the effects of endocannabinoids (eCBs). The eCBs represent a family of molecules, lipids in nature, which bind to the same receptors to which marijuana is known to bind. The active metabolite of marijuana (delta-9-tetrahydrocannabinol [THC]) is known to bind to the CB1 receptors and produce a series of effects including relaxation and sleep. Following the discovery of several eCBs by the research groups of Mechoulam and Lerner, we have tested anandamide and oleamide as sleep inducers. Results have indicated that both molecules and a third one, 2-arachidonyl glycerol, induce sleep (mainly REM sleep).

  In the present review insomnia is speculated to be a consequence of chronic stress. Several animal models of early stress are also discussed to better understand the role of stress in the causation of insomnia. The current limitations in the availability of ideal hypnotic medications prompt us to argue in favor of continued efforts to find additional, novel pharmacologic interventions to treat this condition. In this context, the potential use of endocannabinoid compounds is proposed as a possible new line of hypnotic medications. While eCBs have been used so far only in animal models, they have been amply successful in promoting the expression of non-REM and REM sleep. The endocannabinoid system has the potential to induce sleep and thus suggest that endocannabinoid agonists offer a new research venue for the exploration of novel pharmacologic interventions in the treatment of insomnia.