Author: Théophile Niyitegeka

{In sleep-deprived mice, caffeine and other drugs to promote wakefulness ease pain better than analgesics}

New research from Boston Children’s Hospital and Beth Israel Deaconess Medical Center (BIDMC) shows that chronic sleep loss increases pain sensitivity. It suggests that chronic pain sufferers can get relief by getting more sleep, or, short of that, taking medications to promote wakefulness such as caffeine. Both approaches performed better than standard analgesics in a rigorous study in mice, described in the May 8, 2017 issue of Nature Medicine.

Pain physiologist Alban Latremoliere, PhD, of Boston Children’s and sleep physiologist Chloe Alexandre, PhD, of BIDMC precisely measured the effects of acute or chronic sleep loss on sleepiness and sensitivity to both painful and non-painful stimuli. They then tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil. Their findings reveal an unexpected role for alertness in setting pain sensitivity.

{{Keeping mice awake, through custom entertainment}}

The team started by measuring normal sleep cycles, using tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. “For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is,” says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children’s.

Next, unlike other sleep studies that force mice to stay awake walking treadmills or falling from platforms, Alexandre, Latremoliere and colleagues deprived mice of sleep in a way that mimics what happens with people: They entertained them.

“We developed a protocol to chronically sleep-deprive mice in a non-stressful manner, by providing them with toys and activities at the time they were supposed to go to sleep, thereby extending the wake period,” says Alexandre, who works in the lab of Thomas Scammell, MD, at BIDMC. “This is similar to what most of us do when we stay awake a little bit too much watching late-night TV each weekday.”

To keep the mice awake, researchers kept vigil, providing the mice with custom-made toys as interest flagged while being careful not to overstimulate them. “Mice love nesting, so when they started to get sleepy (as seen by their EEG/EMG pattern) we would give them nesting materials like a wipe or cotton ball,” says Latremoliere. “Rodents also like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball.”

In this way, they kept groups of six to 12 mice awake for as long as 12 hours in one session, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren’t stressed) and testing for pain along the way.

Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin (the agent in hot chili peppers) and then measuring how long it took the animal to move away (or lick away the discomfort caused by capsaicin). The researchers also tested responses to non-painful stimuli, such as jumping when startled by a sudden loud sound.

“We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in otherwise healthy mice,” says Alexandre. “The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli.”

{{Analgesics vs. wake-promoting agents}}

Surprisingly, common analgesics like ibuprofen did not block sleep-loss-induced pain hypersensitivity. Even morphine lost most of its efficacy in sleep-deprived mice. These observations suggest that patients using these drugs for pain relief might have to increase their dose to compensate for lost efficacy due to sleep loss, thereby increasing their risk for side effects.

In contrast, both caffeine and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss. Interestingly, in non-sleep-deprived mice, these compounds had no analgesic properties.

“This represents a new kind of analgesic that hadn’t been considered before, one that depends on the biological state of the animal,” says Woolf, director of the Kirby Center at Boston Children’s. “Such drugs could help disrupt the chronic pain cycle, in which pain disrupts sleep, which then promotes pain, which further disrupts sleep.”

{{A new approach to chronic pain?}}

The researchers conclude that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or sleep-promoting medications at night, coupled with daytime alertness-promoting agents to try to break the pain cycle. Some painkillers already include caffeine as an ingredient, although its mechanism of action isn’t yet known. Both caffeine and modafinil boost dopamine circuits in the brain, so that may provide a clue.

“This work was supported by a novel NIH program that required a pain scientist to join a non-pain scientist to tackle a completely new area of research,” notes Scammel, professor of neurology at BIDMC. “This cross-disciplinary collaboration enabled our labs to discover unsuspected links between sleep and pain with actionable clinical implications for improving pain management.”

“Many patients with chronic pain suffer from poor sleep and daytime fatigue, and some pain medications themselves can contribute to these co-morbidities,” notes Kiran Maski, MD, a specialist in sleep disorders at Boston Children’s. “This study suggests a novel approach to pain management that would be relatively easy to implement in clinical care. Clinical research is needed to understand what sleep duration is required and to test the efficacy of wake-promoting medications in chronic pain patients.”

Source:Science Daily

{When treating depression, the goal is to help individuals achieve full recovery and normal functioning. While traditional treatment such as medication or psychotherapy is effective for many patients, some may not fully recover even with these treatments. Researchers sought to determine if the addition of hatha yoga would improve treatment outcomes for these patients. They found that the benefits of yoga were less pronounced early in treatment, but may accumulate over time.}

The research, entitled “Adjunctive yoga v. health education for persistent major depression: a randomized controlled trial,” has been published in Psychological Medicine. The research was led by Lisa Uebelacker, PhD, a research psychologist in the Psychosocial Research Department at Butler Hospital, a Care New England hospital, and an associate professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University. The team also included Gary Epstein-Lubow, MD; Ana M. Abrantes, PhD; Audrey Tyrka, MD, PhD; Brandon A. Gaudiano, PhD; and Ivan W. Miller III, PhD, of Butler Hospital and the Warren Alpert Medical School; Geoffrey Tremont, PhD and Tanya Tran of Rhode Island Hospital and the Warren Alpert Medical School; Tom Gillette of Eyes of the World Yoga; and David Strong of the University of California, San Diego.

“The purpose of this study was to examine whether hatha yoga is effective for treating depression when used in addition to antidepressant medication,” explained Dr. Uebelacker. “We did not see statistically significant differences between hatha yoga and a control group (health education) at 10 weeks, however, when we examined outcomes over a period of time including the three and six months after yoga classes ended, we found yoga was superior to health education in alleviating depression symptoms.”

According to Dr. Uebelacker, this is the largest study of yoga for depression to date. The team enrolled individuals with current or recent major depression who were receiving antidepressant medication and continued to have clinically significant depression symptoms. Participants were randomized into two groups — those who participated in a hatha yoga class and a control group who took part in a health education class. The intervention phase lasted 10 weeks and participants were followed for six months afterward.

“We hypothesized that yoga participants would show lower depression severity over time as assessed by the Quick Inventory of Depression Symptomatology (QIDS), as well as better social and role functioning, better general health perceptions and physical functioning, and less physical pain relative to the control group,” said Dr. Uebelacker. “We found that yoga did indeed have an impact on depression symptoms.”

Source:Science Daily

{Researchers restore the memory performance of Methuselah mice to a juvenile stage}

Memory performance decreases with increasing age. Cannabis can reverse these ageing processes in the brain. This was shown in mice by scientists at the University of Bonn with their colleagues at The Hebrew University of Jerusalem (Israel). Old animals were able to regress to the state of two-month-old mice with a prolonged low-dose treatment with a cannabis active ingredient. This opens up new options, for instance, when it comes to treating dementia. The results are now presented in the journal Nature Medicine.

Like any other organ, our brain ages. As a result, cognitive ability also decreases with increasing age. This can be noticed, for instance, in that it becomes more difficult to learn new things or devote attention to several things at the same time. This process is normal, but can also promote dementia. Researchers have long been looking for ways to slow down or even reverse this process.

Scientists at the University of Bonn and The Hebrew University of Jerusalem (Israel) have now achieved this in mice. These animals have a relatively short life expectancy in nature and display pronounced cognitive deficits even at twelve months of age. The researchers administered a small quantity of THC, the active ingredient in the hemp plant (cannabis), to mice aged two, twelve and 18 months over a period of four weeks.

Afterwards, they tested learning capacity and memory performance in the animals — including, for instance, orientation skills and the recognition of other mice. Mice who were only given a placebo displayed natural age-dependent learning and memory losses. In contrast, the cognitive functions of the animals treated with cannabis were just as good as the two-month-old control animals. “The treatment completely reversed the loss of performance in the old animals,” reported Prof. Andreas Zimmer from the Institute of Molecular Psychiatry at the University of Bonn and member of the Cluster of Excellence ImmunoSensation.

Years of meticulous research

This treatment success is the result of years of meticulous research. First of all, the scientists discovered that the brain ages much faster when mice do not possess any functional receptors for THC. These cannabinoid 1 (CB1) receptors are proteins to which the substances dock and thus trigger a signal chain. CB1 is also the reason for the intoxicating effect of THC in cannabis products, such as hashish or marihuana, which accumulate at the receptor. THC imitates the effect of cannabinoids produced naturally in the body, which fulfil important functions in the brain. “With increasing age, the quantity of the cannabinoids naturally formed in the brain reduces,” says Prof. Zimmer. “When the activity of the cannabinoid system declines, we find rapid ageing in the brain.”

To discover precisely what effect the THC treatment has in old mice, the researchers examined the brain tissue and gene activity of the treated mice. The findings were surprising: the molecular signature no longer corresponded to that of old animals, but was instead very similar to that of young animals. The number of links between the nerve cells in the brain also increased again, which is an important prerequisite for learning ability. “It looked as though the THC treatment turned back the molecular clock,” says Zimmer.

{{Next step: clinical trial on humans}}

A low dose of the administered THC was chosen so that there was no intoxicating effect in the mice. Cannabis products are already permitted as medications, for instance as pain relief. As a next step, the researchers want to conduct a clinical trial to investigate whether THC also reverses ageing processes in the brain in humans and can increase cognitive ability.

The North Rhine-Westphalia science minister Svenja Schulze appeared thrilled by the study: “The promotion of knowledge-led research is indispensable, as it is the breeding ground for all matters relating to application. Although there is a long path from mice to humans, I feel extremely positive about the prospect that THC could be used to treat dementia, for instance.”

Source:Science Daily