What is your goal?

Nobody likes pain. However, "pain" plays an important role in warning that some part of our body is becoming ill or damaged (physiological role as a body warning system; Figure 1). If you did not dislike pain, you might not visit a hospital, thereby allowing the disease to worsen, or repeat the same mistake which caused the pain. As such, while pain is an important function to protect our bodies, pain that persists for a long duration even after fulfilling the role as a warning is known to significantly decrease our quality of life (QOL), in addition to becoming a trigger for mental disorders such as depression and anxiety disorders (Figure 1). In our laboratory, we are studying the mechanism by which "pain" causes negative emotions including dysphoria, anxiety, depression, and fear in the brain. In previous studies, we have demonstrated that during pain, the release of noradrenaline, which is a neurotransmitter, increases in the extended part of the amygdala in the brain, leading to negative emotions such as dysphoria and anxiety (Figure 2).

Figure 1. Physiological role of affects as a body warning system and inducement of mental disorders due to chronicity thereof

Figure 2. Enhanced release of noradrenalin in the peripheral part of the amygdala induces distaste/anxiety associated with pain

 Emotions such as dysphoria, anxiety, depression, and fear occur not only due to pain but also due to various stresses. It is believed that mental disorders such as depression and anxiety disorders are caused by the accumulation of negative emotions due to these stresses. At our laboratory, we aim to elucidate the mechanisms in the brain causing negative emotions including dysphoria, anxiety, depression, and fear due to pain and stress, and make use of the research results in improving QOL due to chronic pain or preventing and curing mental diseases such as depression and anxiety disorders. We are pursuing our research with the prospect of new medicinal drugs to be developed for the treatment of depression and anxiety disorders based on the brain mechanisms that we discovered.

 

What kind of equipment do you use and what kind of experiments do you conduct?

Unlike humans, experimental animals such as rats and mice do not express their feelings of "dysphoria" or "anxiety" in words. In order to understand the emotional changes of experimental animals, we adopt a method of "behavioral analyses." For example, in the analysis method of "conditioned place aversion test" as shown in Figure 3, on Day 1, the partition between the black room and the white room is opened and the animals are allowed to freely explore the two rooms, while the time spent in each room (black and white) is measured. On Day 2, drugs causing pain are injected into the sole of the foot and animals are confined to one room (the white room in Figure 3) by closing the partition. Animals develop a dislike of the white room, to which they were confined while suffering from pain in the foot and an unpleasant feeling, so on Day 3, when they were once again allowed to explore the two rooms freely, the time spent in the white room decreased compared with Day 1 (Figure 3, right panel). The degree of dysphoria that experimental animals experienced is evaluated by examining the length of the decrease in the time spent in the room paired with pain stimulation. Our research revealed that by injecting drugs that inhibit the function of noradrenalin in the extended part of the amygdala, dysphoria induced by pain decreases, leading to no decrease in the time spent in the room where pain is experienced even after pain stimulation.

On the other hand, in "elevated plus maze test" using the equipment shown in the left image of Figure 4, a plus-shaped maze consisting of a pathway with walls and a pathway without walls is created at a level considered high for rats and mice. When experimental animals are anxious, they spend more time on the pathway with walls, while when they are less anxious, they spend more time on the pathway without walls. During the experiment, the behavior of the animals was recorded through video camera connected with a computer, which automatically analyzes the walking trace of the experimental animals. The two images on the right of Figure 4 are images of the equipment taken from right above, overlaid by the walking trace in yellow lines. For example, by injecting drugs that activate the noradrenalin receptors in animals normally demonstrating the walking trace shown in the upper right image, the time spent on the pathway without walls significantly decreases, as in the lower right image, indicating that the animal became anxious.

The study of elucidating body systems by combining "behavioral analysis" and "drug administration" in this manner is referred to as "behavioral pharmacology."

Figure 3. Evaluation of dysphoria upon conditioned place aversion test.

Figure 4. Evaluation of anxiety upon elevated plus maze test.