Activation of Mitogen-Activated Protein Kinase in Descending Pain Modulatory System

The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) influence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identification of novel targets for a variety of pain syndromes

Establishment and Evaluation of a New Chemiluminescent Enzyme Immunoassay for Carcinoembryonic Antigen Adapted to the Fully Automated ACCESS® System

Peer Reviewe

A new aspect of chronic pain as a lifestyle-related disease

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic intractable pain. We investigated the underlying mechanisms of exercise-induced hypoalgesia (EIH) using a mouse model of neuropathic pain (NPP). Epigenetic changes in activated microglia and maintained GABA synthesis in the spinal dorsal horn may contribute to EIH. Voluntary exercise (VE), a strong reward for animals, also induced EIH, which may be due in part to the activation of dopamine (DA) neurons in the ventral tegmental area (VTA). VE increases the expression of pCREB in dopaminergic neurons in the VTA, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. We demonstrated that neurons in the laterodorsal tegmental and pedunculopontine tegmental nuclei, a major input source of rewarding stimuli to the VTA, were activated by exercise.Chronic pain is at least partly attributed to sedentary and inactive lifestyle as indicated by the Fear-avoidance model. Therefore, chronic pain could be recognized as a lifestyle-related disease. Physical activity/inactivity may be determined by genetic/epigenetic and neural factors encoded in our brain. The hypothalamus and reward system is closely related in the axis of food intake, energy metabolism and physical activity. Understanding the interactions between the mesolimbic DA system and the hypothalamus that sense and regulate energy balance is thus of significant importance. For example, proopiomelanocortin neurons and melanocortin 4 receptors may play a role in connecting these two systems. Therefore, in a certain sense, chronic pain and obesity may share common behavioral and neural pathology, i.e. physical inactivity, as a result of inactivation of the mesolimbic DA system. Exercise and increasing physical activity in daily life may be important in treating and preventing chronic pain, a life-style related disease. Keywords: Exercise-induced hypoalgesia, Chronic pain, Ventral tegmental area, Dopamine, Laterodorsal tegmental nucleus, Physical activity/inactivit

Exercise therapy for chronic pain: How does exercise change the limbic brain function?

We are exposed to various external and internal threats which might hurt us. The role of taking flexible and appropriate actions against threats is played by “the limbic system” and at the heart of it there is the ventral tegmental area and nucleus accumbens (brain reward system). Pain-related fear causes excessive excitation of amygdala, which in turn causes the suppression of medial prefrontal cortex, leading to chronification of pain.Since the limbic system of chronic pain patients is functionally impaired, they are maladaptive to their situations, unable to take goal-directed behavior and are easily caught by fear-avoidance thinking.We describe the neural mechanisms how exercise activates the brain reward system and enables chronic pain patients to take goal-directed behavior and overcome fear-avoidance thinking. A key to getting out from chronic pain state is to take advantage of the behavioral switching function of the basal nucleus of amygdala. We show that exercise activates positive neurons in this nucleus which project to the nucleus accumbens and promote reward behavior.We also describe fear conditioning and extinction are affected by exercise. In chronic pain patients, the fear response to pain is enhanced and the extinction of fear memories is impaired, so it is difficult to get out of “fear-avoidance thinking”. Prolonged avoidance of movement and physical inactivity exacerbate pain and have detrimental effects on the musculoskeletal and cardiovascular systems.Based on the recent findings on multiple bran networks, we propose a well-balanced exercise prescription considering the adherence and pacing of exercise practice. We conclude that therapies targeting the mesocortico-limbic system, such as exercise therapy and cognitive behavioral therapy, may become promising tools in the fight against chronic pain

Brain Mechanisms of Exercise-Induced Hypoalgesia: To Find a Way Out from “Fear-Avoidance Belief”

It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain