We have firstly demonstrated that LPA1 receptor signaling initiates the neuropathic pain and underlying mechanisms including dorsal root (DR) demyelination and up–regulation of Ca_vα2δ1 in dorsal root ganglion (DRG), which are supposedly related to allodynia and hyperalgesia, respectively. Since this report, we have accumulated the findings supporting this discovery. They are the findings that LPA is produced in the spinal dorsal root upon the partial ligation of sciatic nerves of mice, the LPA production is self–amplified through activations of LPA1 ⁄ 3 receptors and microglia. Thus produced LPA may go back to DR and DRG and cause abnormal pain behavior. All these mechanisms may develop the feed–forward amplification of abnormal pain mechanisms, or pain memory. On the analogy of this neuropathic pain, we tested the involvement of LPA1 receptor signaling in experimental fibromyalgia–like mouse models, such as intermittent psychological stress (IPS)–, intermittent cold stress– and repeated intramuscular injection of acid saline–induced models. The deficiency of LPA1 receptor completely lost the hyperalgesia in all these models. The repeated treatments with LPA1 antagonist AM966 completely cured the established pain in the IPS model. All these findings demonstrate that LPA1 signaling plays key roles in the development and maintenance of chronic pain.

Exercise therapy is recommended in the management of patients with chronic pain. However, there is little evidence supporting a relationship between changes in pain or physical disability and changes in physical performance by exercise therapy. Thus, exercise is thought to be involved it directly in the improvement of pain. Exercise has been shown to reduce the peripheral pain sensitivity in healthy subject. This effect, known as exercise–induced hypoalgesia (EIH), may be induced by the activation of central pain modulation systems. However, the effects of acute exercise in chronic pain conditions are heterogeneous and adverse. In patients with chronic pain, for example, exercise seems to decrease pain threshold. Notably, acute exercise followed by physical fatigue induces hyperalgesia. Therefore, regular exercise, rather than acute exercise, is recommended, in the management of patient with chronic pain.

Physical inactivity is a perpetuating factor which can cause pain to become chronic. We investigated the relationship between intensity of physical activity in daily life and the function of central pain inhibitory systems. Our results suggested that the function of central pain inhibitory systems may decrease with a low amount of physical activity in women; therefore, maintaining physical activity may be more important for women than for men in preventing chronic pain.

The effects and mechanisms of pain inhibition through regular exercise have been suggested using the animal model of pain. According to one of these suggested mechanisms, regular exercise increases the release of met–enkephalin in the rostral ventromedial medulla (RVM) and uses opioid receptors centrally to mediate analgesia. We investigated the influences on central pain inhibitory systems by regular exercise in subjects with chronic pain. While regular exercise for 2 weeks carried out three times a week improved the central pain modulation systems, it was ineffective if only done twice a week. However, an effect was seen if twice–weekly exercise continued for 3 weeks. Therefore, we conclude that increasing physical activity in daily life by regular exercise may be important in prevention and management of chronic pain.

A stratified approach for low back pain (LBP) involves targeted treatment for subgroups of patients classified according to their key characteristics such as prognostic psychological factors. This approach tailors therapeutic decisions in ways that maximize treatment benefit and reduce medical care costs. A stratified approach was known as the “Holy Grail” in back pain research over a decade ago.

Psychological factors strongly influence the chronicity of LBP. Evidence suggests that fear avoidance beliefs are prognostic for poor outcomes in subacute LBP. Thus, early treatment, including interventions aimed to reduce fear avoidance beliefs, may prevent delayed recovery and chronicity.

A recent development in the stratified approach is to use brief risk prediction tools such as the short–form Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) and the Keele STarT Back Screening Tool (SBST). These tools identify patients with an increased likelihood of delayed recovery, and facilitate intervention for these patients from day 1, rather than waiting for failure of the first–line care. These tools can also help clinicians to better understand the reasons for a potentially poor prognosis and to choose interventions accordingly. Both of these screening tools focus on assessment of key psychological factors such as fear avoidance beliefs.

Somatic symptom burden is used to evaluate the severity and course of illness. Co–existence of various somatic symptoms including multisite pain may be the core feature of central dysfunctional pain. The 8–item Somatic Symptom Scale (SSS–8) was recently developed as a brief, patient–reported measure of somatic symptom burden. We believe this tool to be useful for screening for functional somatic syndrome including chronic widespread pain.

Chronic pain affects many people and decreases their physical or emotional functioning and their quality of life, and impairs their ability to work. Psychological factors such as depression and less activities lead to chronicity of pain, and multidimensional treatments including psychotherapy for chronic pain patients are required. Cognitive behavioral therapy (CBT) is one of the psychotherapy treatments, and is required positive attitude that patients objectively monitor one’s own emotion, sensation, and social environments and that they continuously modify these maladaptive behavior and cognition, rather than negative attitude. By using acquired skills, they can learn to be able to control their symptoms by themselves. Many meta–analyses show that CBT is more useful for pain experiences, mental health, and social functioning than only drug medication. We have also developed a CBT program for patients with chronic pain since 2011 and have confirmed the improvement of subjective pain perception, depression, anxiety, and QOL after CBT. In this manuscript, we report the concrete program. Furthermore, clinical effects of our program were variable, and lastly, psychosocial or neuroscientific considerations were given to make this program more effective in the near future.

Irritable bowel syndrome (IBS) is the disease in which abdominal pain and related bowel movements such as diarrhea and constipation persist. IBS is classified in chronic primary pain as well as fibromyalgia and non–specific low back pain. Psychological intervention is important in the treatment of refractory IBS. In particular, cognitive behavioral therapy (CBT) which is a kind of psychotherapy has attracted attention recently. We have developed a Japanese version of the cognitive behavioral therapy protocol for IBS which called CBT–IE and have been practicing on IBS patients. When conducting CBT for patients with chronic pain, including IBS, it is important not to target the disappearance of symptoms, but to aim for improving the quality of life.

In Japan, cervical cancer tends to develop at a younger age. Cervical cancer screening rate in Japanese females is extremely low among developed countries. Therefore, HPV vaccine was expected to prevent cervical cancer effectively in Japan. An urgent promotion project for HPV vaccination was initiated by the Ministry of Health, Labour and Welfare (MHLW) in 2010. From April 2013, periodical vaccination of 12 to 16–year–old was initiated. However, so–called serious adverse events upon HPV vaccinations was repeated­ly reported in the media and the MHLW announced suspension of the recommendation of HPV vaccination in June 2013. Consequently, the inoculation rate has sharply declined, and a unprotected group against HPV will result in higher incidences of HPV infection and cervical cancer. It is necessary for us to face the increased risk of HPV infection and cervical cancer for girls who have refrained from HPV vaccination.

Fibromyalgia (FM) is characterized by chronic widespread pain with mecha­nical allodynia and hyperalgesia. However, the neural mechanisms of nociception and pain are largely unknown. The aim of this study was to examine the responsiveness of peripheral nociceptive afferents and super­ficial dorsal horn (SDH) neurons by using a manifest rat model of FM, that was induced by reserpine (RES) injection. Repeated administration of RES (1 mg/kg, s.c., once daily for three consecutive days) caused a significant decrease in the mechanical withdrawal threshold of the plantar skin. Single–fiber electrophysiological recordings in vitro revealed that mechanical responses of mechano–responsive C–fibers were increased, although the proportion of mechano–responsive C–nociceptors was paradoxically de­creased. Next, we performed in vivo extracellular recordings of the SDH neurons. Although the SDH neurons showed mechanical stimulus intensity–dependent increases in the discharge rate both in the vehicle (VEH) and the RES–injected group, the response magnitude was significantly greater in the RES–injected group. Some SDH neurons in the RES–injected rats exhibited spontaneous firing with low frequencies, although those in the VEH–injected rats did not. These results suggest that increased mechanical sensitivity of the mechano–responsive C–fibers and the SDH neurons are involved in mechanical allodynia and hyperalgesia in a rat model of RES–induced pain. Similar mechanisms may underlie in patients with FM.