The importance of perioperative management has been emphasized in recent years so that patients who go through surgeries may return to their normal life as quickly as possible. In achieving this objective, pain management plays a key role in that alleviating pain in the earliest possible timing not only provides favorable effects both physically and psychologically but may also contribute toward preventing development of chronic postsurgical pains (CPSPs). While the actual risk of developing CPSP is comprised of a complex mixture of various factors before, during and after surgeries, 70％ of such pains are considered to be predictable based on clinical factors. In order to prevent the development of CPSP, then, finding high–risk patients from among those who are to go under surgeries and providing them with pre–surgery patient education as well as continuous postsurgical pain management and care by interdisciplinary teams should be helpful. The authors look forward to seeing more postsurgical pain management teams with anesthesiologists as their pivotal members to be formed in Japan.

The central amygdala (CeA), especially the capsular part (CeC), receives nociceptive information from the superficial layer of the spinal dorsal horn and the caudal subnucleus of the trigeminal nucleus via the lateral parabrachial nucleus (LPB). The synapse between LPB and CeC neurons, forming the final stage of this spino–(trigemino–)parabrachio–amygdaloid pathway, undergoes robust synaptic potentiation in various types of rodent pain models, thus contributing to the enhanced nociception–emotion link in persistent pain. A remarkable feature of the CeA activation in animals with inflammatory pain is the right–side predominance. Using a trigeminal pain model by injecting formalin to the upper lip unilaterally, we analyzed the right–left differences in LPB–CeC synaptic potentiation and c–Fos expression in the LPB and the amygdala to reveal what determines the right–predomi­nance in CeA activation. Unilateral trigeminal inflammation induced 1) a significant bilateral increase in c–Fos–expression in the LPB, 2) a right–predominant LPB–CeC synaptic potentiation and 3) a right–predominant increase in c–Fos–expression in the CeA, regardless of the side of the inflammation. Though c–Fos expression in the basolateral amygdala (BLA) was not significantly increased in this model, the number of c–Fos positive cells between the BLA and CeA was correlated compared to that between the LPB and CeA. Therefore, the right–side predominance of the CeA activation in the inflammatory pain models would not be a simple consequence of lateralized LPB activation but rather involves non–Hebbian plasticity inherent to the CeA neurons and inputs they receive.

Pain experience is strongly affected by emotions, and especially, negative emotions cause more painful perception. And as mechanisms of linking to chronic pain, negative emotions are also important factors. We have been gradually studying the association between negative emotions and painful perception, and we will review these relationship by using clinical symptoms and neuroimaging data.

Our studies have been approved by the Hiroshima University ethics committee.

Although it is well known that pain varies from patient to patient, tailor–made medicine for patients in pain has not yet been realized. Anesthesiologists often encounter patients whose pain persists after surgery, even though could be managed before the operation. It can be difficult to alleviate such prolonged pain a generic. In the future, to respond to pain in individual patients, it will be necessary to analyze pain–related signals that reflect not only the findings captured in conventional images and examinations, but also the physiological state, genetic background, and the state of the disease in patients. We have been searching for pain–related signals through basic research. Our functional MRI studies showed that the pain pathway was activated if analgesics were not administered under general anesthesia during surgery. This induced epigenomic modification in the spinal cord and brain, which was speculated to lead to prolonged pain as well as secondary emotional and sleep disorders. We also found that cytokine storms caused by surgery were the source of prolonged pain. Furthermore, in microRNA (miRNA) studies, early peripheral neuropathy significantly increased the expression of several miRNAs caused by inflam­matory cytokines in the dorsal root ganglia. This led to concomitant increases in the expression of inflammation–derived exosomal miRNAs in the blood. We believe these findings will provide new information for next–generation pain treatment. In the future, “stratify” pain patients, it will be necessary to collect informa­tion from procedures such as liquid biopsies. Individual and common para­meters can be created based on mathematical analysis, data compression, and clustering analysis. Based on this information, we will create highly limited and diverse animal models of by individually introducing pain parameter–induced genes, and study pathological analysis and treatment methods. If such translational pain research becomes possible, tailor–made medicine for pain will become closer to reality.

Patients with spinal cord injury suffered from not only motor paralysis but also intolerable neuropathic pain. Regarding the mechanism, various theories such as functional changes in the brain, disorders within the spinal dorsal horn and/or spinothalamic tract have been proposed. However, the feasible animal models with solid reproducibility has been insufficiently verified. We have established the mice fMRI system, reported the results of mice–fMRI after L5 nerve injury and resting state–fMRI imaging after thoracic cord transection injury in mice. Furthermore, in a clinical setting we evaluated the brain morphometry of the cases with spinal intra­medullary tumor surgery by VBM, and found the gray matter volume of some brain regions was increased related with pain intensity. Besides fMRI and VBM analysis, we developed diffusion MRI techniques which could depict neuronal axons and myelination within the spinal cord (“diffusion tensor tractgraphy” and “myelin map”, respectively). In this review, I would like to outline our results of MRI analysis of neuropathic pain so far.

Functional magnetic resonance imaging (fMRI) is expected as a biomarker of pain because it can objectively evaluate changes in cerebral blood flow associated with neuron activity against pain. We have developed pain models for cynomolgus macaques because it is more compatible with humans in regard to the structures and functions of brain regions which is suggested to be involved in pain in humans. Aside from humans, the cynomolgus macaques are the most widespread primate genus, ranging from Japan to North Africa. Since the macaques are the animal species closest to humans among those which can be used for invasive experiments, they are widely used to understand the mechanisms of the human brain. The purpose of this study is to elucidate pain–related brain activation regions in the macaque models using fMRI. Generally, pain testing in animal models has been based on avoidance behavior against pain stimuli. However, we identified pain–related brain activation regions using fMRI under propofol anesthesia as a more objective evaluation method. In the macaque model of chymopapain–induced discogenic low back pain, the activity of the insular cortex occurred in response to lumbar compression stimulation. In the macaque model of oxaliplatin–induced neuropathic cold hypersensitivity, activation of the insular cortex also occurred in response to cold stimuli. As a result of evaluating pregabalin, duloxetine and tramadol, only duloxetine showed behavioral effectiveness and suppressed activation of the insular cortex due to oxaliplatin–induced neuropathic pain. In the macaque model of postoperative pain, activation of the insula cortex was mainly activated by pressure stimulation. As a result of evaluating morphine, pregabalin and diclofenac, only morphine showed behavioral effectiveness and suppressed activa­tion of the insular cortex due to postoperative pain. However, macaques with naturally occurring endometriosis exhibited a pain response against pressure stimuli to the abdomen, and had activation of the thalamus. As a result of evaluating morphine, meloxicam and acetaminophen, only morphine showed behavioral effectiveness and suppressed activation of thalamus due to abdominal pain from endometriosis. It was suggested that the brain activation regions could change due to various conditions that can cause the pain, as the acute pain increased activation in the insula cortex and the chronic pain increased activation in the thalamus. This study demonstrated the usefulness of fMRI as a pain biomarker, and fMRI analysis using the macaques might provide an advantage for the translation of the findings to human patients. Therefore, these study will contribute to the development of new analgesics for each pain as well as to the progress in the areas of brain research.