Nerve growth factor (NGF) was found as a trophic factor that is essential for survival and differentiation of primary sensory neurons of neural crest origin and sympathetic neuron. Essential role of NGF in development of nociceptors was confirmed by observation of patients with congenital change in NGF receptor (TrkA) gene. These patients (Congenital Insensitivity to Pain with Anhidrosis, CIPA) can sense neither pain, nor warmth ⁄ coolness and itch. In addition, they do not sweat. In adulthood, NGF is not needed for survival of nociceptive neurons, but play a pivotal role in pain in pathological condition. In this review we introduce involvement of NGF in painful conditions in inflammation and after nerve injury, and visceral painful conditions such as ulcerative colitis, Crohn disease, and so on. In some cancers, cancer cells themselves produce NGF and induce very painful condition, especially painful condition is bone metastasis that is difficult to treat. In addition in animal models for chronic regional pain syndrome type I and in fibromyalgia involvement of NGF in pain has been suggested. It is hoped these painful conditions are treated by antagonizing NGF action.

We experienced a case in which stimulating the central side of the lesion successfully induced an extensive paresthesia at and below the spinal lesion, despite the severe sensory impairment in the same area. A woman in her 50s had a spinal tumor at T5–8 that was removed about 30 years ago. She had residual pain in both her lower extremities and the right side of the chest accompanied by a severe sensory disturbance below the T5 level, which were resistant to medication. She finally opted for an SCS to treat her neuropathic pain. During the stimulation trial, we placed a percutaneous cylindrical lead at the midline in the epidural space at C7–T2 through a puncture at T2–3. Tonic stimulation at T1–2 induced paresthesia at both sides in the axilla, trunk, and lower extremities, which has led to an improvement in the pain score from 10 to 7 (numerical rating scale; NRS). During the definitive implantation, we placed two cylindrical leads at the midline at C6–T2. With the same parameters as the trial stimulation, her pain score improved to 5 in NRS, which has led to an overall improvement of her quality of life, psychological conditions, and activity of daily living. Despite the severely damaged spinal sensory pathways and the broadly distributed pain area, it was possible to induce paresthesia and to achieve pain relief by stimulating the midline of the dorsal spinal cord and intact sensory pathways above the level of the spinal lesion.

Neurorehabilitation is one of rehabilitation techniques to elicit neural plastic changes in the central nervous system. The concept of neurorehabilitation is being applied to patients with chronic pain. The present review firstly explained about neural plasticity, and then mentioned phantom limb pain as a topic to explain how experts of rehabilitation conduct neurorehabilitation. Phantom–limb pain (PLP) is commonly classified as neuropathic pain following amputation, brachial plexus avulsion injury or spinal cord injury, and is often resistant to pharmacotherapy and traditional rehabilitation techniques. Patients suffering from PLP commonly experience a phantom limb that is paralyzed or fixed in one or more particular positions. Recent quantitative studies revealed that PLP patients commonly exhibit impaired voluntary movement in their phantom hand. Thus, neurorehabilitation techniques such as the mirror visual feedback method have been conducted in clinical practice to restore phantom limb movement. In the present review, we explained neurorehabilitation techniques using virtual reality system for phantom limb movement and pain. Additionally, we introduced neurorehabilitation using transcutaneous electrical nerve stimulation (TENS) to alleviate PLP.

Previous epidemiological surveys for chronic pain noted that the most prevalent location of the pain is lower back. It is known that in the chronic low back pain patients, the quality of life, especially mental health, is poor. In addition, the group in which a discrepancy arose between disability and severity of low back pain found some associated factors, such as feeling stress, less satisfaction of their job and relationship with coworkers. Social and psychological factors are involved in the pathogenesis of chronic low back pain, therefore, evaluating the condition of chronic low back pain patients should be conducted from various directions and is not a simple task.

In recent years, analysis of brain activity which is associated with chronicity of pain has been focused on. In addition, brain imaging techniques as a non–invasive tool have developed and play an active role for pain research using functional magnetic resonance imaging (fMRI), MR spectroscopy (MRS), etc. MR spectroscopy (MRS) is used for evaluating metabolites in the chosen brain area. After performing MRI, relative or absolute concentrations of metabolites in the brain are measured. One of the metabolites is N–acetyl aspartate (NAA), which is an amino acid specifically localized in neurons, using as a marker of neuronal function.

Comparison between chronic low back pain (CLBP) patients and healthy control subjects was performed using MRS. The relationship between patients’ social and psychia­tric background and metabolites in the anterior cingulate cortex (ACC) were evaluated. In the CLBP patients, the NAA level was lower, whereas glutamate + glutamine ⁄ creatine (Glx ⁄ Cr) and Glx ⁄ myoinositol (Ins) ratios were higher in the ACC compared with the control subjects. In addition, the Ins level was found to have a negative correlation with depression and anxiety using the questionnaire of Hospital Anxiety and Depression Scale (HADS), but no correlation with severity of pain was found. These results suggested that myoinositol, as a marker of glial cells, is found in low level in those with depression and anxiety. In contrast, evaluation of MRS in the chronic pain patients without psycho–social background has been reported. Brain metabolites were compared between the lumbar spinal disease patients with unilateral pain and the healthy control subjects. The NAA ⁄ Cr and NAA ⁄ choline ratios in the thalamus for the lumbar spinal disease patients were significantly lower compared with the control patients, and have a negative correlation with severity of pain. These results suggested that NAA might be useful for evaluation of presence ⁄ degree of pain objectively. Some chronic low back pain patients have brain disorders, and the causal relationship between brain function and chronic pain has not been clarified in cross–sectional studies, therefore this fact should be kept in mind when evaluating brain imaging for interaction between brain function and chronic pain.

Non–coding RNAs, including microRNA and lncRNA, affect various cellular functions primarily by regulating diverse stages of gene expression, such as transcription, translation, and epigenetic modulation. In recent years, it has been shown that many non–coding RNAs are dysregulated in pain disorders and can be a potential therapeutic target. Intriguingly, a part of non–coding RNAs are encapsulated in extracellular vesicles and are abundantly released into the extracellular space. These extracellular non–coding RNAs can be taken up by nearby or even distant cells and exert their own functions, indicating that they act as important mediators of cell–cell communication. In fact, some extracellular microRNAs have been shown to cause hyperalgesia by acting nearby neurons and immune cells. In addition, extracellular non–coding RNAs in blood and cerebrospinal fluid are expected as a biomarker for various purposes, such as diagnosis, drug responsiveness prediction and prognosis, in pain disorders. In this review, we summarize current insights into the significance of extracellular non–coding RNA in pain disorders and their treatment.

Damage to peripheral sensory nerves causes plastic changes in the circuits of the central nervous system (CNS), leading to the reorganization of the neural circuits. As a result, the body map, which is the body part information of the brain, is reorganized. It has also been proposed that such a phenomenon is the pathological basis of ectopic chronic pain including phantom limb pain and CRPS. However, most of the mechanism of neural circuit remodeling that accompanies the reconstruction of the body site map in CNS is still unclear. In this review, we describe the mechanism of the reorganization of neural circuits and body map in the mouse thalamus after the nerve injury.