Neuropathic pain, a debilitating chronic pain condition, is a common consequence of damage to the nervous system that can be induced by cancer, diabetes mellitus, infection, autoimmune diseases, or traumatic injury. The underlying mechanisms remain unclear, and currently available treatments are frequently ineffective. Thus, effective treatment of neuropathic pain is a major clinical challenge. A growing body of evidence indicates that peripheral nerve injury (PNI) converts spinal microglia into reactive cells that are required for the development and maintenance of neuropathic pain. Therefore,to identify pain molecules in spinal glial cells would advance our understanding of the pathogenesis of neuropathic pain and would provide a new target for treating this pain. Results of our laboratory have demonstrated that following PNI, P2X4 receptors (P2X4Rs) are upregulated in spinal microglia and are necessary for neuropathic pain. We have further found the upregulation of the transcription factor interferon regulatory factor 8 (IRF8) in microglia after PNI. IRF8–knockout mice exhibited reductions in upregulation of genes associated with the activated processes of microglia, including P2X4R, and in PNI–induced tactile allodynia. Our study has recently identified IRF5 as a target of IRF8 and as being required for upregulation of P2X4R expression through its binding to the promoter region of the P2rx4 gene. These results provide a new mechanism for neuropathic pain and its therapeutic targets.

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   Voxel–based morphometry (VBM) is a morphological brain imaging method. VBM can statistically detect morphological changes of the brain and measure gray matter volume. VBM is utilized not only for evaluation of changes in the brain from normal aging, but also for brain diseases such as schizophrenia or dementia. In this study, morphological changes in the brain were examined using VBM, and pain assessment was conducted using PDAS (Pain Disability Assessment Scale), PCS (Pain Catastrophizing Scale), HADS (Hospital Anxiety and Depression Scale), and NRS (Numerical Rating Scale), involving 23 patients with chronic low back pain, with the aim of clarifying correlation between such changes and the scores from each scale. VBM was performed using BAAD (brain anatomical analysis using DERTEL) software. The results showed a statistically significant difference between right and left gray matter volume of amygdala.Right amygdala showed a decrease in gray matter volume more so than left amygdala. Gray matter volume of amygdala was not correlated with PCS, HADS, or NRS scores. Correlation coefficients between gray matter volume of amygdala and PDAS scores were 0.40 (p=0.06). These results suggest that there may be an association between structural changes of amygdala and PDAS scores. It is said that amygdala is associated with negative emotions, such as that which occurs with chronic pain, and dysfunction of amygdala influences chronic pain as expression of pain behavior. Examining changes in gray matter of the brain using VBM and simultaneously evaluating the scale of pain may be one method of a multifaceted approach to pain.

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   Aroma–oil compounds derived from plants have a variety of clinical effects including local anesthesia. We have previously reported that various aroma–oil compounds reduce the peak amplitudes of fast–conducting and Na⁺–channel blocker tetrodotoxin–sensitive compound action potentials (CAPs) recorded from the frog sciatic nerve in a manner dependent on their chemical structures. The present study further examined this structure–activity relationship by applying the air–gap method to the frog sciatic nerve. Cyclic alcohols ((+)–borneol, (–)–borneol, α–terpineol), chain alcohols ((–)–linalool, citronellol, geraniol) and esters (bornyl acetate, geranyl acetate) reduced CAP peak amplitudes with the half–maximal inhibitory concentration (IC₅₀) values of 1.5 mM, 2.3 mM, 2.7 mM, 2.0 mM, 0.35 mM, 0.53 mM, 0.44 mM and 0.51 mM, respectively. This IC₅₀ value for (–)–linalool was similar to that for (±)–linalool (1.7 mM), a value as reported previously. On the other hand, hydrocarbon (p–cymene) at a high concentration such as 2 mM reduced CAP amplitude by only 20%. The efficacy sequence of the aroma–oil compounds was esters ≧ alcohols ＞ hydrocarbons, and was thus consistent with one reported previously, i.e., phenols ≧ aldehydes ≧ esters ＞ alcohols ＞ ketones ＞ oxides ≫ hydrocarbons. There was a variation in IC₅₀ value among the alcohols used; chain alcohols were more effective in inhibiting CAPs than cyclic ones. Similar IC₅₀ values of (–)–linalool and (±)–linalool and also of (+)–borneol and (–)–borneol indicate no difference in efficacy between the steroisomers in inhibiting CAPs. There was no correlation between IC₅₀ value for CAP inhibition by aroma–oil compound and its octanol–water partition coefficient value. The present study confirmed that aroma–oil compounds inhibit nerve conduction in a manner specific to their chemical structures.

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   Several studies have demonstrated that perceived body image of pain region is distorted in patients with complex regional pain syndrome (CRPS), chronic non–specific lower back pain and phantom limb pain. Moreover, perceived body image was associated with abnormal pain sensation in patients with these conditions. However, it is not well known whether patients with chronic non–specific neck pain (CNSNP) have symptoms and distorted perceived body image like chronic non–specific lower back pain. The purpose of the present study was to examine based on body image drawings whether two point discrimination (TPD) and selected clinical findings are different in subgroups of individuals with CNSNP.
   Twenty patients with CNSNP and healthy volunteers were assessed through perceived body image, TPD. CNSNP patients were also assessed through clinical profiles (pain intensity, pain catastrophizing, and fear avoidance beliefs). Perceived body image of neck was assessed by drawing their own outline of neck as they feel in their mind.
   Of patients with CNSNP, 50% reported that they had distorted body image and significantly different to control group. This result suggested that pathological condition of CNSNP was associated with cortical dysfunction as well as CRPS, chronic non–specific lower back pain and phantom limb pain. In the secondary analysis, we divided patients with CNSNP into two groups by the presence or absence of distorted body image (normal image; NI group, distorted image; DI group) and compared TPD threshold and clinical symptoms in three group (NI , DI and control group). TPD threshold of NI–pain side and DI–pain side were significantly higher than control. All other clinical symptoms were not significantly different in three groups. We couldn’t find the factor that was specifically associated with distorted body image of patients with CNSNP in the present study. Further study is needed to elucidate the clinical factors associated with perceived body image.

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   Chronic neuroinflammation mediated by activated immune cells is important for the pathogenesis of neuropathic pain. Increasing evidence suggests that matrix metalloproteases (MMPs), which are proteases for degradation of extracellular matrix, may involve in neuroinflammation through induction of cytokines and chemokines. In this study, we focused on the function of MMP12 in peripheral nerve injury–induced neuropathic pain. Neuropathic pain model mice were produced by partial sciatic nerve ligation (PSL). After PSL, the gene expression of MMP12 was increased in the injured sciatic nerve (SCN). By immunohistochemistry, MMP12 protein was also up–regulated and localized on infiltrating macrophages in the injured SCN after PSL. By fluorescent dye, DiI, for labeling peripheral blood vessels, angiogenesis and vascularization were observed in the injured SCN, and DiI leaked into the surrounding tissue, indicating the enhancement of vascular permeability. Macrophages accumulated around DiI labeled peripher al vessels in the injured site of SCN after PSL. To determine the source of MMP12, EGFP⁺ chimeric mice were produced by bone marrow transplantation (BMT). After BMT, EGFP⁺ cells migrated around the SCN after PSL, but not in BMT–subjected sham. Moreover, MMP12 was localized on EGFP⁺ cells. Furthermore, the perineural injection of MMP408 (10 ng ⁄ 10 µl), MMP12 specific inhibitor, suppressed PSL–induced thermal hyper algesia and tactile allodynia, which were evaluated by Hargreaves test and von Frey test, respectively. These results suggest that MMP12, which was produced by bone marrow derived macrophages, acts as an exacerbating factor of neuropathic pain. Taken together, MMP12 may be a novel molecule for the treatment of neuropathic pain.

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   Background: In a previous study, we revealed that repetitive transcranial magnetic stimulation (rTMS)using figure-8 shaped coil could relieve neuropathic pain (NP) less effectively in the lower extremities than the upper ones. We speculated that it depended on the depth of the targeted primary cortex (M1).Deep rTMS is a novel development that can stimulate deep neuronal regions effectively, termed the H-coil. In this study, we compared the clinical effects for NP patients in their lower extremities between rTMS with H-coil, rTMS with figure-8 shaped coil and sham stimulation.
   Methods: This was a randomized, double-blind, three-way crossover trial.12 NP patients in their lower extremities received three types of stimulations for 5 consecutive days with 17 days follow-up. In each rTMS session, 5-Hz rTMS to M1 corresponding to the painful lower extremity was administered. Outcome measures were visual analogue scale (VAS) and Japanese version of the short form of the McGill pain questionnaire 2 (SF-MPQ2).
   Results: H-coil rTMS, compared with the sham, showed significant pain improvement soon and one hour after rTMS in VAS (p<0.001). On the other hand, pain improvement after rTMS with figure-8 shaped coil was not significant in VAS. Both types of rTMS didn't show significant pain improvement in SF-MPQ2.No serious adverse events were observed.
   Conclusions: Our findings demonstrated that rTMS with H-coil could be tolerable and provide modest pain relief in NP patients in their lower extremities.

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