The review was performed to investigate the functional brain alterations in patients with various kinds of chronic pain including fibromyalgia, chronic low back pain, migraine and the other chronic pain conditions. In these patients functional connectivity was different not only in the sensory–motor system but also in the affective and reward system. New technology have allowed us to identify and understand the neural mechanisms contributing to chronic pain, which provides us novel targets for future research and treatment.

Knee pain is a major source of disability in patients with knee osteoarthritis (OA). Although the mechanism of OA progression has been well documented, pain pathophysiology is largely unknown. Recent accumulating clinical evidence indicates that subchondral bone marrow lesions (BMLs) detected on MRI in knee OA are strongly associated with intense pain. In this review we describes bone pain in knee osteoarthritis clarified by our basic and clinical studies.

In basic studies, we clarified nociceptive phenotype alterations of subchondral bone afferents of the distal femur in mono–iodoacetate (MIA)–induced OA rats. Two different retrograde tracers were separately injected into the knee joint cavity and the subchondral bone to identify synovium and subchondral bone afferents. OA caused an up–regulation of calcitonin gene–related peptide (CGRP) and tyrosine receptor kinase A (TrkA) in both synovium and subchondral bone afferents. CGRP and TrkA expression in subchondral bone afferents gradually increased over 6 weeks. Furthermore, up–regulation of CGRP and TrkA in subchondral bone afferents displayed a strong correlation with the subchondral bone damage score. Up–regulation of CGRP and TrkA in subchondral bone afferents correlated with subchondral bone damage, suggesting that subchondral bone is a therapeutic target, especially in the case of advanced stage knee OA.

In clinical studies, we clarified the association of subchondral BMLs with pain in medial compartment knee osteoarthritis. Total BMLs size were significantly correlated with walking pain (Spearman’s r=0.59, p<0.01). As a result of the multi regression analysis, subchondral BMLs became a factor of walking knee pain in the case of advanced stage knee OA (Regression coefficient = 0.75, p<0.01). Subchondral BMLs are potentially therapeutic targets to treat pain associated with subchondral bone in knee osteoarthritis.

In conclusion, subchondral bone, in itself, is a therapeutic target, especially in the case of advanced stage knee OA. In particular, BMLs are potentially therapeutic targets to treat joint pain associated with the subchondral bone in OA.

We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain–like behavior in ovariectomized (OVX)mice. In addition,we have shown that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment caused by osteoclast activation under a high bone turnover state. We, therefore, hypothesize that another osteoporosis model mouse might reveal the induction of pain–like behaviors in relation with osteoporotic changes. In this study, we demonstrated that regional osteoporosis of hind limbs induced pain–like behaviors using tailsuspended mice as another osteoporosis model.

The hind limbs of tail–suspended mice were unloaded for 2 weeks, during which time the mice revealed significant regional osteoporotic changes in their hind limbs accompanied by osteoclast activation. In addition, these changes were significantly recovered by the resumption of weight bearing on the hind limbs for 4 weeks. Consistent with the pathological changes in the hind limbs, pain–like behaviors in the mice were induced by tail suspension and recovered by the resumption of weight bearing. Moreover, treatment with bisphosphonate significantly prevented the triggering of the regional osteoporosis and pain–like behaviors, and antagonists of the acid–sensing nociceptors, such as transient receptor potential channel vanilloid subfamily member 1 and acid–sensing ion channels, significantly improved the painlike behaviors in the tail–suspended mice.

We, therefore, believe that pathologic changes of osteoporosis due to osteo clast activation might be a trigger for the pain–like behaviors in osteoporosis patients.

Bone is a supporting tissue consisting of a variety of bone cells (osteo blasts,osteoclasts, osteocytes), calcified bone matrix, blood vessels, nerves and so forth. Bone diseases — osteoporosis, bone fracture, arthritis, bone metastasis — often induce bone pain, presumably due to various kinds of nociceptors linked to the signaling in sensory nerves. Nociceptive pain in bone is caused by several stimuli of acid secreted by osteoclasts, physiochemical damaging on peripheral nerves, ATPs, prostaglandins, and so forth. However, precious knowledge on the biological function of bone cells may provide a clue for better understanding on the cellular mechanism of bone pain. In a physiological state, normal bone is always remodeled by balanced osteoclastic bone resorption and subsequent osteoblastic bone formation. Osteocytes connect to neighboring osteocytes and to osteoblasts on the bone surface by means of thin cytoplasmic processes that go through narrow passageways. i.e., osteocytic canaliculi, and thereby building functional syncytia referred to as osteocytic lacunar–canalicular system. Thus, osteocytes are at the center of bone turnover’s mainframe. In this review, we will introduce histological and ultrastructural aspects of bone cells, and give a rough outline of bone pain.

Pain derived from musculoskeletal disorders play a major role in the health profile of the general population. Especially osteoporotic state itself can generate pain, called osteoporotic pain. One mechanism for that pain includes increased expression of an inflammatory pain–related biomarker, calcitonin gene–related peptide (CGRP), in the dorsal root ganglia (DRG) innervating osteo porotic vertebrae in ovariectomized (OVX) rats, that induces susceptibility to pain. Also the involve ment of neuropathic pain was revealed using a mechan ically compressed coccygeal vertebrae model in OVX rats to evaluate the effect of longitudinal gravity, which contains a factor of mechanical injury induced by the compression axial stress itself. These findings demonstrate that the osteoporotic state itself can generate pain under conditions susceptible to compression stress of axial loading in addition to the neural alteration in sensory innervation. Osteoporosis treatment predominantly aims to increase the bone mineral density (BMD)of patients in order to prevent possible fragile fractures, that sometimes leads to a critical condition or result in a poor quality of life. In addition to the enhancement in BMD, some basic researches have shown the evidences of pharmacological or non–pharmacological treatment strategies to relieve the osteoporotic pain. Physicians should always keep these matters in mind in treating osteoporotic pain patients.

Objective. Although central poststroke pain (CPSP)might be understood as a network reorganization disorder that leads to a maladaptive central state, the mechanisms of CPSP are poorly understood. In this study, we investigated key structures to develop CPSP using voxel–based lesion mapping.

Methods. Subjects were 98 CPSP patients with three–dimensional T1 weighted images (mean age, 61.4 ± 8.8 years; thalamic lesion, n=45; putaminal lesion, n=41; brainstem lesion, n=9; cortical ⁄ subcortical lesion, n=3). The stroke lesion was segmented as a three–dimensional volume on MR images. These volumes of interest were spatially normalized, and group voxel–based analyses were performed with SPM12 to detect an overlap of the lesions.

Results. The overlaps of the stroke lesion were localized in the two structures, the putamen and thalamus. The overlap in the putamen extended in an anteroposterior direction, and its peak was located at the most posterior part of the putamen. The damage of the posterior limb of the internal capsule has been thought to cause CPSP up to now, however the finding from this study suggested that the insular cortex, secondary somatosensory area, and neural connections toward these regions could be involved in development of CPSP. The peak of the thalamic lesion was located at the border of the ventral posterior nucleus and pulvinar. The posterior ventral medial nucleus of the thalamus, which was a proposed relay point for thermosensory and nociceptive fibers, could be also involved in development of CPSP.

Conclusions. This study suggested that the specific lesions in the thalamus or putamen could develop CPSP, and the damage of the thalamic insular pathway was one of the key structure to develop CPSP.

Voluntary wheel running (VWR) is a strong natural reward for the rodents, and also can attenuate pain behaviors in model animals of neuropathic pain (NPP) (exercise–induced hypoalgesia: EIH). On the other hand, it has been known that activation of the mesolimbic reward pathway contributes to suppression of tonic pain. Therefore we hypothesized that activation of the mesolimbic reward pathway by VWR may play a role in producing EIH. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of VWR on dopaminergic neurons in the lateral region of anterior ventral tegmental area (lVTA) that is one of the key reward regions in the brain. PSL–Runner mice freely traveled on the running wheel during 15 days after PSL surgeries, while PSL–Sedentary mice were kept in the cage with the locked running wheel. Although in PSL–Runner mice, PSL surgery dramatically reduced the running distance at 1 day post–surgery, these levels returned to nearly pre–surgical level at 15 days post–surgery. Withdrawal thresholds of von Frey test and latencies of plantar test in PSL–Runner mice were significantly higher than those in PSL–Sedentary mice from 5 days to 15 days after the surgery. In addition, a significant positive–correlation was observed between the assessment of pain behavioral tests and total running distances in PSL–Runner mice. In immunohistochemical analysis, PSL–Sedentary mice showed a marked decrease of tyrosine hydroxylase (TH) immuno reactivities in the lVTA of the contralateral side compared with the ipsilateral side of the surgery, but VWR prevented such a decrease. In addition, the reduced number of phosphorylated cyclic AMP response element–binding protein (pCREB)⁺ ⁄ TH⁺ (dopaminergic) neurons in the lVTA of PSL–Sedentary mice was significantly restored by VWR in PSL– Runner mice. Furthermore, we found a significant positive–correlation between the assessment of pain behavioral tests and the number of pCREB⁺ ⁄ TH⁺ neurons in the lVTA in PSL–Runner mice. The present study showed that VWR increases the expression of pCREB in the dopaminergic neurons in the lVTA of PSL mice, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. Therefore, we conclude that EIH may be achieved, at least in part, by activation of the mesolimbic reward pathway via VWR.