Long non–coding RNAs (lncRNAs), which are generally defined as non–coding RNAs that are longer than 200 nucleotides, have recently emerged as an important regulator of pain. Most lncRNAs exhibit tissue– or even cell type–specific expression, and a large number of lncRNAs are preferentially expressed in the nervous system, suggesting their importance in neurological functions. Accordingly, expression changes of lncRNAs in the somatosensory nervous system have been reported in various pain disorders. lncRNAs affect various gene expression processes, including epigenetic regulation and transcription, through interaction with DNA, RNA and protein at several subcellular compartments. Dysregulation of lncRNAs significantly impacts pain perception by affecting mechanisms relevant to pain, including neuronal excitability and neuroinflammation. Intriguingly, lncRNAs are released into the extracellular space with encapsulated in extracellular vesicles, such as exosome. The extracellular lncRNAs may have a role in regulating nociceptive signaling through intercellular communication, as with other non–coding RNAs such as microRNAs. In addition, extracellular lncRNAs that entered the bloodstream have great potential as diagnostic biomarkers for pain disorders. In this review, we summarize current insights into potential applications of lncRNAs as an analgesic target and a biomarker in pain disorders.

This study aimed to investigate the relationship between women’s health issues (WHI) and pain symptoms among Japanese female workers, influencing health–related quality of life (HRQOL) and work productivity. A population–based cross–sectional online survey targeting Japanese female workers aged 20–69 years was conducted in July 2023. A total of 3,564 participants with 2,999 valid responses were recorded. The prevalence of pain was 49.8%, with comorbidity rate of 29.9% for pain and WHI. The key risk factors included menstrual–related symptoms, menopausal symptoms, and pelvic floor disorders. The number of pain sites was greater in women experiencing both pain and WHI than in those experiencing pain alone. Women with menstrual, menopausal, and pelvic floor disorders reported more severe pain in multiple areas of the body, along with elevated levels of occupational stress, reduced HRQOL, increased psychological distress, and markedly higher levels of presenteeism than those with pain alone. Overall, this study highlights the coexistence of WHI, such as menstrual, menopausal, and pelvic floor disorders, with pain in female workers, which potentially exacerbates pain severity, lowers HRQOL, and negatively impacts work productivity. Therefore, addressing the WHI in female workers experiencing pain is crucial for alleviating the symptoms, enhancing HRQOL, and improving workplace productivity.

We experienced a case in which treatment with traditional Chinese herbal and acupuncture successfully reduced pain and increased the quality of life. A woman in her 90s had a herpes-zoster 7 years ago, and developed chronic postherpetic neuralgia (PHN). She underwent nerve block therapies several times, but they were ineffective. When we started to treat, she was taking a low dose of pregabalin. Her pain score of visual analogue scale (VAS) was 100 mm. We evaluated the effect of our treatment by VAS score and SF-8 acute version for 6 months. We treated her with keishikajutsubuto extract granules, a frequently used remedy for neuralgia aggravated by cold. Acupuncture treatment was executed once a week. The VAS score dropped to 17 mm and the intense pain that struck her several times a day was drastically reduced after 6 months treatment. Physical function-and mental health-related parameters from the SF-8 analysis were also improved. Despite a very elderly woman with many comorbidities and refractory PHN seven years after the onset of the disease, it was possible to reduce her pain and improve her quality of life by the addition of oriental medicine such as Chinese herbal medicine and acupuncture, while continuing conventional western medical treatment.

Central sensitization (CS) is defined as an increased responsiveness of nociceptive stimuli caused in the central nervous system (CNS), and is widely used to explain hypersensitivity, pain to non–noxious stimuli (allodynia), and expanded painful area. CS is assessed by the dynamic quantitative sensory testing including temporal summation, off–set analgesia, and conditioned pain modulation. Aftersensation, which is a painful sensation remained after noxious stimuli cease, is also useful to diagnose the CS, as people with chronic pain report significantly longer aftersensation. A previous brain imaging study identified a global brain disruption associated with pain intensity in people with chronic pain. Furthermore, the mesocorticolimbic pathway, amygdala, and hippocampus were associated with predisposition of transition to chronic pain. These findings indicate a multiple–hit theory to explain a mechanism of chronic pain. Given that pain management program recovered amygdala and hippocampal volumes, treatment of the brain plasticity should be a therapeutic target in chronic pain.

Relationship between chronic pain and cortical activity was shortly reviewed. Change in cortical neural activity in patients with chronic pain has been reported in many previous papers. Those previous reports showed characteristics finding of basic rhythm, such as increment of theta activity, depending on the degree of pain and the pathological condition in patients with peripheral and central chronic pain syndrome. Recent studies, including our studies, suggested quantitative analysis of cortical neural activity, such as current density, frequency distribution, and connectivity between pain–related cortical areas, could evaluate subjective chronic pain. Connectivity analysis also suggested chronic pain might induce modulation of large scale network including default mode network, which resulted in modification of sensory and motor cognition and psychological responses in daily life of patients.

Cluster analysis can classify patients with chronic pain using multiple scales, and classification of chronic pain will be adopted in the International Classification of Diseases 11th revision (ICD–11) in 2022. In the present study, we aimed to investigate whether cluster analysis was practical for classifying chronic pain and to determine the association between these two classifications for chronic pain. This study included 229 patients with chronic pain who completed a self–reported questionnaire at the first visit to a pain clinic in a university hospital. Patients were clustered using a two–step cluster analysis (TSCA), a machine learning method, for the scores of nine questionnaires. Thereafter, the proportions of clusters among major and several minor classifications were tested using the analysis of covariance adjusted for age and doctor. The following three clusters were calculated using TSCA: mild, moderate, and severe symptoms. Among the major classifications of chronic pain in ICD–11, the distribution of clusters significantly differed, but the proportions of these three clusters in each chronic pain classification did not differ. Our findings suggested that TSCA for multiple measures may be a better approach for the classification of chronic pain, but its classification is not associated with the classification of chronic pain in ICD–11.

Physical inactivity or sedentary lifestyle is recognized as a risk factor for many diseases including cardiovascular disease, diabetes, cancer, depression, dementia and chronic pain, whereas physical exercise such as running, swimming and cycling is approved as an effective non–pharmacological intervention to improve pain. Many clinical and animal studies demonstrated that physical exercise sig­nificantly improves pain–related behaviors such as mechanical allodynia and heat hyperalgesia (exercise–induced hypoalgesia: EIH). Furthermore, multiple events including marked alterations in cytokines, neurotrophins, neurotransmitters and endogenous opioids in injured peripheral nerves, dorsal root ganglia, spinal dorsal horns and the brainstem following physical exercise have been proposed as potential mechanisms of EIH effects. On the other hand, neuroimaging analysis in chronic pain patients demonstrated that dysfunction of the mesocortico–limbic system including the ventral tegmental area (VTA), amygdala (Amyg), hippocampus (Hipp), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) plays critical roles in the development and maintenance of chronic pain, which provided an important clue to elucidate novel mechanisms underlying EIH effects. Voluntary exercise (VE) in neuropathic pain (NPP) model mice significantly improved pain behaviors of these mice, and significant positive–correlation was observed between their total running distances and pain thresholds, suggesting that the increase of physical activity enhances analgesic levels. VE in NPP model mice significantly activated dopamine neurons in the lateral VTA, GABA neurons in the NAc lateral shell, glutamate (Glu) neurons in the medial basal Amyg and the deep layers of mPFC, whereas GABA neurons in the central nucleus of Amyg, Glu neurons in the lateral basal Amyg and GABA neurons in the superficial layers of mPFC were inhibited by VE. These changes may promote functional restoration of the mesocortico–limbic system leading to hypoalgesia and euphoria. Thus, the present review has shed light on the role of mesocortico–limbic system in the mechanisms underlying the EIH effects.

Objective: The goal of treating chronic pain is becoming more focused on improving ADL and QOL than on pain itself. In this study, we evaluated patients with central post–stroke pain (CPSP) by a multifaceted evaluation and examined factors related to ADL and QOL.

Microglia are parenchymal tissue–resident macrophage within the central nervous system (CNS) and originate from erythromyeloid precursor cells in the yolk sac. A growing body of evidence suggests that microglia engage in CNS development, homeostasis and diseases, including chronic pain. Peripheral nerve injury and inflammation produce persistent pain hypersensitivity via CNS sensitization, in which activated microglia have critical roles. Activation of microglia occurs at both spinal and supraspinal levels after nerve injury and inflammation; however, their spatial distribution in the intact tissue remains poorly understood. Recently, tissue clearing methods and high–resolution imaging techniques have been greatly advanced, and these techniques will improve our understanding of pain mechanisms. Therefore, we attempted to clarify the three–dimensional localization of microglia in the intact CNS after peripheral inflammation by analyzing the reporter mouse line Iba–1 (iCre/+); CAG–floxed STOP tdTomato with CUBIC (Clear, Unobstructed Brain ⁄ Body Imaging Cocktails and Computational analysis). In this review, we focus on recent advances in understanding of microglial activation under pathological pain conditions.