Transient receptor potential vanilloid 1 (TRPV1), a capsaicin receptor, and anoctamin 1 (ANO1, also called TMEM16A), a calcium–activated chloride channel, are major ion channels involved in pain sensation in the periph­eral nervous system. Pain–related behaviors dependent on each ion channel are reported­ly reduced in its deficient mice. We previously found that TRPV1 and ANO1 interact with each other upon making a physical complex, and the functional linkage exacerbates capsaicin–induced acute pain sensation. However, the significance of TRPV1 and ANO1 interaction in the inflammatory condition remains unknown. Activation thresholds of TRPV1 become low upon its phosphorylation. Here, we performed whole–cell patch–clamp recordings using phorbol 12–myristate 13–acetate, an activator of protein kinase C to phosphorylate TRPV1, mimicking the inflam­matory conditions in HEK293T cells express­ing mouse TRPV1 and mouse ANO1. We also showed that phosphorylated TRPV1 interacts with ANO1 with a low concentration of capsaicin or innocuous heat stimulation of approxi­mately 37°C. Furthermore, we performed immunoprecipitation to investigate whether TRPV1–ANO1 inter­action is enhanced by phosphorylation. However, the protein–protein interaction was not changed. Thus, ANO1 activa­tion could be enhanced by the acceleration of TRPV1 activity. These facts indicate that interactions between phosphorylated TRPV1 and ANO1 could explain inflammatory pain sensations, for instance, in heat allodynia. Therefore, our findings contribute to clarifying the new molecular mechanisms involved in pathological pain and development of analgesia.

Allodynia, pain induced by innocuous mechanical stimuli, is attributed to central nervous system dysfunction. We recently identified spinal dorsal horn (SDH) neuronal subsets that were captured by adeno–associated virus (AAV) vectors carrying a promoter of neuropeptide Y or prodynorphin (AAV–NpyP and –PdynP, respectively). Our previous studies demonstrated that both AAV–NpyP⁺ neuron inhibition and AAV–PdynP⁺ neuron excitation contribute to neuropathic allodynia–like behavior in rats. However, the potential interaction between these two subsets remains unknown. The present study employed tools that enable the optogenetic stimulation of touch–sensing Aβ fibers and neuronal subset–selective manipulations. Our findings revealed that the Aβ fiber–derived allodynia–like behavior in rats with AAV–NpyP⁺ neuron ablation was prevented by the simultaneous ablation of AAV–PdynP⁺ neurons. Furthermore, the removal of AAV–NpyP⁺ neurons allowed AAV–PdynP⁺ neurons to receive Aβ fiber–derived excitatory inputs. These results reveal an interaction between these subsets that are crucial for Aβ fiber–mediated allodynia.

Fatty acid–binding protein 3 (FABP3) is involved in intracellular lipid transport to cytosolic organelles. It also performs unique physiological functions, acting as a diagnostic or predictive biomarker for various diseases. We previously reported that hypothalamic FABP3 levels are upregulated under pain and that FABP3 is co–expressed in microglia. However, the specific roles of FABP3 in microglia remain unknown. Therefore, in this study, we aimed to assess the involvement of FABP3 in lipopolysaccharide (LPS)–induced increase in inflammatory cytokine levels and determine its effects on pain in mouse microglial MG6 cells and postoperative pain model mice. MG6 cells were treated with LPS to activate the cells and the cytoplasmic fraction was collected as a sample after 24 hours. FABP–IN–1 was used as a non–selective FABP inhibitor, and FABP3 small interfering RNA (siFABP3) was used for FABP3 knockdown. Changes in the expression of each gene were analyzed via real–time polymerase chain reaction. In MG6 cells, LPS (100 and 1000 ng/mL) significantly increased the tumor necrosis factor–α, interleukin–6, and FABP3 mRNA levels; however, FABP–IN–1 or siFABP3 significantly suppressed this effect. Furthermore, repeated intracerebroventricular injection of FABP–IN–1 suppressed pain behavior in the postoperative pain model mice. Overall, our results suggest that FABP3 is partly involved in the induction of inflammatory cytokine expression via microglial activation, thereby affecting the pain behavior in brain.

The aim of this study was to investigate the most important aspects of patient–reported outcome measures (PROMs) for pain assessment and their predictive value in treatment response. We analyzed 367 patients with acute–to–chronic pain (age: ≥ 20 years) who visited the pain clinic of a university hospital for the first time and responded to nine PROMs related to pain symptoms. Principal component analysis (PCA) was applied to the PROMs data, deriving principal components with their component scores (i.e., a composite scale). Data from 175 patients who completed the same PROMs three months after their initial visit were then analyzed. Multiple regression was used to examine whether these principal components, along with age, sex, and pain chronicity, could predict changes in pain intensity, as measured by a numerical rating scale (NRS) over three months. In addition, we stratified the patients based on pain chronicity and categorized pain as primary, neuropathic, or musculoskeletal. We also examined the relative risk associated with the principal components derived from PCA and other variables for clinically significant improvement in pain intensity, defined as a reduction of at least two points on the NRS. We identified four principal components (pain intensity, pain quality, disability, and cognition ⁄ affect for pain) for the clinical assessment of patients with pain. At the initial visit, pain intensity, pain–related cognition ⁄ affect, and pain chronicity were predictors of pain management difficulties. Pain quality was a specific predictor for primary and musculo­skeletal conditions. Our findings provide evidence for the use of PROMs in pain management.

Background: A therapeutic target for patients with chronic musculoskeletal pain is improvement in quality of life (QOL). However, factors associated with QOL are poorly understood.

Purpose: To explore factors affecting QOL among patients with chronic musculoskeletal pain.

Methods: This was a cross–sectional study. Participants were 166 patients that attended our hospital from April 2015 to March 2020. Data collected included participants’ age and scores on the Brief Pain Inventory (BPI), Pain Catastrophizing Scale, Pain Disability Assessment Scale (PDAS), Hospital Anxiety and Depression Scale, Pain Self–Efficacy Questionnaire (PSEQ), EuroQol Five Dimensions Questionnaire (EQ–5D), and Athens Insomnia Scale (AIS). Standardized (beta) regression coefficients showed significant associations between the independent variables (BPI, PDAS, PSEQ, and AIS scores) and the dependent variable (QOL measured using the EQ–5D). For the statistical analyses, we performed Shapiro–Wilk tests, descriptive statistics, paired t–tests, and multiple regression analysis with forward stepwise selection.

Results: The paired t–tests showed a significant difference between males and females only in PSEQ scores. Multiple regression analysis with forward stepwise selection yielded an R2 of 0.58.

Conclusions: We clarified that among patients with chronic musculoskeletal pain, QOL was closely related to pain levels, self–efficacy, pain disability, and sleep disorders.

The mechanism involved in conditioned pain modulation (CPM), a phenomenon wherein pain is controlled by heterotopic conditioning stimuli (CS), remains unclear in humans and involves a delicate balance between inhibition and excitation. The present study aimed to investigate the effect of intravenous administration of an α1–adrenoceptor agonist, phenylephrine (PE), and an α1–adrenoceptor antagonist, phentolamine (PT), on CPM in healthy humans. Two men and seven women (33.2 ± 2.7 years; mean ± standard error) participated in this double–blind randomized study. Three sequential sessions were performed in two groups: the PE and normal saline (NS, control) groups. The first (baseline ⁄ control) session involved NS infusion (PE_1st and N_1st). The second involved PE (1 mcg/kg/min, PE_2nd) or NS infusion. The third involved PT (10 mcg/kg/min, PE_3rd) or NS infusion. Painful electrical tooth stimulation was used as the test stimulus to assess somatosensory evoked potential amplitude (ampSEP) and tooth pain intensity measured with a visual analog scale (VASt). CO₂ laser stimulation was used for CS. The CPM inhibition rate was calculated as follows: [1–(ampSEP or VASt with CS) ⁄ (ampSEP or VASt without CS)] × 100 (%). One–way repeated analysis of variance and multi­ple comparisons were used for statistical analysis. In the PE_1st, PE_2nd, and PE_3rd sessions, the ampSEP inhibition rates were 42.8% ± 7.7%, 22.2% ± 9.4%, and 44.9% ± 8.9%, respectively (22.2 < 42.8; P = 0.028); the respective VASt inhibition rates were 26.0% ± 5.9%, 3.0% ± 9.0%, and 16.6% ± 3.4% (3.0 < 26.0; P = 0.046). Systemic admin­istration of PE inhibited CPM, which was restored to the baseline value by PT, suggesting the role of the noradrenergic pathways in mediating CPM.

Opioids are widely used for chronic pain; however, they often cause constipation, affecting the quality of life (QOL) and treatment satisfaction and lead to non–adherence to opioid treatment. We conducted a web–based questionnaire survey amongst Japanese patients (overall patients, n=294) with and without opioid induced constipation (OIC) receiving weak opioids for chronic non–cancer musculoskeletal pain to investigate the effect of OIC on QOL, pain, work productivity, and satisfaction with and adherence to analgesics. We compared the data from age– and sex–matched OIC (n=147) vs non–OIC (n=147) groups. In both groups, 97 (66.0%) patients were male and 143 (97.3%) were aged ≥40 years. Tramadol and acetaminophen combination was prescribed to 70.1% (OIC) vs 80.3% (non–OIC) patients. OIC group showed significantly lower QOL than non–OIC group with lower scores for physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotional and mental health (P<0.001). The pain Numerical Rating Scale score was significantly higher (P=0.001) in OIC vs non–OIC group. The overall work impairment (a compo­nent of work productivity–activity impairment) was significantly higher (P=0.032) in OIC group. Significantly high (P<0.001) proportion of patients with OIC (58%) reported difficulty in balancing the treatment effectiveness and side effects in overall patients. The low back pain subgroup had comparable results. Overall, patients with OIC receiving weak opioids for chronic non–cancer musculoskeletal pain including low back pain had significantly lower QOL with pain and activity impairments than those without OIC. Aggressive management of OIC might be useful for improving the QOL and pain.

UMIN registration number: UMIN000050413

Background: While severe complications after cervical selective nerve root block (CSNRB) with an anterolateral approach have been reported, CSNRB via a posterolateral approach (PL–CSNRB) could reduce inadvertent intravascular injections. Because fluoroscopy–guided PL–CSNRB is technically difficult, PL–CSNRBs are often CT– or ultrasound–guided. CT guidance is safe but time–consuming and has a higher risk of radiation exposure. Ultrasound guidance can visualize the vessels but whether it reduces intravascular injections remains debatable.

Purpose: This study described CSNRB using a fluoroscopy–guided posterolateral oblique technique (PLO–CSNRB) and assessed its clinical usefulness.

Methods: A total of 707 PLO–CSNRBs were performed on 260 patients (186 cervical diseases and 74 cervical zoster–associated pain; CZAP) between May 2016 and December 2020. Under fluoroscopy guidance, a needle was inserted posterolaterally and kept in contact with the articular pillar and advanced toward the exit of the intervertebral foramen (C3–C8). A block was considered successful if the intervertebral foramen was filled with contrast (foraminal filling; FF).

Results: The success rate was 94.5% (668/707). The main contrast pattern observed with FF was periradiculography (619) followed by transforaminal epidurography (233). Venography was observed in 135 (19.1%) injections with 52 (38.5%) simultaneously observed with FF. Contrast in the radicular and vertebral arteries was respectively observed in 4 and 2 injections, which disappeared after needle reposition. The effective rates were 83.9% and 55.1% for cervical diseases and CZAP, respectively. No serious complications were noted.

Conclusions: PLO–CSNRB is a useful technique that ensures safe needle advancement to the nerve root at the exit of the intervertebral foramen.

Recently, multifunctional roles of Tmem120A ⁄ TACAN in mechanotransduction and mechanical pain hyper­sensitivity have been suggested. Here, we examined the mRNA expression of the molecule in the skeletal muscle and dorsal root ganglia (DRG) using two muscle pain models induced by exercise and myositis. The hind limb muscles of rats were subjected to either lengthening contractions (LC) or carragee­nan injection. The muscles and DRGs were sampled and analyzed using real–time RT–PCR to examine the mRNA expression profiles of Tmem120A. Tmem120A mRNA in muscles increased 6–48 h after LC and 12 h after carrageenan injection. Tmem120B, a paralog of Tmem120A, was upregulated in the muscles of the myositis model, but not in the exercise–induced muscle pain model. Neither Tmem120A nor Tmem120B mRNA level was altered in the DRG of the two muscle pain models. These results indicate that upregulations of Tmem120A ⁄ TACAN and Tmem120B play a role in muscles after inflammation and/or exercise.

Cytokines play important roles not only in immune, but also in pain control systems. Since mice lacking interleukin (IL)–27 displayed pain hypersensitivities, we investigated the role of IL–27 in pain due to hip osteoarthritis in this clinical study. Twenty–one female patients with hip osteoarthritis (a mean age of 65.4 years) were enrolled. The levels of serum IL–27 at admission for surgery were evaluated and compared with the score of painDETECT (PD) questionnaire based on self–assessment of neuropathic pain, as well as the pain numeric rating scale (NRS) completed by all patients. The serum IL–27 levels significantly correlated with the NRS pain scores (R=–0.467, P=0.033), but not with the PD scores. These results indicate that serum IL–27 may control pain in osteoarthritis. Since serum IL–27 levels were not significantly affected by the type of pain, nociceptive or neuropathic, serum IL–27 may be a potential biomarker for chronic pain due to locomotor disorders.