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Background and Purpose: Psychological factors including fear of pain, re-injury during movement (kinesiophbia) affect return-to-sport rates after anterior cruciate ligament (ACL) reconstructive surgery. Clinicians often encounter in the daily practice that athletes explain lack of self-confidence or psychological readiness during the sports activity. The Tampa Scale for Kinesiophobia (TSK) has been used to evaluate psychological outcomes in patients with ACL injuries in many countries and translated into Japanese version in 2013. However, no researchers validated its reliability, validity, and responsiveness of TSK for patients with ACL injury up to now. The purpose of this study was to evaluate the measurement properties of the Japanese version of the TSK (TSK-J) in patients with ACL injuries., Study Design: Cohort study (Diagnostic); Level of evidence, 2., Methods: This prospective study was performed in the department of orthopaedic surgery at the university hospital of Juntendo from Sep 2016 and Apr 2017. Patients who diagnosed with ACL injury with or without reconstruction surgery completed several patient-reported outcome measures (PROMs) were included in this study. The COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines were used to evaluate reliability, validity, responsiveness, and interpretability of the TSK-J., Results: 222 patients were included in this study. The TSK-J for ACL injured patients showed good internal consistency (Cronbach's alpha = 0.79) and excellent test-retest reliability (intra-class correlation coefficient, ICC 2,1  = 0.90, 95% CI = 0.81 to 0.95). In addtion, the TSK-J was significantly but moderately correlated with the IKDC-SKF (r = - 0.49, P <0.001), VAS-Sports (r = - 0.48, P <0.001), and JACL-25 (r = 0.48, P <0.001). The effect size (ES) was small with the Cohen's d = - 0.2. The minimal important difference (MID) was - 1.3 points. No significant TSK-J score change was observed over 1-year after ACL reconstruction (r = - 0.12, P <0.001). There were no floor or ceiling effects., Conclusions: Our study demonstrated that the Japanese version of TSK has good reliability. However, its low validity and responsiveness indicate that it may not the best way to assess psychological factors for patients with ACL injury.

Background: Affections are thought to regulate pain perception through the descending pain inhibitory system in the central nervous system. In this study, we examined in mice the affective change by inhalation of the lemon oil, which is well used for aromatherapy, and the effect of lemon odor on pain sensation. We also examined the anterior cingulate cortex (ACC) and descending pain inhibitory system to such regulation of pain., Results: In the elevated plus maze, the time spent in the open arms was increased by inhalation of lemon oil. The pain behavior induced by injection of formalin into the hind paw was decreased. By inhalation of lemon oil, the number of c-Fos expression by formalin injection was significantly increased in the ACC, periaqueductal grey (PAG), nucleu raphe magnus (NRM) and locus ceruleus, and decreased in the spinal dorsal horn (SDH). The destruction of the ACC with ibotenic acid led to prevent the decrease of formalin-evoked nocifensive behavior in mice exposed to lemon oil. In these mice, the change of formalin-induced c-Fos expression in the ACC, lateral PAG, NRM and SDH by lemon odor was also prevented. Antagonize of dopamine D1 receptor in the ACC prevented to the analgesic effect of lemon oil., Conclusions: These results suggest that the analgesic effect of lemon oil is induced by dopamine-related activation of ACC and the descending pain inhibitory system.

Neuronal plasticity in the pain-processing pathway is thought to be a mechanism underlying pain hypersensitivity and negative emotions occurring during a pain state. Recent evidence suggests that the activation of astrocytes in the anterior cingulate cortex (ACC) contributes to the development of negative emotions during pain hypersensitivity after peripheral inflammation. However, it is unknown whether these activated astrocytes contribute to neuronal plasticity in the ACC. In this study, by using optical imaging with voltage- and Ca(2+)-sensitive dyes, we examined the long-term facilitation of neuronal excitation induced by high-frequency conditioning stimulation (HFS) in ACC slices of control mice and mice with peripheral inflammation induced by the injection of complete Freund adjuvant (CFA) to the hind paw. Immunoreactivity of glial fibrillary acidic protein in laminae II-III of the ACC in the CFA-injected mice was higher than in the control mice. Neuronal excitation in ACC slices from the CFA-injected mice was gradually increased by HFS, and the magnitude of this long-term facilitation was greater than in the control mice. The long-term facilitation in the CFA-injected mice was inhibited by the astroglial toxin, the N-methyl-d-aspartate (NMDA) receptor antagonist and NMDA receptor glycine binding site antagonist. The increase of intracellular Ca(2+) concentration in astrocytes during HFS was higher in the CFA-injected mice than in the control mice and was inhibited by l-α-aminoadipate (l-α-AA). These results suggest that the activation of astrocytes in the ACC plays a crucial role in the development of negative emotions and LTP during pain hypersensitivity after peripheral inflammation., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Strontium-89 chloride has been available at our hospital for painful osseous metastases since October 2008. Of the 17 patients(22 treatments)seen until September 2010, response to initial treatment of 13 patients was analyzed. These included cancers of the lung(5 patients, 6 treatments), breast(4 patients), thyroid(2 patients, 5 treatments), liver, 1, and prostate, 1. Other treatments patients received within 1 month of Sr-89 injection were; chemotherapy, 5 patients; radiotherapy, 3 patients; and bisphosphonate, 9 patients. The treatment effects were assessed 1 month after injection, and for 11 of the 13 patients, pain-relief was obtained in a mild and gradual manner. Transient flare was frequently observed, some of which made assessment of pain-relief in 6 patients difficult. We recognized that the bone marrow function before treatment was well above the 'Optimal Treatment Manual Japan ' criteria. After treatment, bone marrow functions kept above the value of grade 2(CTCAE), and even in 5 patients with recent or concomitant chemotherapy, it remained above grade 3 of the CTCAE criteria. These results led us to the conclusion that the indication and inclusion criteria for strontium-89 chloride treatment should be patients with an earlier bone metastasis burden that is currently manifested, without too much attention to bone marrow function criteria.

Novel agents that inhibit nerve growth factor signaling are required for the treatment of inflammatory pain. The present study investigated the effect of local administration of inhibitory peptide of TrkA (IPTRK3), a synthetic cell-penetrating peptide that antagonizes TrkA function, in complete Freund's adjuvant (CFA)-induced hyperalgesia in rats. Three hours after subcutaneous injection of CFA into the plantar surface of the rat's left hind paw, 10 mM IPTRK3 was injected at the same site. Thermal and mechanical hyperalgesia were tested in the ipsilateral hind paw until 7 days after CFA injection. The ipsilateral dorsal root ganglion (DRG) was dissected out for immunohistochemical analysis of transient receptor potential vanilloid subfamily member 1 (TRPV1) channels and TrkA. Local injection of this peptide significantly suppressed both thermal and mechanical hyperalgesia produced by CFA and also significantly reduced TRPV1 expression at the DRG. These results suggest that local administration of IPTRK3 is likely effective in the treatment of inflammatory pain in rats.

Inflammation and trauma lead to enhanced pain sensitivity (hyperalgesia), which is in part due to altered sensory processing in the spinal cord. The synaptic hypothesis of hyperalgesia, which postulates that hyperalgesia is induced by the activity-dependent long-term potentiation (LTP) in the spinal cord, has been challenged, because in previous studies of pain pathways, LTP was experimentally induced by nerve stimulation at high frequencies ( approximately 100 hertz). This does not, however, resemble the real low-frequency afferent barrage that occurs during inflammation. We identified a synaptic amplifier at the origin of an ascending pain pathway that is switched-on by low-level activity in nociceptive nerve fibers. This model integrates known signal transduction pathways of hyperalgesia without contradiction.

Purpose: To assess the efficacy of chemoradiotherapy on pain relief in patients with intrapelvic recurrence of rectal cancer., Methods: The records of 30 patients treated with radiotherapy with or without chemotherapy for intrapelvic recurrence of rectal cancer between September 1993 and February 1999 were retrospectively reviewed. There were 17 patients in the chemoradiotherapy (CRT) group and 13 patients in the radiotherapy alone (RTA) group. Simultaneous extrapelvic distant metastases were found in 11 patients in the CRT group and in seven patients in the RTA group. Radiotherapy was administered with a median total dose of 50 Gy in both groups. In the CRT group, 15 patients received 5-fluorouracil by continuous infusion and two patients received irinotecan in a biweekly infusion schedule during the course of radiotherapy. The response rate and duration of pain relief were evaluated and were compared between the two groups., Results: The response rate of pain relief in the CRT and RTA was 100 and 77%, respectively. The median duration of pain relief in the CRT and RTA groups was 7.8 and 4.0 months, respectively and there was a significant difference between the two groups (P = 0.019). The median survival time from the start of radiotherapy was 15.1 and 9.3 months in the CRT and RTA groups, respectively, and there was a significant difference between the two groups (P = 0.046)., Conclusions: The results suggest that chemoradiotherapy for intrapelvic recurrence of rectal cancer for the purpose of pain relief appears to be more effective than radiotherapy alone.

Objectives Orthodontic mechanical force on the periodontal ligament induces extracellular adenosine triphosphate (ATP) release. However, mechanosensitive molecules have not been confirmed functionally in periodontal ligament cells. In the present study, we examined the roles of mechanosensitive PIEZO channels in the mechanically stimulated release of ATP in human periodontal ligament fibroblasts (HPdLFs). Materials and methods To examine PIEZO expression in HPdLFs, we performed reverse transcription–quantitative polymerase chain reaction, fluorescent immunostaining, and Ca2+ imaging. ATP concentrations were measured in culture medium after applications of the PIEZO1 agonist Yoda1 and compression force in a newly developed in vitro weight-loaded cell model (IVWLC) using balance weights and a 48-well plate. The mechanosensitive channel inhibitor GsMTx4 and the ATP-releasing route inhibitors clodronic acid, meclofenamic acid, and probenecid were used. To suppress PIEZO1 expression, short interference RNA (siRNA) treatment of the PIEZO1 gene was performed. Results PIEZO1 mRNA was expressed more abundantly than PIEZO2 mRNA in HPdLFs. HPdLF cell bodies were immunoreactive to anti-PIEZO1 antibody. Yoda1 increased intracellular Ca2+ and extracellular ATP concentrations in a dose-dependent manner. ATP release was inhibited by GsMTx4 and inhibitors of ATP release routes. In the IVWLC, HPdLFs released ATP in response to compression force but not in response to hypoxic stimulation that was simultaneously applied to cells. Mechanically stimulated ATP release was inhibited by GsMTx4, inhibitors of ATP-releasing routes and siRNA treatment of PIEZO1. Conclusions PIEZO1 on the cell membranes of HPdLFs is activated by compression force and then induces ATP release via intracellular Ca2+-dependent exocytosis and ATP-permeable channels. [ABSTRACT FROM AUTHOR]

Abstract: We examined the propagation pattern of neuronal excitation in slices from the central nucleus of the rat amygdala (CeA) using optical imaging with a voltage-sensitive dye. We analyzed the mechanisms for the long-term potentiation (LTP) of neuronal excitation induced by conditioning stimulation. High-frequency conditioning stimulation induced NMDA receptor-, cAMP-, and PKA-dependent LTP of neuronal excitation in the lateral part of the CeA. The bath application of forskolin also induced LTP that was PKA-dependent. These results suggest that the potentiation of neuronal excitation in the lateral part of the CeA is induced by the activation of intracellular cAMP/PKA signaling, which is triggered by the influx of Ca2+ via NMDA receptors. [ABSTRACT FROM AUTHOR]

By imaging neuronal excitation in rat spinal cord slices with a voltage-sensitive dye, we examined the role of glial cells in the P2X receptor agonist αβ-methylene ATP (αβmeATP)-triggered long-term potentiation (LTP) in the dorsal horn. Bath application of αβmeATP potentiated neuronal excitation in the superficial dorsal horn. The potentiation was inhibited in the presence of the P2X receptor antagonists TNP-ATP, PPADS and A-317491, and was not induced in slices taken from rats neonatally treated with capsaicin. These results suggest that αβmeATP acts on P2X receptors, possibly P2X3 and/or P2X2/3, in capsaicin-sensitive primary afferent terminals. Furthermore, the potentiation was inhibited by treatment with the glial metabolism inhibitor monofluoroacetic acid. Results obtained with the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, tumour necrosis factor-α (TNF-α) and interleukin (IL)-6, and antibodies to TNF-α and IL-6, as well as by double immunolabelling of activated p38 MAPK with markers of astrocytes and microglia, demonstrated that αβmeATP activated p38 MAPK in astrocytes, and that the presence of proinflammatory cytokines and p38 MAPK activation were necessary for the induction of αβmeATP-triggered LTP. These findings indicate that glial cells contribute to the αβmeATP-induced LTP, which might be part of a cellular mechanism for the induction of persistent pain. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is thought to be involved in the central mechanism of hyperalgesia and allodynia at the spinal level. Recently, we reported that NO played an important role in the induction of long-term potentiation (LTP) of synaptic strength in spinal dorsal horn, which is believed to underlie hyperalgesia and allodynia. In this study, to elucidate the relationship of NO to LTP in spinal dorsal horn, we measured the spatiotemporal distribution of NO signal with the NO-sensitive dye, DAR-4M, and neuronal excitation with the voltage-sensitive dye, RH482, in rat spinal cord slices, elicited by dorsal root stimulation. In superficial dorsal horn, neuronal excitation evoked by C fiber-activating dorsal root stimulation was potentiated for more than 2 h after low-frequency conditioning stimulation (LFS, 240 pulses at 2 Hz for 2 min). In the same slices that exhibited LTP, NO was produced and distributed in the superficial dorsal horn during the delivery of LFS, and the amplitude of LTP and amount of NO production showed close correlation from slice to slice. LTP and production of NO were inhibited in the presence of the NO synthase inhibitors and an inhibitor of heme oxygenase, the synthetic enzyme for carbon monoxide (CO). These results suggest that production and distribution of NO is necessary for the induction of LTP in spinal dorsal horn, and that CO contributes to the LTP induction and NO production by LFS. [ABSTRACT FROM AUTHOR]

We examined the effects of corticotropin-releasing factor (CRF) on plasticity of optically recorded neuronal activity in the substantia gelatinosa (lamina II) of 12–18-day-old rat spinal cord slices stained with a voltage-sensitive dye. Single-pulse test stimulation to the dorsal root that activated A and C fibres evoked prolonged (>100 ms) light-absorption change in the lamina II. This response represents the gross membrane potential change of all elements along the slice depth. After conditioning high-frequency stimulation of A-fibre-activating strength, test stimulus elicited less neuronal activity [−27±1% (7), (average±SE (n)), P<0.01 (*) at 45–60 min after conditioning]. When CRF (1 μM, 10 min) was applied during conditioning, the neuronal activity was facilitated rather than suppressed [+20±3% (5), P<0.05]. CRF alone exhibited insignificant effect [−5±1% (4), P=0.2]. In the presence of the inhibitory amino acid antagonists bicuculline (1 μM) and strychnine (0.3 μM) in the perfusate, in contrast, the conditioning facilitated it [+27±1% (12)*], and CRF treatment during conditioning inhibited the facilitation dose-dependently [0.1 μM: +18±2% (5)*, 1 μM: +13±1% (7)*]. Although interneuronal actions might contribute, these results suggest that CRF may have dual effects on excitatory synaptic transmission within the lamina II depending upon cellular conditions: a conversion from the induction of long-term depression to long-term potentiation (LTP), and inhibition of LTP induction. Since the LTP is thought to be responsible at least in part for the persistent pain, CRF could regulate the induction. [Copyright &y& Elsevier]

Abstract The neuronal circuitry through which prolonged excitation is generated in the spinal dorsal horn was investigated using optical imaging of neuronal excitation in transverse slices of rat spinal cords. It is known that tetanic stimulation (20 Hz for 1 s) of the dorsal root that activates both A and C primary afferent fibres elicits slow intrinsic optical signals (IOS) in the dorsal horn, seen most intensely in the substantia gelatinosa (SG), lamina II, and that IOS expresses in part the slow synaptic response recorded intracellularly in dorsal horn neurons. We here report that the slow IOS within the SG were completely abolished after an incision was made at the border between the SG and the deeper laminae, but not after an incision within the deeper dorsal horn of the laminae III–V. The result demonstrates directly that, in order to generate prolonged excitation in the SG, the neuronal elements in the deeper dorsal horn must be intact. Thus, the afferent information might be received first by the deeper elements and then transmitted to the SG region, and/or collaboration between the SG and deeper elements is necessary to maintain prolonged excitation in the SG. [ABSTRACT FROM AUTHOR]

Effect of caffeine on C-fibre-evoked excitation in the superficial dorsal horn of rat spinal cord slices was investigated in Ca2+-free medium using the optical imaging technique. Perfusing slices with Ca2+-free solution reversibly suppressed the late phase of dorsal-root stimulus-induced excitation, leaving short-lasting optical responses that primarily represent the excitation of presynaptic elements. Under the Ca2+-free condition, 0.1–10 mM caffeine depressed the peak optical amplitude in a concentration-dependent and reversible manner (IC50 4.5 mM, Imax 84%). The volatile anaesthetic halothane at a clinical concentration (0.6 mM) also depressed the peak optical amplitude. Pretreatment with caffeine augmented the inhibitory effect of halothane. These results suggest that caffeine and halothane may interact presynaptically to cause synergistic inhibition of C-fibre-induced excitation in the dorsal horn. [Copyright &y& Elsevier]