Search

Additional file 1. Additional images for cover letter

Background To identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn. Methods In experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining. Results In experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group. Conclusions Systemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.

To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement.The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography.CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P0.05) and significantly reduced by SPR inhibition (P0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement.SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.

Background: Intraoperative awakening is one of the complications which should be avoided. The minimum alveolar concentration of volatile anesthetics is an important factor in the suppression of biological response to nociceptive stimulation. A bispectral index (BIS) monitor is valuable for the maintenance of appropriate sedation; we have previously reported the minimum alveolar concentration (MAC) of desflurane at which the BIS index does not exceed 50 during nociceptive stimulation (MAC-BIS50-tetanus) was 4.27 % (95%CI: 4.15 u2013 4.39 %) in the adult patients (aged from 31 to 65 years). In this study, we investigated MAC-BIS50-tetanus in the elder patients (aged over 65 years).Method: This study was approved by the ethics committee at Tsukuba University Hospital. The patients undergoing scheduled operation were recruited to this study, and written informed consent was obtained from all of them. The patients who had psychological disease and received sedatives were excluded. Anesthesia was induced with sevoflurane and 60% of nitrous oxide in 40% of oxygen and air. After the administration of rocuronium (0.6 mg/kg), a supra-glottic device (LMA or igel) was introduced. Then, administration of nitrous oxide and sevoflurane was then terminated, and we confirmed that the pre-determined end-tidal concentration of desflurane maintained for 10 minutes. The neuromuscular monitoring was used as a nociceptive stimulator; the altitude of the stimulation was 80 mA for 10 seconds, which is reported to be equal to skin incisional pain in the ulnar nerve. The BIS index was recorded every 10 seconds for 1 minute from beginning 1 minute after the stimulation. We defined the average of 6 BIS values as the BIS index for each patient. The MAC-BIS50-tetanus was determined using Dixonu2019s up-and-down method.Result: A total of 19 elder patients were registered in this study. The MAC-BIS50-tetanus of desflurane was 3.53% (95%CI: 3.38u2013 3.69 %) in adult patients.Conclusion: The MAC-BIS50-tetunus of desflurane was 3.53% (95%CI: 3.38 u2013 3.69 %) in the elder patients. It was significantly lower than that of middle aged patients group. In elder patients, when the end-tidal concentration of desflurane is 3.53 %, the BIS index is suggested to exceed 50 in half of the patients during nociceptive stimulation.