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Abstract: High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterior-superior insula (PSI) may produce analgesic effects. However, the alterations in cortical activity during PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended 2 sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10 Hz, 100 pulses per train, 15 trains) ∼50 minutes postcapsaicin administration. Transcranial magnetic stimulation-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found after active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak ∼45 ms (N45) TEP relative to baseline. After active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, after sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain numerical rating scale scores after active vs sham rTMS was correlated with and partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia. This study demonstrates that high-frequency rTMS targeting the posterior-superior insula reduces capsaicin-induced pain and alters cortical activity, with changes in the N45 TMS-evoked potential peak mediating the analgesic effects., (Copyright © 2024 International Association for the Study of Pain.)

Homeostatic plasticity is a mechanism that stabilizes cortical excitability within a physiological range. Most homeostatic plasticity protocols have primed and tested the homeostatic response of the primary motor cortex (M1). This study investigated if a homeostatic response could be recorded from the primary sensory cortex (S1) after inducing homeostatic plasticity in M1. In 31 healthy participants, homeostatic plasticity was induced over M1 with a priming and testing block of transcranial direct current stimulation (tDCS) in two different sessions (anodal and cathodal). S1 excitability was assessed by early (N20, P25) and middle-latency (N33-P45) somatosensory evoked potentials (SEP) extracted from 4 electrodes (CP5, CP3, P5, P3). Baseline and post-measures (post-priming, 0-min, 10-min, and 20-min after homeostatic induction) were taken. Anodal M1 homeostatic plasticity induction significantly facilitated the N20-P25, P45 peak, and N33-P45 early SEP components up to 20-min post-induction, without any indication of a homeostatic response (i.e., reduced SEP). Cathodal homeostatic induction did not induce any significant effect on early or middle latency SEPs. M1 homeostatic plasticity induction by anodal stimulation protocol to the primary motor cortex did not induce a homeostatic response in SEPs., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Homeostatic plasticity (HP) is a negative feedback mechanism that prevents excessive facilitation or depression of cortical excitability (CE). Cortical HP responses in humans have been investigated by using 2 blocks of noninvasive brain stimulation with a no-stimulation block in between. A healthy HP response is characterized by reduced CE after 2 excitatory stimulation blocks and increased CE when using inhibitory stimulation. Conversely, impaired HP responses have been demonstrated in experimental and chronic pain conditions. Therefore, this systematic review aimed to provide an overview of the effect of pain on cortical HP in humans. Scopus, Embase, and PubMed were searched from inception until November 20, 2023. The included studies (1) compared experimental or clinical pain conditions with healthy controls, (2) induced HP using 2 blocks of stimulation with a no-stimulation interval, and (3) evaluated CE measures such as motor-evoked potentials. Four studies were included, consisting of 5 experiments and 146 participants, of whom 63 were patients with chronic pain and 48 were subjected to an experimental pain model. This systematic review found support for an HP impairment in pain compared with that in pain-free states, reflected by a lack of CE reduction after excitatory-excitatory HP induction over the primary motor cortex. Inhibitory-inhibitory HP induction did not produce a consistent HP response across studies, independent of pain or pain-free states. Standardization of HP induction protocols and outcome calculations is needed to ensure reproducibility and study comparison. Future HP studies may consider investigating sensory domains including nociception, which would further our understanding of abnormal HP regulation in pain conditions., Competing Interests: Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121). The authors have no conflicts of interests to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: The underlying mechanisms for shoulder pain (SP) are still widely unknown. Previous reviews have reported signs of altered pain processing in SP measured with quantitative sensory testing (QST). Evidence suggests that QST might hold predictive value for SP after an intervention, yet it is not known whether QST profiles can be modulated in response to different treatments. Therefore, this systematic review and meta-analysis aimed to assess whether QST parameters can be modified by interventions for patients with SP., Methods: Three databases were searched to identify eligible studies. Eligible studies had a prospective design, with at least one QST variable as an outcome in conjunction with an intervention measured before and after the intervention. Studies that involved SP caused by spinal or brain injury and studies looking at combined chronic neck pain and SP were excluded., Results: Nineteen studies investigating SP were eligible for inclusion in this review. Pressure pain threshold (PPT) was the most frequently used QST parameter to investigate local and widespread hyperalgesia. A meta-analysis was performed on data from 10 studies with a total of 16 interventions. Results demonstrated an overall acute effect (<24 hours after intervention) of interventions in favor of local decreased pain sensitivity and remote decreased pain sensitivity when PPTs before and after interventions were compared., Conclusions: This study demonstrates that interventions such as exercise and manual therapy can modulate PPTs acutely, both locally and remotely, in patients with SP. Further research investigating the acute and long-term modulatory ability of these interventions on other QST parameters is needed in patients with SP., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Offset analgesia (OA) induces a brief pain inhibition and studies suggest OA impairment in patients with chronic pain when compared to healthy subjects. Conditioned pain modulation remains the most studied descending pain inhibitory control mechanism and is modulated by centrally-acting analgesics. Since OA may be mediated by similar neural substrates as conditioned pain modulation, understanding if OA is a peripheral or central proxy of pain modulation is important. The modulatory effect of centrally-acting drugs on OA in healthy and chronic pain populations has not yet been systematically reviewed and meta-analyzed, and this systematic review and meta-analysis aimed to identify studies employing interventions for modulating OA magnitude., Methods: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library yielded 146 records of which 11 (172 healthy pain-free subjects, 106 chronic pain patients) were eligible for qualitative synthesis, and 10 for meta-analysis on overall modulatory effect of interventions on OA, and subgroup analysis of patients and healthy pain-free subjects., Results: Risk of bias was evident for study participation and study confounding in the included studies. Several different methods for assessing and calculating OA magnitude were identified, which may affect interpretability of findings and warrants standardization. The meta-analysis showed no modulatory effects on OA overall (standardized mean difference (SMD) [95%CI]: 0.04 [-0.22, 0.30], Z =0.29, p=0.77), or in the subgroup analysis for patients (SMD [95%CI]: -0.04 [-0.63, 0.71], Z =0.13, p=0.90) or healthy pain-free subjects (SMD [95%CI]: 0.01 [-0.21, 0.24], Z =0.11, p=0.91). Moderate to substantial heterogeneity was found for the overall analysis (I 2 =47%, p=0.03) and patient subgroup analysis (I 2 =75%, p=0.003)., Conclusions: The current systematic review and meta-analysis conclude that centrally-acting drugs and exercise do not influence OA. Evidence on the peripheral contribution to OA response requires further investigations. Preclinical models of OA should be established to identify the neurophysiology and -biology behind OA., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Sleep disturbances are increasingly recognized as a major part of chronic pain pathology. Obstructive sleep apnea (OSA) is a common occurrence in patients with chronic pain attending specialized pain clinics, yet its prevalence remains unclear. Using screening tools such as the Berlin and STOP-BANG questionnaires may aid in early identification of OSA and improve clinical care. This study i) examined the frequency of OSA based on objective sleep monitoring in patients with high-impact chronic pain, ii) explored potential differences in self-reported pain and sleep characteristics between patients with and without OSA, and iii) tested the agreement between OSA classification based on objective assessment and two OSA screening questionnaires., Methods: A consecutive cohort of 90 patients (71 women and 19 men; mean age: 47.1 ± 11.0 years) referred for interdisciplinary pain treatment, underwent one night of sleep monitoring using portable respiratory polygraphy (RP), and suspected OSA was confirmed with polysomnography (PSG). Self-reported data on clinical pain (severity, pain drawings and health-related quality of life), sleep characteristics (sleep quality insomnia, sleepiness), and risk of OSA (Berlin and STOP-BANG questionnaires) were collected the day before RP assessment., Results: Forty-six (51.1%) patients were classified with OSA according to RP and verified with PSG. Twenty-eight patients (31.1%) had moderate or severe OSA (apnea-hypopnea index [AHI] >15). Patients with OSA reported lower sleep quality compared with patients without OSA. Scores on pain severity, disability, quality of life, insomnia and sleepiness were comparable between patients with and without OSA. Sensitivity and specificity were 78.6 and 45.2% respectively for the Berlin questionnaire, and 71.4 and 58.1% respectively for the STOP-BANG questionnaire. The agreement for both questionnaires with objective assessment was poor-to-fair. Both questionnaires had acceptable negative predictive values but low positive predictive values reducing the clinical utility to identify patients with low OSA-risk in this sample., Conclusions: The current study demonstrates a high prevalence of OSA in patients with high-impact chronic pain referred to specialized pain treatment, however the clinical pain profiles were similar in patients with and without OSA. The Berlin and STOP-BANG questionnaires have poor specificity and low-to-fair agreement with RP/PSG questioning their clinical utility in identifying OSA in this sample., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: To investigate the analgesic effects of vibro-acupuncture (VA), a novel acuvibrator was developed. Objectives: To compare the analgesic effects of VA with those of manual acupuncture (MA) and placebo acupuncture (PA) on subjects with normal sensory perception (Study I), experimentally induced acute pain (Study II), and clinical chronic pain (Study III)., Methods: Thirty healthy volunteers (21 males, age: 20-30 years) participated in Study I. Fourteen healthy volunteers (8 males, age: 20-32 years) participated in Study II in which experimental pain was induced by injection of hypertonic saline. Fourteen patients suffering from unilateral epicondylalgia (9 males, age: 30-61 years) participated in Study III. All participants received VA, MA, and PA at LI4 and LI10 points in a randomized, crossover, and double-blinded manner. Quantitative sensory testing (QST) was performed on the ipsilateral forearm before and after each treatment. Data were analyzed using repeated-measures (RM) ANOVA., Results: A significantly higher vibration detection threshold (VDT) was observed after treatment of VA than after MA and PA ( p < 0.001). No significant treatment effect on experimental pain intensity was detected ( p > 0.086). Significantly lower pain intensity ( p = 0.005) and a smaller drawing area ( p = 0.011) of unilateral epicondylalgia were found after VA treatment than after PA., Conclusion: A specific effect on the VDT beyond that of MA and PA was evoked by VA. Patients with epicondylitis showed significantly lower pain intensity during VA than during PA. This study indicated that VA may be beneficial in individuals with clinical chronic musculoskeletal pain; however, further studies are needed.

Homeostatic plasticity complements synaptic plasticity by stabilising neural activity within a physiological range. In humans, homeostatic plasticity is investigated using two blocks of non-invasive brain stimulation (NIBS) with an interval without stimulation between blocks. The aim of this systematic review and meta-analysis was to investigate the effect of homeostatic plasticity induction protocols on motor evoked potentials (MEP) in healthy participants. Four databases were searched (Medline, Scopus, Embase and Cochrane library). Studies describing the application of two blocks of NIBS of the primary motor cortex with an interval of no stimulation between blocks reporting changes in corticospinal excitability by MEP amplitude were included. Thirty-seven reports with 55 experiments (700 participants) were included. Study quality was considered poor overall, with heterogeneity in study size, sample and designs. Two blocks of excitatory stimulation at the primary motor cortex produced a homeostatic response (decreased MEP) between 0 and 30 min post-protocols, when compared with a single stimulation block. Two blocks of inhibitory stimulation at the primary motor cortex using interval duration of 10 min or less produced a homeostatic response (increased MEP) between 0 and 30 min post-protocols, when compared with a single stimulation block. There were no differences in MEPs when compared with baseline MEPs. In conclusion, homeostatic plasticity induction using two blocks of NIBS with an interval of 10 min or less without stimulation between blocks produces a homeostatic response up to 30 min post-protocol. Improvements in participant selection, sample sizes and protocols of NIBS techniques are needed., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA., Design: Prospective cohort with follow-up 12 months after surgery., Patients: A consecutive sample of 131 knee osteoarthritis patients undergoing TKA., Methods: Pain intensity, Pain Catastrophizing Scale (PCS) scores, PainDETECT Questionnaire scores, conditioned pain modulation (CPM), and Oxford Knee Score (OKS) were obtained before and 12 months after TKA., Results: TKA improved pain (P < 0.001), PCS scores (P < 0.001), PainDETECT Questionnaire scores (P < 0.001), and OKSs (P < 0.001). Preoperative pain correlated with preoperative PCS scores (r = 0.38, P  <  0.001), PainDETECT scores (r = 0.53, P  <  0.001), and OKSs (r = -0.25, P  =  0.001). Preoperative PainDETECT scores were associated with preoperative PCS scores (r = 0.53, P  <  0.001) and OKSs (r = -0.25, P  =  0.002). Higher postoperative pain was correlated with high preoperative pain (r = 0.424, P  <  0.001), PCS scores (r = 0.33, P  <  0.001), PainDETECT scores (r = 0.298, P  =  0.001), and lower CPM (r = -0.18, P  =  0.04). The combination of preoperative pain, PCS score, and CPM explained 20.5% of variance in follow-up pain. PCS scores had a significant effect on pain trajectory when accounting for patient variance (t  =  14.41, P  <  0.0005)., Conclusion: The combination of high preoperative clinical pain intensity, high levels of pain catastrophizing thoughts, and impaired CPM may predict long-term postoperative pain 12 months after surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Studies have suggested that quantitative sensory testing (QST) might hold a predictive value for the development of chronic postoperative pain and the response to pharmacological interventions. This review systematically summarizes the current evidence on the predictive value of QST for chronic postoperative pain and the effect of pharmacological interventions. The main outcome measures were posttreatment pain intensity, pain relief, presence of moderate-to-severe postoperative pain, responders of 30% and 50% pain relief, or validated questionnaires on pain and disability. A systematic search of MEDLINE and EMBASE yielded 25 studies on surgical interventions and 11 on pharmacological interventions. Seventeen surgical and 11 pharmacological studies reported an association between preoperative or pretreatment QST and chronic postoperative pain or analgesic effect. The most commonly assessed QST modalities were pressure stimuli (17 studies), temporal summation of pain (TSP, 14 studies), and conditioned pain modulation (CPM, 16 studies). Of those, the dynamic QST parameters TSP (50%) and CPM (44%) were most frequently associated with chronic postoperative pain and analgesic effects. A large heterogeneity in methods for assessing TSP (n = 4) and CPM (n = 7) was found. Overall, most studies demonstrated low-to-moderate levels of risk of bias in study design, attrition, prognostic factors, outcome, and statistical analyses. This systematic review demonstrates that TSP and CPM show the most consistent predictive values for chronic postoperative pain and analgesic effect, but the heterogeneous methodologies reduce the generalizability and hence call for methodological guidelines.

Chronic pain patients often suffer from insomnia or impaired sleep which has been associated with increased pain sensitivity, but a limited amount of studies have investigated the effects of total sleep deprivation on central pain mechanisms. Therefore, the aim of this study was to determine the effects of total sleep deprivation on temporal summation, conditioned pain modulation, thermal and pressure pain sensitivity in healthy participants. Twenty-four healthy participants took part in this two-session trial. The measurements were conducted after a night of habitual sleep (baseline) and following 24 hours of total sleep deprivation. Detection thresholds for cold and warmth and pain thresholds for cold and heat were assessed. Cuff induced pressure pain detection and tolerance thresholds, temporal summation and conditioned pain modulation were assessed with user-independent, computer-controlled cuff algometry. Conditioned pain modulation was significantly impaired, temporal summation was significantly facilitated and pain sensitivity to pressure and cold pain were significantly increased at follow-up compared with baseline. In conclusion, this study found that one night of total sleep deprivation impaired descending pain pathways, facilitated spinal excitability and sensitized peripheral pathways to cold and pressure pain. Future studies are encouraged to investigate if sleep therapy might normalize pain sensitivity in sleep-deprived chronic pain patients., Competing Interests: NociTech is partly owned by Aalborg University and that I, K. K. Petersen, was partly employed by NociTech from January 2015 to December 2016. The work conducted by me, K. K. Petersen, in this period did not affect any of my research in that period or in future projects. The remaining authors have no conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Musculoskeletal pain reduces corticomotor excitability (CE) and methods modulating such CE reduction remain elusive. This study aimed to modulate pain-induced CE reduction by performing action observation and motor imagery (AOMI) during experimental muscle pain. Twelve healthy participants participated in 3 cross-over and randomized sessions separated by 1 week. During the AOMI session subjects performed an AOMI task for 10 minutes. In the AOMI+PAIN session, hypertonic saline was injected in the first dorsal interosseous muscle before performing the AOMI task. In the PAIN session, participants remained at rest for 10 minutes or until pain-resolve after the hypertonic saline injection. CE was assessed using transcranial magnetic stimulation motor-evoked potentials (TMS-MEPs) of the first dorsal interosseous muscle at baseline, during, immediately after, and 10 minutes after AOMI and/or PAIN. Facilitated TMS-MEPs were found after 2 and 4 minutes of AOMI performance (P < .017) whereas a reduction in TMS-MEPs occurred at 4 minutes (P < .017) during the PAIN session. Performing the AOMI task during pain counteracted the reduction in CE, as evident by no change in TMS-MEPs during the AOMI+PAIN session (P > .017). Pain intensity was similar between the AOMI+PAIN and PAIN sessions (P = .71). This study, which may be considered a pilot, demonstrated the counteracting effects of AOMI on pain-induced decreases in CE and warrants further studies in a larger population. PERSPECTIVE: This is the first study to demonstrate a method counteracting the reduction in CE associated with acute pain and advances therapeutic possibilities for individuals with chronic musculoskeletal pain., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Next to winning, minimizing injuries during training and matches is one of the primary goals of professional team sports games. Soreness and pain can be early indicators and risk factors for acute or long-term injuries. Monitoring pain intensity and duration, as well as potential sources, are useful for planning practices and can be effective means for preventing injury. The aim of this study was to assess the areas and locations of pain in young soccer goalkeepers during a training camp, and to differentiate the area and frequency between pain arising from the muscles (MP), joints (JP), or as a result of an impact (IP). Recordings of the MP, JP, and IP location along with the area were performed using digital body mapping software (Navigate Pain Android app, Aalborg University, Denmark) installed on a tablet personal computer at the end of each training day across a 5-day training camp. There was a significant difference in the area between the three types of pain (p < 0.001). The post hoc analysis revealed statistically significant differences between the pixel areas of IP versus JP (p < 0.001), IP versus MP (p < 0.001), and JP versus MP (p < 0.001). There was no significant time-effect for the IP area between 1-5 days of training (p = 0.610), neither for MP (p = 0.118) or JP (p = 0.797) and no significant difference for all three pain areas between the front and the back side of the body. The body regions most often reported for MP were thighs, while for JP they were groin and hips, and for IP the hips, shoulders, and forearms were most frequently indicated. This is the first study to map and report the pain distribution associated with training across a 5-day training camp in soccer goalkeepers, and these findings emphasize the value of using digital pain drawings clinically as well as for monitoring the health status of soccer players., (© 2019 Jarosław Muracki, Martyna Kumorek, Aleksandra Kisilewicz, Beata Pożarowszczyk, Dennis Boye Larsen, Adam Kawczyński, Shellie Boudreau, published by Sciendo.)

Experimental pain inhibits primary motor cortex (M1) excitability. Attenuating pain-related inhibition of M1 excitability may be useful during rehabilitation in individuals with pain. One strategy to attenuate M1 excitability is to influence prefrontal and premotor cortex activity. Working memory tasks, e.g. the two-back task (TBT), engage prefrontal and premotor cortices and may influence M1 excitability. We hypothesized that performing the TBT during pain would influence pain-related changes in M1 excitability. Participants (n = 28) received rigorous training in the TBT before baseline testing. Experimental pain was induced by injecting hypertonic saline into the first dorsal interosseous (FDI) muscle. Participants rated pain intensity on a 0-10 numerical rating scale (NRS) every second min until pain-resolved (PR) during the performance of the TBT (n = 14) or during REST (n = 14). In the TBT, letters were presented pseudo-randomly, and accuracy and reaction time to identified letters corresponding to letters shown two times back were recorded. M1 excitability was assessed using transcranial magnetic stimulation. Motor-evoked potentials (MEPs) were recorded at baseline, and at PR, PR + 10, PR + 20, and PR + 30 min. Four minutes after hypertonic saline injection, the pain NRS scores were higher in the TBT group than the REST group (p = 0.009). No time × group interaction was found for MEPs (p = 0.73), but a main effect of time (p < 0.0005) revealed a reduction of MEPs at PR up until PR + 30 (p < 0.008). The TBT accuracy improved at PR + 30 in both groups (p = 0.019). In conclusion, the pain-induced reduction in corticomotor excitability was unaffected by performing a working memory task, despite greater pain in the TBT group.

Experimental muscle pain inhibits corticomotor excitability (CE) of upper limb muscles. It is unknown if this inhibition affects overlapping muscle representations within the primary motor cortex to the same degree. This study explored CE changes of the first dorsal interosseus (FDI) and extensor carpi radialis (ECR) muscles in response to muscle pain. Participants ( n = 13) attended two sessions (≥48 hours in-between). Hypertonic saline was injected in the ECR (session one) or the FDI (session two) muscle. CE, assessed by transcranial magnetic stimulation (TMS) motor-evoked potentials (MEPs), was recorded at baseline, during pain, and twenty minutes postinjection together with pain intensity ratings. Pain intensity ratings did not differ between the two pain sites ( p = 0.19). In response to FDI muscle pain, the MEPs of the FDI muscle were reduced at 2 and 4 min postinjection ( p ≤ 0.03), but not after ECR muscle pain. No significant MEP change was detected for the ECR muscle ( p = 0.62). No associations between MEPs and pain intensity were found ( p > 0.2). The present results indicate that the output from overlapping cortical representations of two muscles differentially adapts to acute muscle pain.

The molybdate-catalysed transfer hydrodeoxygenation (HDO) of benzyl alcohol to toluene driven by oxidation of the solvent isopropyl alcohol to acetone has been investigated by using a combination of experimental and computational methods. A Hammett study that compared the relative rates for the transfer HDO of five para-substituted benzylic alcohols was carried out. Density-functional theory (DFT) calculations suggest a transition state with significant loss of aromaticity contributes to the lack of linearity observed in the Hammett study. The transfer HDO could also be carried out in neat PhCH 2 OH at 175 °C. Under these conditions, PhCH 2 OH underwent disproportionation to yield benzaldehyde, toluene, and significant amounts of bibenzyl. Isotopic-labelling experiments (using PhCH 2 OD and PhCD 2 OH) showed that incorporation of deuterium into the resultant toluene originated from the α position of benzyl alcohol, which is in line with the mechanism suggested by the DFT study., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background/aim: To potentially enhance the effects of conventional acupuncture, a novel acu-vibrator (prototype) has been developed to perform vibro-acupuncture (VA). The aim of this psychophysical study was to investigate the subjective sensations of VA compared with conventional manual acupuncture (MA) and non-penetrating sham acupuncture (SA)., Methods: 30 young healthy volunteers (21 men and 9 women) received VA, MA, and SA at LI4 and LI10 in a randomised, single-blind, placebo-controlled, cross-over manner. After 25 min of treatment, the Massachusetts General Hospital (MGH) acupuncture sensation scale (MASS), McGill pain questionnaire (MPQ), and numerical rating scale (NRS; 0-10) were employed followed by the acupuncture credibility and indication scale. Adverse events were investigated after treatment. Data were analysed using Friedman's test for repeated measures on ranks and post hoc Wilcoxon signed-rank tests with Bonferroni correction., Results: The MASS scores were significantly higher during MA and VA compared with SA at both LI4 and LI10 (p<0.017). Treatment with VA evoked significantly higher vibration sensations compared with MA and SA (p<0.005). Treatment with SA yielded significantly lower NRS and MPQ scores compared with MA and VA (p<0.001) with no difference between MA and VA (p>0.05). Blinding of participants was achieved for SA and MA; however, VA was correctly identified in 29 of 30 subjects due to the characteristic vibrational stimulation. No serious adverse events were recorded for any of the treatments., Conclusions: Subjective sensations were influenced by treatment mode, with MA and VA yielding higher stimulation responses compared with SA. VA evoked specific vibrational sensations beyond MA, which might have specific effects in various disorders., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub-chronically with either vehicle (0.9% saline) or PCP (2mg/kg two doses per day for 7 days), followed by a 7 days washout period. 30 min prior to the acquisition trial of the NOR task animals were dosed with either vehicle, CX546 (10, 40 or 80 mg/kg) or CX516 (0.5, 2.5, 10, 40 or 80 mg/kg). Our results show that sub-chronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this disruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment of cognitive deficits in schizophrenia.

Rationale: Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present., Objective: The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models., Methods: Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally)., Results: The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516., Conclusion: Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task.

The transcription factor hypoxia-inducible factor (HIF) is essential for the activation of several genes that promote the survival of cells exposed to oxidative stress. Expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme in the dopamine (DA) synthesis, is one of the genes that are positively regulated by HIF. Accordingly, HIF induction results in elevated DA release in various cell lines in vitro. HIF prolyl hydroxylase (HPH) is critically involved in the negative regulation of HIF levels. We investigated the in vivo effects of the HPH inhibitor FG0041 on brain DA function in rats by microdialysis in freely moving rats, locomotor activity, and Western blot analysis. Administration of FG0041 (10 mg/kg i.p.), as an acute (single injection), or as subchronic (once daily for 6 days) treatment and cobalt chloride (CoCl2) (60 mg/kg s.c.) potentiated potassium (K+) induced increases in extracellular levels of DA levels in the rat striatum. The increase in extracellular DA of freely moving rats was sought in relationship to locomotor activity in rats. A significant increase in locomotor activity was observed in FG0041-treated rats compared with vehicle on a cocaine challenge. In support of these findings, protein levels of TH in the rat brain stem were increased after treatment with FG0041. These data indicate that FG0041 augments DA function in the rat brain. Inhibition of HPH enhances DA function by increasing DA release, which has implications for the use of HIF induction in the treatment of neurodegenerative diseases., (Copyright 2009 Wiley-Liss, Inc.)

A non-randomized cross-over study was performed with bupivacaine HCl (5 mg x ml(-1)) aqueous solution and bupivacaine free base (4.44 mg x ml(-1)) in Viscoleo/castor oil 2:1 (v/v) administered s.c. to male Wistar rats. Plasma levels were analyzed by LC-MS. Plasma profiles obtained after administration of oily solution showed a prolonged bupivacaine release with lower peak plasma levels as compared to administration of an aqueous formulation applied in the same compartment. t(1/2), t(max), C(max) and AUC(0-infinity) for the aqueous solution were 63+/-8 min, 19+/-16 min, 194+/-46 ng x ml(-1) and 25,000+/-3000 ng min x ml(-1), respectively, while the corresponding data for the oil solution were 368+/-89 min, 334+/-186 min, 36+/-25 ng x ml(-1) and 25,000+/-6000 ng x min x ml(-1). The present data indicate the potential of designing an oil formulation of bupivacaine with a prolonged local analgetic effect exhibiting a minimum of systemic toxicity. In vivo release of bupivacaine from the oil solution was evaluated by a numerical deconvolution method. In vivo release kinetics was found to be first-order and corresponded well with in vitro release kinetics found using a rotating dialysis cell. This led to establishment of an in vitro/in vivo correlation for this particular formulation.

In vitro rate of drug release from oil solutions was investigated in a rotating dialysis cell. A log linear correlation was established between the rate constant (k(obs)) for attainment of equilibrium and apparent partition coefficient (P(app)) between oil vehicle and release media using various weak acids and bases and non-electrolytes. Collander like linear free energy relationships were observed allowing various oil-aqueous buffer partition coefficients to be calculated from known octanol-aqueous buffer partition coefficients. Solubility of the various drug substances in oil vehicles were investigated. A linear correlation was observed between log molar solubility and melting point of the solutes. Release profiles obtained for release of two local anaesthetics dissolved in the same oil vehicle exhibited an unexpected behavior involving an initial delayed release of the most lipophilic local anaesthetic.

In oily vehicles containing different hydrogen bond donating excipients rates of transfer of the weak electrolytes naproxen and lidocaine from the oil phase to the aqueous medium were measured by using the rotating dialysis cell. A logarithmic linear correlation was established between the apparent partition coefficient, P(app), and the first-order rate constant related to attainment of equilibrium between the two phases, k(obs), which fitted well with results from former publications. Further, release data for the non-electrolyte testosterone were found to fit into this linear correlation. Apparent partition coefficients were determined between oil vehicles containing various amounts of hydrogen bond donating excipients and phosphate buffer, pH 6.00, revealing a rise in log P(app) with increasing concentration of excipient. Viscosity was measured for castor oil containing vehicles showing a linear relationship between percentage (v/v) castor oil and log viscosity (mPas) of the mixed vehicle.

Extracellular matrices (ECM) generated by trophoendodermal stem cells transplanted into the peritoneum of host rats were investigated. Two types of trophoendodermal transplants were studied: (1) free-floating cystic structures, and (2) solid masses adherent to various abdominal organs. Trophoendodermal stem cell ECM obtained from either transplant source was dominated by the presence of laminin similar to Engelbreth-Holm-Swarm (EHS) tumour ECM. However, in contrast to EHS tumour ECM, another ECM component, entactin, was below the level of detection in trophoendodermal stem cell ECM. The laminins present in the two types of trophoendodermal stem cell transplants exhibited distinct differences. Tissues used as sources of one type of laminin were devoid of the other type of laminin. The two species of rat laminin behaved similarly on sodium dodecyl sulphate-polyacrylamide gels and had virtually identical amino acid compositions. The laminins also had similar cruciform patterns when examined by rotary shadowing. Rat laminins differed in their binding to an ion exchange resin: laminin isolated from peritoneal cysts bound to the resin (acidic laminin); laminin isolated from solid masses failed to bind (basic laminin). Acidic rat laminin showed reduced capacity to form laminin-laminin associations when compared with basic rat laminin. Acidic/soluble laminin proved to be a useful reagent in the development of a radio-immunoassay for laminin. Laminin concentrations in the peritoneal fluid of transplant-bearing rats was very high (approximately 400 micrograms/ml) and entirely of the acidic/soluble form. In summary, trophoendodermal stem cell ECM possesses a distinct composition with a lack of detectable entactin, and trophoendodermal stem cells are capable of modulating the characteristics of laminin, depending upon their organization. These features of trophoendodermal stem cell ECM may represent signals responsible for at least some of the unique features of the trophoendodermal stem cell transplants.