Pain Inhibition Research Articles

Chronic excruciating forearm pain in a child with intra-neural hemangioma: A challenging case report.

Introduction and importanceCavernous hemangioma is a rare form of hemangioma. It usually arises in the central nervous system, but the tumor has also been reported in the liver, retina and skin with a lower prevalence. Its occurrence into the peripheral nerves has only been reported a few times. Herein, we report an extremely rare case of intra-neural hemangioma in the ulnar nerve and discuss the complications we faced following surgery.Case presentationWe present a 6-year-old boy with history of severe progressive left forearm pain in the last two years. Imaging studies revealed a soft tissue mass and histopathological exam was in favor of a cavernous hemangioma. Patient underwent surgery to excise the tumor. Despite temporary response, he began to experience excruciating pain shortly after surgery which caused him to adopt bizarre postures.Clinical discussionIn the more common form of nerve involvement in a hemangioma, the nerve is displaced and surrounded by the tumor. However, in cases with intra-neural involvement, the nerve would have to be sacrificed. This case report brings some rare but important characteristics of a hemangioma in to attention, such as the intra-neural location, possibility of recurrence and aggravating pain with bizarre positions as a result.ConclusionIn cases of intra-neural hemangioma, there is a chance that the patient experiences recurrence and/or excruciating pain following surgery. The orthopedic surgeon should be prepared for the possibility of nerve transfer, repeat surgeries and the need for prolonged palliative pain suppression modalities in the approach to intra-neural hemangioma.

Ibuprofen-loaded centrifugally spun microfibers for quick relief of inflammation in rats

The conventional dosage forms (tablets, capsules) of ibuprofen have less potential in the suppression of pain and inflammation due to their slow dissolution rates and lower bioavailability. The aim of this study was to fabricate fibrous solid dispersion of ibuprofen for improved dissolution rate and quick therapeutic action. Drug-loaded microfibers were fabricated using centrifugal melt spinning (CMS) technique from the physical mixture of sucrose, ibuprofen and a hydrophilic polymer, PVP. These fibers were characterized by SEM, PXRD, DSC, and FTIR spectroscopy. The selected formulation was also pressed into tablets by direct compression method followed by its in vitro and in vivo characterization. The production yield of fibers was 75 ± 2% with an average diameter of 15 ± 5 µm. The drug loading efficiency (DLE) was 85 ± 5%. The tablets dissolved rapidly (<40 s). In vitro dissolution studies have shown >85% of ibuprofen dissolved from tablet within first 2 min which was ∼5 times quicker than drug alone. Dissolution efficiency has improved from 0.63 of ibuprofen to 0.95 of that in fibers with ∼7 times reduction in mean dissolution time. PXRD, and DSC have shown the amorphous state of ibuprofen in the formulation and FTIR spectra demonstrated no interaction of drug with excipients. In vivo anti-inflammatory studies using rabbits revealed a significant (p < 0.05) reduction in paw volume (mm) in the groups treated with fibrous formulation. This study concludes that microfibers produced by centrifugal melt spinning have improved dissolution rates and bioavailability of ibuprofen. Incorporation of polymer in the formulations improves the production yield and drug loading efficiency of microfibers.

Physical activity behavior in the first month after mild traumatic brain injury is associated with physiological and psychological risk factors for chronic pain.

The purpose of this study was to determine whether self-reported physical activity (PA) in the first month after mild traumatic brain injury (mTBI) predicts endogenous pain modulatory function and pain catastrophizing at 1 to 2 weeks and 1 month after injury in patients with mTBI. Patients with mild traumatic brain injury completed study sessions at 1 to 2 weeks and 1 month after injury. Assessments included a headache survey, Pain Catastrophizing Scale, International Physical Activity Questionnaire-Short Form, and several quantitative sensory tests to measure endogenous pain modulatory function including conditioned pain modulation (CPM), temporal summation, and pressure pain thresholds of the head. Hierarchical linear regressions determined the relationship between the PA variables (predictors) and pain catastrophizing and pain modulation variables (dependent variables) cross-sectionally and longitudinally, while controlling for potential covariates. In separate hierarchical regression models, moderate PA, walking, and total PA at 1 to 2 weeks after injury predicted pain inhibition on the CPM test at 1 month, after controlling for significant covariates. In addition, a separate regression revealed that minutes sitting at 1 month predicted CPM at 1 month. Regarding predicting pain catastrophizing, the regression results showed that sitting at 1 to 2 weeks after injury significantly predicted pain catastrophizing at 1 month after injury. Greater self-reported PA, especially moderate PA, 1 to 2 weeks after injury longitudinally predicted greater pain inhibitory capacity on the CPM test at 1 month after injury in patients with mTBI. In addition, greater sedentary behavior was associated with worse pain inhibition on the CPM test and greater pain catastrophizing at 1 month after injury.

Phytochemical investigation and assessment of pharmacological properties of leaves of Duabanga grandiflora

Duabanga grandiflora- a medicinal plant from Lythraceae family, is native to some countries of South Asian region. This plant has many uses in folk medicine. But there are lack of scientific reports comparing to its therapeutic importance. Our study was designed to assess phytochemical and biological effects of D. grandiflora leaves. From the phytochemical investigation we came to know that this extract possesses many important phytochemical groups as secondary metabolites. This extract showed the presence of many antioxidant compounds in both qualitative and quantitative antioxidant assays. In DPPH radical and hydrogen peroxide scavenging assay, the SC50 were 58 and 50 μg/ml, respectively. In FeCl3 reducing power assay, the RC50 was found to be 57 μg/ml. Total content of phenolic, flavonoid and tannin were measured as 127 mg GAE/g, 285 mg QE/g and 132 mg GAE/g, respectively. This plant showed significant blood glucose level reduction over the short period of time in oral glucose tolerance test and for long term in alloxan-induced diabetic tests, although it did not express any significant response to α-glucosidase enzyme inhibition. In acetic acid-induced writhing test, this plant showed significant pain inhibition which was followed by significant reduction in paw edema induced by formalin. D. grandiflora increased the latency of defecation and decreased the stool count in castor oil-induced diarrheal test. Lastly, we also observed prominent CNS depression activity of this extract in open field model in mice. All of these results were compared with standard drugs and the responses were found in dose-dependent manner. These observations signify the utilization of this plant in folk medicinal system and we hope that these initial results will be beneficial to conduct higher research on this plant to isolate newer bioactive molecules.

Effect of High-definition Transcranial Direct Current Stimulation on Conditioned Pain Modulation in Healthy Adults: A Crossover Randomized Controlled Trial

The disorder of the conditioned pain modulation (CPM) system is one of the main causes of pain perception in individuals. High-definition transcranial direct current stimulation (HD-tDCS) targeting specific brain areas was indicated to have an analgesic effect possibly by activating the endogenous pain inhibition pathway evident in CPM. However, discrepancies were found in previous limited studies of varied homogeneity and quality. Therefore, the present study applied 2 mA HD-tDCS (20 min) in the left primary motor cortex (M1) among 35 healthy adults with a blinded crossover study design, to investigate its effectiveness on optimizing the analgesic effect in healthy individuals through assessing changes of the CPM. The univariate and multivariate general linear models were used to evaluate the intervention effect between-group on the Δ-value (after-intervention minus before-intervention) during CPM (primary outcome), pressure pain threshold (PPT), and cold pressure threshold (CPT) (secondary outcome), respectively. A significant between-group difference in Δ-CPM was found for active stimulation. HD-tDCS significantly improved the analgesic efficiency of Δ-CPM, compared with the sham control, after adjusting the confounding factors including age, gender, psychological status, as well as the sequence effect. The changes of CPM were positively correlated with the total physical activity volume. In conclusion, our findings provide evidence support to the effectiveness of HD-tDCS on endogenous pain modulation among healthy adults. Further studies are required to explore the analgesic effect of tDCS among patients with chronic pain, thereby facilitating optimal chronic pain management.

Modulation of offset analgesia in patients with chronic pain and healthy subjects- a systematic review and meta-analysis.

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. 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. 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 (I2=47%, p=0.03) and patient subgroup analysis (I2=75%, p=0.003). 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.

3D microelectrode cluster and stimulation paradigm yield powerful analgesia without noticeable adverse effects.

The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organization frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.

Evaluation of analgesic and anti-inflammatory activities of Warionia saharae essential oil

Warionia saharae Benth &amp; Coss (W.s) (Asteraceae) is a monospecific genus endemic to Algeria and Morocco. Its leaves are used in their traditional medicine, such as gastrointestinal and inflammatory diseases; for instance, rheumatoid arthritis treatment. In this work, our team investigated the anti-inflammatory and analgesic effects of essential oil extracted from the dried upper parts of Warionia saharae based on different standard experimental test models. The analgesic activity was assessed by central and peripheral models, such as “hot plate” and “writhing” tests on Swiss albino mice. The hot plate test used latency measurements to assess acute cutaneous pain sensitivity, as a result; the latency of the hind-paw pain response was by licking and either shaking or jumping, those occurrences were recorded. Writhing test as a chemical method used to induce pain of peripheral origin in mice by injecting acetic acid intraperitoneally (IP). This results in characteristic stretching behavior of the animals (cramps and contortions). The evaluation of the analgesic activity, shows that the essential oil of this plant induces a decrease in the number of abdominal cramps in the contortion test and a maximum inhibition of pain. As for the anti-inflammatory effect, it was studied by the “paw edema” test, a phlogogenic agent (formaldehyde) was used to stimulate inflammation in the paws of mice. Anti-inflammatory properties can be observed by inhibiting this edema compared to the standard drug Diclofenac. In conclusion, Warionia saharae essential oil (75 mg/kg) showed a strong anti-inflammatory and analgesic activities which supports the conventional use of this plant in traditional medicine.

5-HT7 Receptor Is Involved in Electroacupuncture Inhibition of Chronic Pain in the Spinal Cord.

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT1, 5-HT2, and 5-HT3 receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT7 receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT7 receptor is involved in EA analgesia. The 5-HT7 receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT7 receptor in the dorsal spinal cord. Intrathecal injection of 5-HT7 receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT7 receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABAA receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT7 receptor activates GABAergic neurons through the Gs–cAMP–PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.

Radioactive Particle Implantation Combined with Chemotherapy for Treatment of Pancreatic Adenocarcinoma.

HomeRadiology: Imaging CancerVol. 3, No. 5 PreviousNext Research HighlightsFree AccessRadioactive Particle Implantation Combined with Chemotherapy for Treatment of Pancreatic AdenocarcinomaFrancesca RigiroliFrancesca RigiroliFrancesca RigiroliPublished Online:Sep 17 2021https://doi.org/10.1148/rycan.2021219020MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: To determine the efficacy of iodine 125 (125I) radioactive particle implantation plus regional arterial chemotherapy perfusion versus regional arterial chemotherapy perfusion therapy alone for treatment of patients with advanced pancreatic ductal adenocarcinoma.■ Key Result: This retrospective study showed significantly improved survival and overall clinical benefit of 125I radioactive particle implantation plus regional arterial chemotherapy.■ Impact: This preliminary study supports further evaluation of combined 125I radioactive particle implantation plus regional arterial chemotherapy to improve outcomes in advanced stage pancreatic ductal adenocarcinoma.Pancreatic ductal adenocarcinoma is often diagnosed at an advanced stage of disease, causing an extremely low survival rate at 1 year. While regional arterial infusion chemotherapy, obtained through catheterization of gastroduodenal, superior mesenteric, or splenic arteries, increases regional drug concentrations, responses remain low. Recent studies suggest that combining this therapy with 125I radioactive particle implantation improves inhibition of tumor growth and pain management.This retrospective study compared patients treated with 125I radioactive particle implantation plus arterial infusion chemotherapy (n = 11) versus those treated only with arterial infusion chemotherapy (n = 12). Treatment with combined 125I radioactive particle implantation plus regional arterial chemotherapy significantly improved radiologic response to therapy (73% vs 42%, P < .05) and 6-month and 9-month survival (91.7% and 50% vs 63.6% and 18.2%, respectively; P < .05) as compared with regional arterial chemotherapy alone. Combined therapy also reduced pain and improved overall quality of life to a greater extent.This study describing benefits of a “double” interventional radiologic approach suggests that development of upgraded materials and novel interventional techniques can improve treatment outcomes in pancreatic ductal adenocarcinoma. Several limits may affect the applicability of this approach, including the retrospective nature, small sample size, and preliminary application only to patients with advanced-stage disease. A future prospective study is needed to confirm these results.Highlighted ArticleYang L, Li C, Wang Z, et al. The clinical efficacy of computed tomography-guided 125I particle implantation combined with arterial infusion chemotherapy in the treatment of pancreatic cancer. J Cancer Res Ther 2021;17(3):720–725. doi: doi.org/10.4103/jcrt.jcrt_563_20Highlighted Article1. Yang L, Li C, Wang Z, et al. The clinical efficacy of computed tomography-guided 125I particle implantation combined with arterial infusion chemotherapy in the treatment of pancreatic cancer. J Cancer Res Ther 2021;17(3):720–725.doi: doi.org/10.4103/jcrt.jcrt_563_20 Crossref, Medline, Google ScholarArticle HistoryPublished online: Sept 17 2021 FiguresReferencesRelatedDetailsRecommended Articles Tumor-Vessel Relationships in Pancreatic Ductal Adenocarcinoma at Multidetector CT: Different Classification Systems and Their Influence on Treatment PlanningRadioGraphics2016Volume: 37Issue: 1pp. 93-112Preoperative CT Classification of the Resectability of Pancreatic Cancer: Interobserver AgreementRadiology2019Volume: 293Issue: 2pp. 343-349CT Radiomic Features of Superior Mesenteric Artery Involvement in Pancreatic Ductal Adenocarcinoma: A Pilot StudyRadiology2021Volume: 301Issue: 3pp. 610-622Pancreatic Adenocarcinoma Staging in the Era of Preoperative Chemotherapy and Radiation TherapyRadiology2018Volume: 287Issue: 2pp. 374-390Imaging-based Risk Scores for Treatment Selection in Early Pancreatic Cancer: A Step Forward for Tailored TreatmentRadiology2020Volume: 296Issue: 3pp. 552-553See More RSNA Education Exhibits Pancreatic Cancer: Early Detection, Diagnosis and StagingDigital Posters2020Beyond Surgical Resectability: Pearls and Pitfalls in Preoperative Imaging for PancreatoduodenectomyDigital Posters2020Missed Imaging Findings of Pancreatic Ductal Adenocarcinoma: Lessons Learned from Difficult Cases  Digital Posters2020 RSNA Case Collection Superior Mesenteric Artery SyndromeRSNA Case Collection2021Primary pancreatic lymphoma RSNA Case Collection2020Flipped hepatic Artery Infusion Pump ReservoirRSNA Case Collection2022 Vol. 3, No. 5 Metrics Altmetric Score PDF download

Suppression of joint pain in transient receptor potential vanilloid 4 knockout rats with monoiodoacetate-induced osteoarthritis.

Transient receptor potential vanilloid 4 (TRPV4) modulates osteoarthritic (OA) pain in animal models. However, the pathophysiological function of TRPV4 in regulating OA pain remains poorly understood. We developed TRPV4-knockout (TRPV4-KO) rats and assessed the effects of Trpv4 gene deficiency in a monoiodoacetate (MIA)-induced OA pain model (MIA rats) by examining pain-related behavior, pathological changes, and electrophysiological changes in dorsal root ganglion (DRG) neurons. The changes detected in TRPV4-KO rats were confirmed in wild-type rats using a TRPV4 antagonist. Transient receptor potential vanilloid 4-KO rats showed the same pain threshold as wild-type rats for thermal or pressure stimuli under normal conditions. Trpv4 gene deletion did not suppress the development of osteoarthritis pathologically in MIA rats. However, the OA-related mechanical pain behaviors observed in MIA rats, including decreased grip strength, increased mechanical allodynia, and reduced weight-bearing on the ipsilateral side, were completely suppressed in TRPV4-KO rats. The DRG neurons in wild-type but not TRPV4-KO MIA rats were depolarized with increased action potentials. Transient receptor potential vanilloid 4 antagonist treatments recapitulated the effects of genetic Trpv4 deletion. Transient receptor potential vanilloid 4 was sensitized in the DRG neurons of MIA rats and played a critical role in the development of OA pain. These results suggest that the inhibition of TRPV4 might be a novel potent analgesic strategy for treating OA pain.

Spinal cord neural activity of patients with fibromyalgia and healthy controls during temporal summation of pain: an fMRI study.

The cause for the increased sensitivity of patients with fibromyalgia (FM) to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in patients with FM and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Sixteen HC and 14 FM participants received repetitive heat stimuli to the hand at 0.4 Hz to achieve TSSP during functional imaging with a 3 T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neurovascular coil, multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by deactivation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.NEW & NOTEWORTHY "Windup" and its behavioral correlate "temporal-summation-of-second pain" (TSSP) represent spinal cord mechanisms of pain augmentation associated with central sensitization and chronic pain. Fibromyalgia (FM) is a chronic pain disorder, where abnormal TSSP has been demonstrated. We used fMRI to study spinal cord and brainstem activation during TSSP. We characterized the time course of spinal cord and brainstem BOLD activity during TSSP which showed abnormal brainstem activity in patients with FM, possibly due to deficient pain modulation.

Phytochemical and pharmacological investigations of different extracts of leaves and stem barks of Macropanax dispermus (Araliaceae): a promising ethnomedicinal plant

BackgroundMacropanax dispermus is traditionally used to treat various diseases by ethnic people. The present research reports the pharmacological properties with phytochemical profiling of the crude extracts of M. dispermus leaves (MDML), its n-hexane (MDHL), carbon tetrachloride (MDTL), chloroform (MDCL), ethyl acetate (MDEL), and aqueous (MDAL) fractions, and crude methanol extracts of its stem barks (MDMS). The in vitro thrombolytic activity was done on human erythrocytes whereas the cytotoxic activity was done by brine shrimp lethality assay. The in vivo analgesic activity was examined by acetic acid-induced writhing, tail immersion, and formalin-induced paw licking method. In contrast, antipyretic activity was done by the brewer’s yeast-induced pyrexia method.ResultsMDHL and MDMS showed 37.05% and 42.21% of significant (p < 0.01) thrombolytic activity, respectively. MDCL and MDMS showed the lower LC50 values of 23.15 and 37.11 µg/ml during cytotoxicity test, respectively. In acetic acid writhing method, MDTL and MDEL showed significant (p < 0.001) inhibition of writhing by 79.34% and 80.17%, respectively. MDMS showed significant (p < 0.001) maximal possible effect (%MPE) of 45.95%, 62.26%, 65.79%, 89.69% and elongation of time in pain reaction of 48.53%, 60.28%, 58.76%, and 70.14% at 30, 60, 90, and 120 min intervals, respectively. MDML at 400 mg/kg exhibited significant (p < 0.001) 82.72% of inhibition of pain at the late phases. MDEL at 400 mg/kg of dose exhibited significant (p < 0.001) reduction of rectal temperature by 36.31%, 62.42%, 89.81%,, and 96.82% at 1, 2, 3, and 4 h intervals, respectively.ConclusionThe current research suggests that the plant extracts possess potential thrombolytic, cytotoxic, analgesic, and antipyretic activities.

Recovery of motor function in ambulatory hand trauma using chloroprocaine 2%

Chloroprocaine 2% is an ester local anaesthetic offering a shorter onset, duration of action, and offset than other commonly used agents, making it particularly suitable for ambulatory surgery.1 Although established for short-acting spinal anaesthesia, it has only recently launched on the UK market for peripheral nerve block.2 We evaluated recovery of motor function in patients undergoing awake surgery using chloroprocaine 2% for ambulatory hand trauma procedures. Thirteen patients received an ultrasound-guided axillary brachial plexus block with 30 ml chloroprocaine 2%, of which 5 ml (100 mg) were specifically deposited around the musculocutaneous nerve. We established baseline biceps muscle strength (peak force over a 3-s period) with a handheld dynamometer (Lafayette). Patients also received supplemental distal blocks of the median, ulnar and superficial radial nerves as appropriate with levobupivacaine for postoperative analgesia. Biceps strength was assessed at fixed time points after block until >75% return of baseline function. Mean block performance time was 11 min (7–14 min). Surgery started 5–22 min (mean 12 min) thereafter with an operative time between 13 and 50 min (mean, 34 min). Median peak force immediately after block was 0% (0–25%) of pre-block strength. Six of 13 patients had >50% recovery of biceps strength by 70 min after block (Fig. 3). All had ≥75% recovery by 120 min (Table 1). Surgical conditions were excellent for all patients, and none received supplemental analgesia or reported tourniquet discomfort. Chloroprocaine 2% provided rapid onset block, good surgical conditions, and rapid recovery of motor function. In terms of offset and readiness for discharge, chloroprocaine 2% was a marked improvement on our previous awake surgery local anaesthetic mixture of lidocaine 1.5% with epinephrine. This has benefits for theatre efficiency, and patient safety and satisfaction. Of note patients were able to dress themselves in the PACU without aid. Five patients recorded higher peak force postoperatively compared with baseline, which may have been attributable to pain inhibition. We plan to recommend wider use of chloroprocaine 2% for procedures where operative duration is anticipated to be ≤1 h. Supplemental distal blocks can limit any concerns about postoperative analgesia.Table 1Biceps muscle strength post block.Duration since block finish (min)Median biceps muscle strength (% of baseline)00%7057%8085%12098% Open table in a new tab 1.Saporito A, Anselmi L, Borgeat A, Aguirre J. J Clinical Anesth 2016; 32: 119–262.Jafari S, Kalstein A, Nasrullah H, et al. Anesth Analg 2008; 107: 1746–50

Somatosensory dysfunction in patients with posttraumatic headache: A systematic review.

Aim of the review is to summarize the knowledge about the sensory function and pain modulatory systems in posttraumatic headache and discuss its possible role in patients with posttraumatic headache. Posttraumatic headache is the most common complication after traumatic brain injury, and significantly impacts patients' quality of life. Even though it has a high prevalence, its origin and pathophysiology are poorly understood. Thereby, the existing treatment options are insufficient. Identifying its mechanisms can be an important step forward to develop target-based personalized treatment. We searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with headache after brain injury. The studies showed heterogenous alterations in sensory profiles (especially in heat and pressure pain perception) compared to healthy controls and headache-free traumatic brain injury-patients. Furthermore, pain inhibition capacity was found to be diminished in subjects with posttraumatic headache. Due to the small number of heterogenous studies a distinct sensory pattern for patients with posttraumatic headache could not be identified. Further research is needed to clarify the underlying mechanisms and biomarkers for prediction of development and persistence of posttraumatic headache.

Advancing our understanding of neuropathic pain in diabetes mellitus using conditioned pain modulation: further considerations for age and testing site.

Neuropathy is common among individuals with diabetes mellitus, and is associated with decreased quality of life, greater comorbidity, and substantial economic burden. However, the mechanisms underlying painful diabetic polyneuropathy has yet to be fully elucidated. While it is recognized that diabetic polyneuropathy places patients at a greater risk for developing neuropathic pain, it is still not clear why some individuals develop pain and others do not. Similar to other chronic pain conditions, painful diabetic neuropathy is likely driven by alterations in both the peripheral and central nervous system. Experimental conditioned pain modulation paradigms have contributed substantially to our current understanding of chronic pain across various disease states. In a new study, researchers have extended this work by examining the efficiency of conditioned pain modulation in patients with painful and non-painful diabetic polyneuropathy. Surprisingly, the results indicate individuals with painful neuropathy experience greater endogenous pain inhibition, which may seem counterintuitive at first blush. Here, we discuss potential explanations and directions for future research, including consideration for age effects, testing site, and disease type, with the goal of further advancing this important line of research.

Exposure to Gulf War Illness-related agents leads to the development of chronic pain and fatigue

AimsA substantial contingent of veterans from the first Gulf War continues to suffer from a number of Gulf War-related illnesses (GWI) affecting the neurological and musculoskeletal systems; the most common symptoms include chronic pain and fatigue. Although animal models have recapitulated several aspects of cognitive impairments in GWI, the pain and fatigue symptoms have not been well documented to allow examination of potential pathogenic mechanisms. Main methodsWe used a mouse model of GWI by exposing mice repeatedly to a combination of Gulf War chemicals (pyridostigmine bromide, permethrin, DEET, and chlorpyrifos) and mild immobilization stress, followed by investigating their pain susceptibilities and fatigue symptoms. To assess whether enhanced antioxidant capacity can counter the effects of GW agents, transgenic mice overexpressing extracellular superoxide dismutase (SOD3OE) were also examined. Key findingsThe mouse model recapitulated several aspects of the human illness, including hyperalgesia, impaired descending inhibition of pain, and increased tonic pain. There is a close association between chronic pain and fatigue in GWI patients. Consistent with this observation, the mouse model showed a significant reduction in physical endurance on the treadmill. Examination of skeletal muscles suggested reduction in mitochondrial functions may have contributed to the fatigue symptoms. Furthermore, the negative impacts of GW agents in pain susceptibilities were largely diminished in SOD3OE mice, suggesting that increased oxidative stress was associated with the emergence of these Gulf War symptoms. Significancethe mouse model will be suitable for delineating specific defects in the pain pathways and mechanisms of fatigue in GWI.

PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib

Skeletal interoception regulates bone homeostasis through the prostaglandin E2 (PGE2) concentration in bone. Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging. We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain. Importantly, treatment with a high-dose cyclooxygenase 2 inhibitor (celecoxib, 80 mg·kg−1 per day) decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability. However, this treatment impaired bone formation in porous endplates, and spinal pain recurred after discontinuing the treatment. Interestingly, low-dose celecoxib (20 mg·kg−1 per day, which is equivalent to one-quarter of the clinical maximum dosage) induced a latent inhibition of spinal pain at 3 weeks post-treatment, which persisted even after discontinuing treatment. Furthermore, when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib, endplate porosity was reduced significantly, which was associated with decreased sensory nerve innervation and spinal pain. These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity, thereby reducing sensory innervation and spinal pain in mice.

Functional and Anatomical Characterization of Corticotropin-Releasing Factor Receptor Subtypes of the Rat Spinal Cord Involved in Somatic Pain Relief

Corticotropin-releasing factor (CRF) orchestrates our body’s response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund’s complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.

Xylia xylocarpa (Roxb.) Taub. Leaves Ameliorates Inflammation and Pain in Experimental Mice and Computer-Aided Model

Xylia xylocarpa (Roxb.) Taub. is traditionally used to treat several diseases, including leprosy, wound healing, gonorrhea, rheumatism, anemia, diarrhea and ulcer. This study evaluated the anti-inflammatory and anti-nociceptive activities of methanolic extract of Xylia xylocarpa leaves (MEXX) via in vitro, in vivo as well as in silico models. In vitro anti-inflammatory activity was determined by human red blood cell membrane stabilization study and protein denaturation while in vivo anti-nociceptive activity was examined by the acetic acid-induced writhing test (AAWT) and formalin-induced paw licking test (FIPLT). Additionally, trans-5-hydroxypipecolic acid was an identified compound of MEXX which was subjected to molecular docking analysis followed by ADME/T and toxicity analysis. Qualitative phytochemical screening revealed that MEXX was enriched with carbohydrates, flavonoids, alkaloids, proteins, tannins and showed significant total phenolic (1222.66 ± 0.66 mg GAE/g dried extract) and flavonoids contents (325.33 ± 1.76 mg QE/g dried extract) in quantitative phytochemical screening. Inflammatory studies unveiled that; MEXX significantly (p &lt; 0.05) inhibited the hemolysis of membrane and protein at different concentrations (31.25 - 1000 μg/mL). The extract also displayed statistically significant analgesic responses in the acetic acid and formalin-induced test at several doses (200 and 400 mg/kg b.w). In AAWT, the extract exhibited 13.67 and 51.37 % inhibition of writhing at the doses 200 and 400 mg/kg body weight respectively. In formalin-induced paw licking test, the early phase pain inhibition was 54.64 % at the concentration of 400 mg/kg while during the latter phase at 400 mg/kg, the inhibition of pain was 43.82 %. According to molecular docking analysis, trans-5-hydroxypipecolic acid demonstrated a promising docking score against PDE4, COX-1, and COX-2 along with satisfied pharmacokinetic and toxicological properties. Finally, from the results it could be concluded that MEXX has potential anti-inflammatory and an-nociceptive effects that should require further investigation.&#x0D; HIGHLIGHTS&#x0D; &#x0D; Xylia xylocarpa minimizes the inflamation and pain&#x0D; Xylia xylocarpa showed significant analgesic activity&#x0D; Xylia xylocarpa revealed polyphenolic compounds including phenol, and flavonoid&#x0D; In in silico, trans-5-hydroxypipecolic acid possessed significant analgesic activity against COX-1 and COX-2&#x0D; &#x0D; GRAPHICAL ABSTRACT