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Sickle cell disease (SCD) patients experience recurrent episodes of excruciating acute pain and persistent chronic ongoing pain which negatively impacts their quality of life and is the main cause for hospitalizations. Although major progress has been made in understanding the complex SCD pathophysiology, marked deficiencies in the knowledge regarding SCD pain, the factors underlying the transition from acute to chronic pain, pain comorbidities and effective pain management have been realized. Several studies have reported a crucial role of gut microbiota in the pathophysiological features of SCD; however, its role in pain has not been explored. Our study aimed at evaluating the compositional differences in the gut microbiota of SCD transgenic mice and non-sickle control mice and differences in the gut-derived metabolites. We further investigated the role of gut microbiota in SCD pain by utilizing antibiotic-mediated gut microbiota depletion and fecal microbiota transplantation (FMT). We report significant differences in the alpha and beta diversity between the two cohorts. The antibiotic mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in SCD mice. FMT from sickle to non-sickle mice resulted in reduced pain threshold for von Frey (0.95±0.17g vs 0.08±0.02g, p Funding: This study was supported in part by a grant from the National Heart, Lung, and Blood Institute (NHLBI) R35 HL140021 (Z.W.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI or NIH. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

Context Unrelieved cancer pain at the end of life interferes with achieving patient-centered goals. Objective To compare effects of usual hospice care and PAINRelieveIt® on pain outcomes in patients and their lay caregivers. Methods In a five-step, stepped-wedge randomized, controlled study, 234 patients (49% male, 18% Hispanic, 51% racial minorities) and 231 lay caregivers (26% male, 20% Hispanic, 54% racial minorities) completed pre-pain/post-pain measures. They received usual hospice care with intervention components that included a summary of the patient's pain data, decision support for hospice nurses, and multimedia education tailored to the patient's and lay caregiver's misconceptions about pain. Results The intervention effect on analgesic adherence (primary outcome) was not significant. Post-test worst pain intensity was significantly higher for the experimental group, but the difference (0.70; CI = [0.12, 1.27]) was not clinically meaningful. There was nearly universal availability of prescriptions for strong opioids and adjuvant analgesics for neuropathic pain in both groups. Lay caregivers' pain misconceptions (0-5 scale) were significantly lower in the experimental group than the usual care group (mean difference controlling for baseline is 0.38; CI = [0.08, 0.67]; P = 0.01). Conclusion This randomized controlled trial was a negative trial for the primary study outcomes but positive for a secondary outcome. The trial is important for clearly demonstrating the feasibility of implementing the innovative set of interventions.

Recently, interest in using whole food-derived mixtures to alleviate chronic metabolic syndrome through potential synergistic interactions among different components is increasing. In this study, the effects and mechanisms of tuna meat oligopeptides (TMOP) on hyperuricemia and associated renal inflammation were investigated in mice. Dietary administration of TMOP alleviated hyperuricemia and renal inflammation phenotypes, reprogramed uric acid metabolism pathways, inhibited the activation of NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling pathways, and suppressed the phosphorylation of p65-NF-κB. In addition, TMOP treatments repaired the intestinal epithelial barrier, reversed the gut microbiota dysbiosis and increased the production of short-chain fatty acids. Moreover, the antihyperuricemia effects of TMOP were transmissible by transplanting the fecal microbiota from TMOP-treated mice, indicating that the protective effects were at least partially mediated by the gut microbiota. Thus, for the first time, we clarify the potential effects of TMOP as a whole food derived ingredient on alleviating hyperuricemia and renal inflammation in mice, and additional efforts are needed to confirm the beneficial effects of TMOP on humans.

Hyperuricaemia is a disease associated with elevated serum uric acid content, which has emerged rapidly in recent decades. The drugs used to treat clinical hyperuricaemia have side effects, and their safety is poor. However, anserine is a natural carnosine derivative that shows an anti-hyperuricaemic effect. A previous study demonstrated that anserine inhibits uric acid synthesis and promotes uric acid excretion, but there is no evidence regarding the effect of anserine from the perspective of the gut microbiota. In this study, the anti-hyperuricaemic and anti-inflammatory effects of anserine were explored in a diet-induced hyperuricaemic mouse model. Anserine alleviated hyperuricaemia and renal inflammation phenotypes, inhibited uric acid biosynthesis, promoted uric acid excretion, and inhibited NLRP3 inflammasome and TLR4/MyD88/NF-κB signalling pathway activation. The results showed that the anti-hyperuricaemic effect of anserine was dependent on the gut microbiota in the germ-free mice experiment. Furthermore, anserine treatment reversed gut microbiota dysbiosis, repaired the intestinal epithelial barrier and increased short-chain fatty acid production. Moreover, the anti-hyperuricaemic effect of anserine was transmissible by transplanting the faecal microbiota from anserine-treated mice, indicating that the protective effects were at least partially mediated by the gut microbiota. Thus, we identified a new and safe prebiotic material to alleviate hyperuricaemia and provided ideas for the development of oligopeptides.

Brain aging is commonly associated with neurodegenerative disorders, but the ameliorative effect of krill oil and the underlying mechanism remain unclear. In this study, the components of krill oil were measured, and the antiaging effects of krill oil were investigated in mice with d-galactose (d-gal)-induced brain aging via proteomics and gut microbiota analysis. Krill oil treatment decreased the expression of truncated dopamine- and cAMP-regulated phosphoproteins and proteins involved in the calcium signaling pathway. In addition, the concentrations of dopamine were increased in the serum (

Objectives: Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges. Design: In a repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry. Adults with SCD completed 4 study visits 6 months apart, and age- and gender-matched healthy controls completed 1 visit. Results: We recruited and completed measures on 186 patients with SCD and 125 healthy controls. We retained 151 patients with SCD with data at 4 time points over 18 months and 125 healthy controls (1 time point) but encountered many challenges in recruitment and study visit completion. Enrollment delays often arose from patients’ difficulty in taking time from their complicated lives and frequent pain episodes. Once scheduled, participants with SCD cancelled 49% of visits often because of pain; controls canceled 30% of their scheduled visits. To facilitate recruitment and retention, we implemented a number of strategies that were invaluable in our success. Conclusion: Patients’ struggles with illness, chronic pain, and their life situations resulted in many challenges to recruitment and completion of study visits. Important to overcoming challenges was gaining the trust of patients with SCD and a participant-centered approach. Early identification of potential problems allowed strategies to be instituted proactively, leading to success.

Purpose Only a few studies have reported quantitative sensory testing (QST) reference values for healthy African Americans, and those studies are limited in sample size and age of participants. The study purpose was to characterize QST values in healthy, pain-free African American adults and older adults whose prior pain experiences and psychological status were also measured. We examined the QST values for differences by sex, age, and body test site. Patients and methods A cross-sectional sample of 124 pain-free African American adults (age 18-69 years, 49% female) completed demographic and self-reported pain, fatigue and psychosocial measures. QST was performed to obtain thermal and mechanical responses and associated pain intensity levels. Results We found thermal detection values at the anterior forearm were (29.2 °C±1.6) for cool detection (CD) and (34.5 °C±1.2) for warm detection (WD). At that site the sample had cold pain threshold (CPTh) (26.3 °C±5.0), heat pain threshold (HPTh) (37.8 °C±3.6), and mechanical pain thresholds (MPTH) (16.7±22.2 grams of force, gF). There was a significant between sex difference for WD, with women being more sensitive (q=0.027). Lower body sites were less sensitive than upper body sites across all thermal modalities (q

Background Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system, as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications. Objectives The specific aim of this study was to identify the sensory pain quality descriptors that are associated with the QST-derived normal or sensitized classifications. We expected to find that sets of sensory pain quality descriptors would discriminate the classifications. Methods A cross-sectional quantitative study of existing data from 186 adults of African ancestry with SCD. Variables included MPQ descriptors, patient demographic data, and QST-derived classifications. Results The participants were classified as central sensitization (n = 33), mixed sensitization (n = 23), and normal sensation. Sensory pain quality descriptors that differed statistically between mixed sensitization and central sensation compared to normal sensitization included cold (p = .01) and spreading (p = .01). Aching (p = .01) and throbbing (p = .01) differed statistically between central sensitization compared with mixed sensitization and normal sensation. Beating (p = .01) differed statistically between mixed sensitization compared with central sensitization and normal sensation. No set of sensory pain quality descriptors differed statistically between QST classifications. Discussion Our study is the first to examine the association between MPQ sensory pain quality descriptors and QST-derived classifications in adults with SCD. Our findings provide the basis for the development of a MPQ subscale with potential as a mechanism-based screening tool for neuropathic pain.

Migraine is one of the most common neurological disorders characterized by recurrent attacks of typically throbbing and unilateral headaches, affecting up to 20% of the population worldwide. Despite the high prevalence and severity of this primary headache disorder, it remains to be a challenge to fully understand and treat migraine headaches. By characterizing and validating a mouse migraine model, this study aimed to investigate the functional contribution of protein kinase C (PKC) isoforms in migraine. In this study, we identified the presence of migraine-like ongoing pain in mice after chronic intermittent treatment with nitroglycerin (NTG). The peptide antagonist of calcitonin gene-related peptide α-CGRP (8-37), but not topiramate nor sumatriptan, effectively blocked ongoing pain and elicited pain relief-induced conditioned place preference in NTG-treated mice. Prominent activation of PKCδ was observed in chronic NTG-treated mice. Functional inhibition of PKCδ significantly attenuated ongoing spontaneous pain in chronic NTG-treated mice. Furthermore, we recapitulated the NTG-triggered migraine behavior in wild-type mice, but not in PKCδ-null mice. In response to repeated administration of NTG, ongoing spontaneous pain was not developed in mice lacking the specific PKC isoform. This study identified the presence of ongoing pain in mice treated with NTG, a known human migraine trigger that closely resembles the common manifestation of spontaneous migraine attacks in humans. These findings demonstrated a critical regulatory role of PKCδ in migraine pathophysiology, which may offer new pharmacological targets for antimigraine treatment.

Background Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. Methods Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. Results Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. Conclusions S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.

Correction for ‘The gut microbiota mediates the protective effects of anserine supplementation on hyperuricaemia and associated renal inflammation’ by Jiaojiao Han et al., Food Funct., 2021, 12, 9030–9042, DOI: 10.1039/D1FO01884A.

Background: Pain is the quintessential symptom for individuals suffering from sickle cell disease (SCD). Although the degree of suffering and the cost of treatment are staggering, SCD continues to be grossly understudied, including a lack of data for pain-related genes and prevalence of polymorphisms in this population. This lack of data adds to the inadequacy of pain therapy in this population. Pain genetics investigators have recently examined allele frequencies of single-nucleotide polymorphisms from candidate genes in people who have SCD. One of the genes identified was the arginine vasopressin receptor 1A gene (AVPR1A) and its associated single-nucleotide polymorphism (SNP) rs10877969. Progress in explaining pain-related polymorphisms associated with SCD can be facilitated by understanding the literature. Aim/Design: The purpose of this literature review was to describe mechanisms of the polymorphic gene AVPR1A and the phenotypic variations associated with its SNPs relative to health conditions and pain. Methods: Published studies were included if the research addressed AVPR1A and was a full article in a peer-reviewed journal, in the English language, a human or animal study, and published 2009 to present. Abstracts were included if they were in English and provided information not found in a full article. Results: The results of this review revealed that AVPR1A is associated with behavioral phenotypes, which include pair bonding, autism spectrum disorder, musical aptitude, infidelity, altruism, monogamy, mating, substance abuse, and alcohol preference. In addition, there were associations with pain, stress pain by sex, and sickle cell pain. Conclusion: Summary of this literature could provide insights into future pain research of this SNP in people with SCD.

Aim: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease. Method: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score. Results & conclusion: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p

Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4–6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence.

PurposeFrequencies of single nucleotide polymorphisms (SNPs) from pain related candidate genes are available for individuals with sickle cell disease (SCD). One of those genes, the arginine vasopressin receptor 1A gene (AVPR1A) and one of its SNPs, rs10877969, has been associated with pain and disability in other pain populations. In patients with SCD, clinical factors such as pain and stress have been associated with increased health care utilization, but it is not known if the presence of the AVPR1A SNP plays a role in this observation. The study purpose was to explore the relationships between rs10877969 and self-reported pain, stress, and acute care utilization events among individuals with SCD.MethodsIn a cross-sectional investigation of outpatients with SCD, participants completed PAINReportIt®, a computerized pain measure, to describe their pain experience and contributed blood or saliva samples for genetic analysis. We extracted emergency department and acute care utilization from medical records.ResultsThe SNP genotype frequencies (%) for this sample were CC 30 (28%), CT 44 (41%), TT 33 (31%). Acute care utilization and stress as an aggravator of pain were significantly associated with the rs10877969 genotype (p = .02 and p = .002, respectively). The CT genotype had the highest mean utilization and CC genotype was associated with not citing stress as a pain aggravator. Chronic pain was not associated with rs10877969 (p = .41).ConclusionThis study shows that rs10877969 is related to indicators of stress and acute pain. Further research is recommended with other measures of stress and acute pain.

Background In several studies, investigators have successfully used an internet-enabled PAINReportIt tablet to allow patients to report their pain to clinicians in real-time, but it is unknown how acceptable this technology is to patients and caregivers when used in their homes. Objective The aims of this study were to examine computer use acceptability scores of patients with end-stage cancer in hospice and their caregivers and to compare the scores for differences by age, gender, race, and computer use experience. Intervention/methods Immediately after using the tablet, 234 hospice patients and 231 caregivers independently completed the Computer Acceptability Scale (maximum scores of 14 for patients and 9 for caregivers). Results The mean (SD) Computer Acceptability score was 12.2 (1.9) for patients and 8.5 (0.9) for caregivers. Computer Acceptability scores were significantly associated with age and with previous computer use for both patients and caregivers. Conclusions This technology was highly acceptable to patients and caregivers for reporting pain in real time to their hospice nurses. Implications for practice Findings provide encouraging results that are worthy of serious consideration for patients who are in end stages of illness, including older persons and those with minimal computer experience. Increasing availability of technology can provide innovative methods for improving care provided to patients facing significant cancer-related pain even at the end of life.

Scope The effects and mechanism of tuna bone powder (TBP) on glucocorticoid-induced osteoporosis (GIOP) alleviation in terms of signaling pathway coregulation and gut microbiota modulation are investigated. Methods and results The powder size distribution and composition of TBP are measured. The GIOP female mice induced by dexamethasone intramuscular injection are used to examine the anti-osteoporosis effects of TBP in a 10 week experiment, and improved bone mineral density and bone microarchitecture are observed via micro-CT. In addition, qRT-PCR results show that the NF-κB pathway is inhibited to reduce bone resorption, whereas the Wnt/β-catenin pathway is activated to enhance bone formation after treatment. Moreover, TBP treatments suppress the release of pro-inflammatory cytokines, repair dysfunction of the intestinal epithelial barrier, and prevent aggravated systemic inflammation in mRNA levels. Additionally, 16S rRNA gene sequencing indicate that TBP treatments enhance the abundance of anti-inflammatory bacteria and short-chain fatty acid (SCFA) producers, which is consistent with increased SCFA contents in feces measured via GC-MS. Conclusion These data show that TBP ameliorates GIOP in mice through four aspects, including coregulating signaling pathways, blocking proinflammatory cytokines, repairing the intestinal epithelial barrier, and modulating gut microbiota. Therefore, TBP may be a potential prebiotic agent to alleviate osteoporosis in humans.

Evidence supports, but is inconclusive that sensitization contributes to chronic pain in some adults with sickle cell disease (SCD). We determined the prevalence of pain sensitization among adults with SCD pain compared with pain-free healthy adults. In a cross sectional, single session study of 186 African American outpatients with SCD pain (age 18–74 years, 59% female) and 124 healthy age, gender, and race matched control subjects (age 18–69 years, 49% female), we compared responses to standard thermal (Medoc TSA II) and mechanical stimuli (von Frey filaments). Although we observed no significant differences in thermal thresholds between controls and patients, patients with SCD had lower pain thresholds to mechanical stimuli and reported higher pain intensity scores to all thermal and mechanical stimuli at a non-painful body site. Compared with controls, about twice as many patients with SCD showed sensitization: 12% versus 23% at the anterior forearm site (P = .02), and 16% versus 32% across 3 tested sites (P = .004). Among patients with SCD, 18% exhibited some element of central sensitization. Findings indicate that persistent allodynia and hyperalgesia can be part of the SCD pain experience and should be considered when selecting therapies for SCD pain. Perspective Compared with matched healthy controls, quantitative sensory testing in adults with pain and sickle cell disease (SCD) demonstrates higher prevalence of sensitization, including central sensitization. The findings of allodynia and hyperalgesia may indicate neuropathic pain and could contribute to a paradigm shift in assessment and treatment of SCD pain.

BACKGROUND We sought to refine a screening measure for discriminating a sensitized or normal sensation pain phenotype among African American adults with sickle cell disease (SCD). OBJECTIVE To develop scoring schemes based on sensory pain quality descriptors; evaluate their performance on classifying patients with SCD who had sensitization or normal sensation, and compare with scores on the Self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and the Neuropathic Pain Symptom Inventory (NPSI). METHODS Participants completed PAINReportIt, quantitative sensory testing (QST), S-LANSS, and NPSI. Conventional binary logistic regression and least absolute shrinkage and selection operator (lasso) regression were used to obtain 2 sets of weights resulting in 2 scores: the PR-Logistic (PAINReportIt score weighted by conventional binary logistic regression coefficients) and PR-Lasso (PAINReportIt score weighted by lasso regression coefficients). Performance of the proposed scores and the existing scores were evaluated. RESULTS Lasso regression resulted in a parsimonious model with non-zero weights assigned to 2 neuropathic descriptors, cold and spreading. We found positive correlations between the PR-Lasso and other scores: S-LANSS (r = 0.22, P

Individuals with pain from sickle cell disease (SCD) are often treated for nociceptive pain, but recent findings indicate they may also have neuropathic pain. PAIN ReportIt, a computerized version of the McGill Pain Questionnaire, provides a potential subscale that is the summed number of selected neuropathic pain quality words (PR-NNP), but it lacks construct validity. The study purpose was to ascertain PR-NNP construct validity in adults with SCD and chronic pain. In an outpatient setting, 186 participants completed the PAIN ReportIt, Neuropathic Pain Symptom Inventory (NPSI), and Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). PR-NNP was moderately correlated with NPSI ( r = .33, p < .001) and S-LANSS ( r = .40, p < .001). Regression analysis indicated that PR-NNP and pain intensity, but not a nociceptive pain subscale, were significant predictors of NPSI and S-LANSS. Findings support construct validity of PR-NNP, which may be useful as a screening tool for neuropathic pain in patients with SCD.

Aim: Pain is prevalent in sickle cell disease (SCD) patients who display great heterogeneity in pain severity and frequency. Hypothesizing that inflammatory factors are involved in the pathogenesis of SCD pain, we focused on the IL1A C/T polymorphism rs1800587 that is an SNP located in a cis-transcriptional regulatory region. Methods: We genotyped IL1A rs1800587 and performed association studies with phenotype data obtained by a multidimensional pain assessment tool using the PAINReportIt® Questionnaire. Results: Each T allele was associated with a 3.9 increase in composite pain index score (p = 0.04) as determined by multiple linear regression. Conclusion: IL1A rs1800587 may influence chronic pain in SCD.

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

Pain is one of the most challenging and stressful conditions to patients with sickle cell disease (SCD) and their clinicians. Patients with SCD start experiencing pain as early as three months old and continue having it throughout their lives. Although many aspects of the disease are well understood, little progress has been made in understanding and treating pain in SCD. This study aimed to investigate the functional involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) in the persistent and refractory pain associated with SCD. We found non-evoked ongoing pain as well as evoked hypersensitivity to mechanical and thermal stimuli were present in Berkeley sickle cell transgenic mice (BERK mice), but not non-sickle control littermates. Prominent activation of CaMKIIα was observed in the dorsal root ganglia and spinal cord dorsal horn region of BERK mice. Intrathecal administration of KN93, a selective inhibitor of CaMKII, significantly attenuated mechanical allodynia and heat hyperalgesia in BERK mice. Meanwhile, spinal inhibition of CaMKII elicited conditioned place preference in the BERK mice, indicating the contribution of CaMKII in the ongoing spontaneous pain of SCD. We further targeted CaMKIIα by siRNA knockdown. Both evoked pain and ongoing spontaneous pain were effectively attenuated in BERK mice. These findings elucidated, for the first time, an essential role of CaMKIIα as a cellular mechanism in the development and maintenance of spontaneous and evoked pain in SCD, which can potentially offer new targets for pharmacological intervention of pain in SCD.

Opioid-induced hyperalgesia (OIH) is a less-studied phenomenon that has been reported in both preclinical and clinical studies. Although the underlying cause is not entirely understood, OIH is a real-life problem that affects millions of patients on a daily basis. Research has implicated the important contribution of Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) to OIH at the level of spinal nociceptors. To expand our understanding of the entire brain circuitry driving OIH, in this study we investigated the role of CaMKIIα in the laterocapcular division of the central amygdala (CeLC), the conjunctive point between the spinal cord and rostro-ventral medulla. OIH was produced by repeated fentanyl administration in the rat. Correlating with the development of mechanical allodynia and thermal hyperalgesia, CaMKIIα activity was significantly elevated in the CeLC in OIH. In addition, the frequency and amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in CeLC neurons were significantly increased in OIH. 2-[N-(2-hidroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, a CaMKIIα inhibitor, dose dependently reversed sensory hypersensitivity, activation of CeLC CaMKIIα, and mEPSCs in OIH. Taken together, our data for the first time implicate a critical role of CeLC CaMKIIα in OIH.

Aim To test feasibility of a guided audio-visual relaxation intervention protocol for reducing stress and pain in adults with sickle cell disease. Background Sickle cell pain is inadequately controlled using opioids, necessitating further intervention such as guided relaxation to reduce stress and pain. Design Attention-control, randomized clinical feasibility pilot study with repeated measures. Methods Randomized to guided relaxation or control groups, all patients recruited between 2013–2014 during clinical visits, completed stress and pain measures via a Galaxy Internet-enabled Android tablet at the Baseline visit (pre/post intervention), 2-week posttest visit and also daily at home between the two visits. Experimental group patients were asked to use a guided relaxation intervention at the Baseline visit and at least once daily for 2 weeks. Control group patients engaged in a recorded sickle cell discussion at the Baseline visit. Data were analysed using linear regression with bootstrapping. Results At baseline, 27/28 of consented patients completed the study protocol. Group comparison showed that guided relaxation significantly reduced current stress and pain. At the 2-week posttest, 24/27 of patients completed the study, all of whom reported liking the study. Patients completed tablet-based measures on 71% of study days (69% in control group, 72% in experiment group). At the 2-week posttest, the experimental group had significantly lower composite pain index scores, but the two groups did not differ significantly on stress intensity. Conclusion This study protocol appears feasible. The tablet-based guided relaxation intervention shows promise for reducing sickle cell pain and warrants a larger efficacy trial. Trial registration The ClinicalTrials.gov Identifier is: NCT02501447.

In this study, a high-throughput strategy combined with MALDI TOF/TOF-MS and Discovery Studio 2017 was developed to screen peptides with certain functions from hydrolysate. Two dominant peptides, Ile-Cys-Arg-Asp (ICRD) and Leu-Cys-Gly-Glu-Cys (LCGEC), were predicted to have antioxidant activity by Discovery Studio 2017. Then the activity in vitro of peptides had been confirmed via DPPH assay. Both two peptides decreased apoptosis induced by UVB treatment in HaCaT cells and altered Keap1/Nrf2-ARE pathway transcription. Furthermore, the antioxidant activity of LCGEC was achieved after 6-week treatment in mice via regulating the Keap1/Nrf2-ARE pathway, inhibiting the release of proinflammatory cytokines, increasing the abundance of 3-indolepropionic acid and short-chain fatty acids production in feces and modulating gut microbiota composition. This study provided two tuna roe peptides with in vitro and in vivo antioxidant activity.

Introduction: Only a few studies have reported quantitative sensory testing (QST) reference values for healthy African Americans, and those studies are limited in sample size and range of age of participants. The intent of our study was to fill a gap in the understanding of pain and somatosensory function in African Americans by generating QST values for healthy African American adults. In a large cohort of pain-free, healthy African American adults whose past pain experiences and current psychological status were known, our study aim was to determine thermal and mechanical QST values and compare those values at the anterior forearm by age and sex. We also determined the values for 5 other body sites and compared the values for differences by testing site location (upper body versus lower body). Methodology: In this cross-sectional study, 124 pain-free African American adults (age 18 to 69 years, 49% female) completed demographic and self-reported pain, fatigue and psychosocial measures. QST included obtaining thermal and mechanical responses and associated pain intensity levels. We applied the Benjamini-Hochberg procedure to adjust the p values to account for the multiple t tests. Results: We found thermal detection values at the anterior forearm were (29.2°C±1.6) for cool detection (CD) and (34.5°C±1.2) for warm detection (WD). At that site, pain thresholds were: cold pain threshold (CPTh) (26.3°C±5.0), heat pain threshold (HPTh) (37.8°C±3.6), and mechanical pain thresholds (MPTH) (16.7±22.2 grams of force, gF). There was a significant between sex difference for WD, with women being more sensitive (q=0.027). Lower body sites were less sensitive than upper body sites across all thermal modalities (q Citation Format: Keesha L. Powell-Roach, Starja Q. Booker, Yingwei Yao, Marie L. Suarez, Miriam O. Ezenwa, Roger B. Fillingim, Zaijie J. Wang, Robert E. Molokie, Diana J. Wilkie. Age and sex effects on quantitative sensory testing values in healthy African American adults [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D044.

Remifentanil is commonly used clinically for perioperative pain relief, but it may induce postoperative hyperalgesia. Low doses of ketamine have remained a common choice in clinical practice, but the mechanisms of ketamine have not yet been fully elucidated. In this study, we examined the possible effects of ketamine on calcium/calmodulin-dependent protein kinase II α (CaMKIIα) and N-methyl- d -aspartate receptor (NMDAR) subunit NR2B in a mouse model of remifentanil-induced postoperative hyperalgesia (RIPH) in the primary somatosensory cerebral cortex (SI) region. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess mechanical allodynia and thermal hyperalgesia, respectively, before and after intraoperative remifentanil administration. Before surgery, mice received intrathecal injections of the following drugs: ketamine, NMDA, BayK8644 (CaMKII activator), and KN93 (CaMKII inhibitor). Immunofluorescence was performed to determine the anatomical location and expression of activated CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα). Additionally, western blotting was performed to assess p-CaMKIIα and NMDAR expression levels in the SI region. Remifentanil decreased the PWMT and PWTL at 0.5 h, 2 h, and 5 h and increased p-CaMKIIα expression in the SI region. Ketamine increased the PWMT and PWTL and reversed the p-CaMKIIα upregulation. Both BayK8644 and NMDA reversed the effect of ketamine, decreased the PWMT and PWTL, and upregulated p-CaMKIIα expression. In contrast, KN93 enhanced the effect of ketamine by reducing hyperalgesia and downregulating p-CaMKIIα expression. These results suggested that ketamine reversed RIPH by inhibiting the phosphorylation of CaMKIIα and the NMDA receptor in the SI region in mice.

Objective To compare effects of a tailored multimedia education program versus usual-care on barriers to pain management of adult patients with SCD. Methods Pretest/posttest randomized controlled trial (RCT) of 228 outpatients with SCD randomized to the tablet-based PAINUCope intervention focused on barriers to pain management, pain, and analgesic adherence or selection of games (control). Outcomes were barriers to pain management, pain, and analgesic adherence. Results The barriers to pain management and pain scores did not change significantly from pretest to posttest for either condition. Changes in analgesic adherence rates from pretest to posttest were statistically significant for the intervention group (p = .046) but not for the usual care group (p = .419). The group difference was not statistically significant. Conclusions This first RCT of a tailored multimedia education intervention with adult patients with SCD did not significantly reduce the outcomes of interest compared to the control group. Findings provide insights for improving intervention delivery and reinforcement of patient behaviors. Practice implications Study redesign is warranted with modifications that include theoretical and methodological approaches and patient-centered delivery of the intervention that take advantage of recent technology developments.

Pain is the most characteristic feature of sickle cell disease (SCD). Patients with SCD live with unpredictable, recurrent episodes of acute painful crisis, as well as chronic unremitting pain throughout their lifetime. While most of the research and medical efforts have focused on treating vaso-occlusion crisis and acute pain, chronic pain remains a significant challenge faced by patients and physicians. Emerging evidence from human and animal studies has suggested the presence of a neuropathic component in SCD pain. New knowledge on the neurobiology of chronic pain in SCD has significant implications in unraveling the underlying mechanisms. This review focuses on the recent advances on the role of protein kinase C or PKC in promoting and maintaining chronic pain conditions. With a highlight of a specific PKC isoform, PKCδ, we aim to propose PKC as an essential regulator of chronic pain in SCD, which may ultimately lead to innovative therapeutic strategies for treating this devastating life-long problem in patients with SCD.

Aim: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. Methods: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. Results & conclusion: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = −3.76, p = 0.037; dominant model: B = −5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1.37, p = 0.024; recessive model: IRR = 1.81, p = 0.018) with utilization rate. These associations persisted when subjects with HbSS and HbS(−)β genotype only were analyzed. We also identified two haploblocks (rs10483639[G>C]-rs752688 [C>T]-rs4411417[T>C] and rs3783641[T>A]-rs8007267[T>C]) with SNPs in high linkage disequilibrium. Of these, haplotype T-C of haploblock rs3783641-rs8007267 showed significant association with rate of utilization (odds ratio [OR] = 0.31, p = 0.001). Our study indicates potential contribution of GCH1 polymorphisms to the variability of pain in African Americans with SCD.

Patients with sickle cell disease (SCD) report pain scores that appear greater than those reported in a meta-analysis for patients with cancer, but statistical comparisons of the pain scores from both populations have not been published.The goal of the study described here was to compare pain outcomes reported by outpatients with cancer or SCD.Descriptive comparative study.Outpatient oncology or sickle cell clinics.The participants were outpatients (N = 415) from three studies: (1) 106 patients with SCD, 93% African-American (referent group); (2) 140 patients with cancer, 90% Caucasian (race discordant); (3) 169 patients with cancer, 20% Caucasian, 65% African-American (race concordant).Patients completed the PAINReportIt including pain location, quality, pattern, intensity, expectation, satisfaction, and demographic questions. Analyses included the χOutpatients with SCD reported more pain location sites than the race-discordant (p .001) and race-concordant (p .001) cancer groups; higher pain quality than the race-discordant (p .001) and race-concordant (p .001) groups; and greater pain pattern scores than the race-discordant (p .001) and race-concordant (p .001) groups. The race-concordant group reported higher worst pain intensity than the SCD (p .001) and race-discordant (p = .002) groups. The three groups did not differ significantly on pain expectation (p = .06). Regarding satisfaction with pain level, there was a significant difference between the race-concordant and SCD (p = .006) groups, but not between the race-discordant and SCD (p = .12) groups or between the race-discordant and race-concordant (p = .49) groups.Outpatients with SCD reported three of four sensory pain parameters that were greater than those reported by outpatients with cancer. A better understanding of these differences is pertinent to improving pain outcomes.

Pain is a common and severe symptom in multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the CNS. The neurobiological mechanism underlying MS pain is poorly understood. In this study, we investigated the role of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) in driving chronic pain in MS using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that spinal CaMKIIα activity was enhanced in EAE, correlating with the development of ongoing spontaneous pain and evoked hypersensitivity to mechanical and thermal stimuli. Prophylactic or acute administration of KN93, a CaMKIIα inhibitor, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE. siRNA targeting CaMKIIα reversed established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIαT286A point mutation mice showed significantly reduced EAE clinical scores, an absence of evoked pain, and ongoing spontaneous pain when compared with littermate wild-type mice. We found that IL-17 is responsible for inducing but not maintaining mechanical and thermal hyperalgesia that is mediated by CaMKIIα signaling in EAE. Together, these data implicate a critical role of CaMKIIα as a cellular mechanism for pain and neuropathy in multiple sclerosis and IL-17 may act upstream of CaMKIIα in the generation of pain.SIGNIFICANCE STATEMENTPain is highly prevalent in patients with multiple sclerosis (MS), significantly reducing patients' quality of life. Using the experimental autoimmune encephalomyelitis (EAE) model, we were able to study not only evoked hyperalgesia, but also for the first time to demonstrate spontaneous pain that is also experienced by patients. Our study identified a role of spinal CaMKIIα in promoting and maintaining persistent ongoing spontaneous pain and evoked hyperalgesia pain in EAE. We further demonstrated that IL-17 contributes to persistent pain in EAE and functions as an upstream regulator of CaMKIIα signaling. These data for the first time implicated CaMKIIα and IL-17 as critical regulators of persistent pain in EAE, which may ultimately offer new therapeutic targets for mitigating pain in multiple sclerosis.

Adults with sickle cell disease (SCD) have episodic crisis pain and chronic pain. Little is known about SCD chronic pain phenotypes. Quantitative sensory testing (QST) identifies the objective contribution of allodynia and hyperalgesia to chronic SCD pain phenotypes. However, self-report measures are needed to further characterize SCD chronic pain phenotypes. Our aim was to determine associations among QST-determined sensitization and anxiety, depression, and fatigue among outpatients with SCD. In a cross-sectional study, subjects (N=186, mean age 36.6 ± 11.7 years [19-74 years], 97% African American, 59% female; SC type 72% SS, 18% SC, 5% S-β thal+, 4% unknown) completed thermal and mechanical QST [heat/cold/mechanical pain thresholds and levels]) at three body sites. They completed pain intensity (API [average of pain now, least, and worst pain in the past 24 hours]) on a scale of 0 [no pain] to 10 [pain as bad as it could be] and the PROMIS anxiety (α=.90), depression (α=.94), and fatigue (α=.83) scales (higher scores represent more of the concept being measured). Descriptive analysis, Independent t-tests, and multiple linear logistic regression were conducted. QST findings indicated that 58 (31%) patients had sensitization and 126 (68%) did not have sensitization (two had missing data). Bivariate analysis for sensitized vs not sensitized groups were API, 5.3 ± 2.2 vs. 4.0 ± 2.4 (p= 0.001); anxiety, 56.2 ± 8.5 vs 52.6 ± 9.1 (p= 0.01); depression, 55.1 ± 10.2 vs 51.0 ± 9.2 (p= 0.01); and fatigue, 59.8 ± 9.1 vs 54.9 ± 8.6 (p=.001). API, fatigue, depression, and anxiety were not significant in the logistic regression model including all four as predictors of sensitization. Focus of future studies should be on factors that are associated with sensitization in adults with SCD. Supported by grant #: R01 HL124945-01 (MPIs: Wilkie, Molokie, Wang).