Protective effects of tuna meat oligopeptides (TMOP) supplementation on hyperuricemia and associated renal inflammation mediated by gut microbiota.

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.

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management.

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct µ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-µ) to a ligand-free active form (MOR-µ*), which mediates MOR signaling. Moreover, MOR-µ converts spontaneously to MOR-µ* (basal signaling). Persistent upregulation of MOR-µ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-µ and MOR-µ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6ß-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-µ*, naltrexone but not 6ß-naltrexol suppresses MOR-µ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-µ*with high potency, whereas 6ß-naltrexol must compete with agonists at MOR-µ, accounting for ~100-fold lower in vivo potency. Buprenorphine's bell-shaped dose-response curve may also result from opposing effects on MOR-µ and MOR-µ*. In contrast, we find that 6ß-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6ß-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

A QST-based Pain Phenotype in Adults With Sickle Cell Disease: Sensitivity and Specificity of Quality Descriptors.

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 < 0.01), NPSI (r = 0.22, P < 0.01), and PR-Logistic (r = 0.35, P < 0.01). The NPSI and PR-Lasso performed similarly at different levels of required specificity and outperformed the S-LANSS and PR-Logistic at the various specificity points. CONCLUSION: The PR-Lasso offers a way to discriminate a SCD pain phenotype.

CaMKIIα Mediates the Effect of IL-17 To Promote Ongoing Spontaneous and Evoked Pain in Multiple Sclerosis.

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 STATEMENT Pain 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.

Relationship of Pain Quality Descriptors and Quantitative Sensory Testing: Sickle Cell Disease.

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.

Opioid doses and acute care utilization outcomes for adults with sickle cell disease: ED versus acute care unit.

BACKGROUND: Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. METHODS: In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. FINDINGS: Pain on admission to the ED averaged 8.7±1.5 and to the ACU averaged 8.0±1.6. The average pain on discharge from the ED was 6.4±3.0 and for the ACU was 4.5±2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. CONCLUSIONS: Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions.

The AVPR1A Gene and Its Single Nucleotide Polymorphism rs10877969: A Literature Review of Associations with Health Conditions and Pain.

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.

Differences in Sensory Pain, Expectation, and Satisfaction Reported by Outpatients with Cancer or Sickle Cell Disease.

BACKGROUND: 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. AIMS: The goal of the study described here was to compare pain outcomes reported by outpatients with cancer or SCD. DESIGN: Descriptive comparative study. SETTING: Outpatient oncology or sickle cell clinics. SUBJECTS: 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). METHODS: Patients completed the PAINReportIt including pain location, quality, pattern, intensity, expectation, satisfaction, and demographic questions. Analyses included the χ2 test, analysis of variance, and regression. RESULTS: Outpatients 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. CONCLUSIONS: 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.

Nociceptor beta II, delta, and epsilon isoforms of PKC differentially mediate paclitaxel-induced spontaneous and evoked pain.

As one of the most effective and frequently used chemotherapeutic agents, paclitaxel produces peripheral neuropathy (paclitaxel-induced peripheral neuropathy or PIPN) that negatively affects chemotherapy and persists after cancer therapy. The mechanisms underlying this dose-limiting side effect remain to be fully elucidated. This study aimed to investigate the role of nociceptor protein kinase C (PKC) isoforms in PIPN. Employing multiple complementary approaches, we have identified a subset of PKC isoforms, namely ßII, δ, and ϵ, were activated by paclitaxel in the isolated primary afferent sensory neurons. Persistent activation of PKCßII, PKCδ, and PKCϵ was also observed in the dorsal root ganglion neurons after chronic treatment with paclitaxel in a mouse model of PIPN. Isoform-selective inhibitors of PKCßII, PKCδ, and PKCϵ given intrathecally dose-dependently attenuated paclitaxel-induced mechanical allodynia and heat hyperalgesia. Surprisingly, spinal inhibition of PKCßII and PKCδ, but not PKCϵ, blocked the spontaneous pain induced by paclitaxel. These data suggest that a subset of nociceptor PKC isoforms differentially contribute to spontaneous and evoked pain in PIPN, although it is not clear whether PKCϵ in other regions regulates spontaneous pain in PIPN. The findings can potentially offer new selective targets for pharmacological intervention of PIPN.

Inhibition of CaMKIIα in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats.

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.

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1.

AIM: Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. METHODS: Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 µmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg(-1)·d(-1)) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. RESULTS: Pretreatment with quercetin (3, 10, 30 µmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. CONCLUSION: Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and demonstrate the therapeutic potential of quercetin for treating this side effect.

Satisfied or not satisfied: pain experiences of patients with sickle cell disease.

AIMS: To examine the relationship between pain and satisfaction in patients with sickle cell disease. BACKGROUND: Frequency and severity of unrelieved sickle cell pain are positively associated with mortality. Yet, information is scarce on whether sickle cell patients are satisfied with their pain level. DESIGN: A cross-sectional, correlational analysis of baseline data from a randomized clinical trial. METHODS: A randomized sample of adult outpatients was recruited between February 2007-March 2011. Patients completed the PAINReportIt(®) , containing measures of pain, satisfaction and socio-demographics. We analysed data using Kendall's rank correlations, analysis of variance, Tukey-Kramer post hoc tests, Fisher's tests and proportional odds logistic regression. RESULTS: There were statistically significant correlations between pain outcomes and satisfaction with pain level, but average pain intensity more strongly discriminated groups based on satisfaction with pain level. Among pain variables bivariately associated with patient satisfaction with pain level, only pain expectation maintained its significant relationship with satisfaction with pain level when average pain intensity was controlled. A smaller percentage of our sickle cell patients reported moderate to severe pain intensity (28%) or high composite pain index (39%), while reporting being satisfied with pain their level than reported in earlier studies using different measures and populations (70-94%). CONCLUSION: Satisfaction with pain level was an unambiguous measure of patient satisfaction and a promising indicator of pain that did not show the paradoxical relationship between satisfaction and pain seen with past measures.

A randomized controlled pilot study feasibility of a tablet-based guided audio-visual relaxation intervention for reducing stress and pain in adults with sickle cell disease.

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.

Safety and Utility of Quantitative Sensory Testing among Adults with Sickle Cell Disease: Indicators of Neuropathic Pain?

OBJECTIVES: Pain is the hallmark symptom of sickle cell disease (SCD), yet the types of pain that these patients experience, and the underlying mechanisms, have not been well characterized. The study purpose was to determine the safety and utility of a mechanical and thermal quantitative sensory testing (QST) protocol and the feasibility of utilizing neuropathic pain questionnaires among adults with SCD. METHODS: A convenience sample (N = 25, 18 women, mean age 38.5 ± 12.5 [20-58 years]) completed self-report pain and quality-of-life tools. Subjects also underwent testing with the TSA-II NeuroSensory Analyzer and calibrated von Frey microfilaments. RESULTS: We found that the QST protocol was safe and did not stimulate a SCD pain crisis. There was evidence of central sensitization (n = 15), peripheral sensitization (n = 1), a mix of central and peripheral sensitization (n = 8), or no sensitization (n = 1). The neuropathic pain self-report tools were feasible with evidence of construct validity; 40% of the subjects reported S-LANSS scores that were indicative of neuropathic pain and had evidence of central, peripheral or mixed sensitization. DISCUSSION: The QST protocol can be safely conducted in adults with SCD and provides evidence of central or peripheral sensitization, which is consistent with a neuropathic component to SCD pain. These findings are novel, warrant a larger confirmatory study, and indicate the need for normative QST data from African American adults and older adults.

Curcumin attenuates opioid tolerance and dependence by inhibiting Ca2+/calmodulin-dependent protein kinase II α activity.

Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca(2+)/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug's poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1-10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity.

Composite Pain Index: Reliability, Validity, and Sensitivity of a Patient-Reported Outcome for Research.

OBJECTIVE: A single score that represents the multidimensionality of pain would be an innovation for patient-reported outcomes. Our aim was to determine the reliability, validity, and sensitivity of the Composite Pain Index (CPI). DESIGN: Methodological analysis of data from a randomized controlled, pretest/post-test education-based intervention study. SETTING: The study was conducted in outpatient oncology clinics. SUBJECTS: The 176 subjects had pain, were 52 ± 12.5 years on average, 63% were female, and 46% had stage IV cancers. METHODS: We generated the CPI from pain location, intensity, quality, and pattern scores measured with an electronic version of Melzack's McGill Pain Questionnaire. RESULTS: The internal consistency values for the individual scores comprising the CPI were adequate (0.71 baseline, 0.69 post-test). Principal components analysis extracted one factor with an eigenvalue of 2.17 with explained variance of 54% at baseline and replicated the one factor with an eigenvalue of 2.11 at post-test. The factor loadings for location, intensity, quality, and pattern were 0.65, 0.71, 0.85, and 0.71, respectively (baseline), and 0.59, 0.81, 0.84, and 0.63, respectively (post-test). The CPI was sensitive to an education intervention effect. CONCLUSIONS: Findings support the CPI as a score that integrates the multidimensional pain experience in people with cancer. It could be used as a patient-reported outcome measure to quantify the complexity of pain in clinical research and population studies of cancer pain and studied for relevance in other pain populations.

Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality.

OBJECTIVE: Poor prognosis of sepsis is associated with bacterial lipopolysaccharide (LPS)-induced intravascular inflammation, microvascular thrombosis, thrombocytopenia, and disseminated intravascular coagulation. Platelets are critical for thrombosis, and there has been increasing evidence of the importance of platelets in endotoxemia. The platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), mediates platelet adhesion to inflammatory vascular endothelium and exposed subendothelium. Thus, we have investigated the role of GPIb-IX in LPS-induced platelet adhesion, thrombosis, and thrombocytopenia. APPROACH AND RESULTS: LPS-induced mortality is significantly decreased in mice expressing a functionally deficient mutant of GPIbα. Furthermore, we have developed a micellar peptide inhibitor, MPαC (C13H27CONH-SIRYSGHpSL), which selectively inhibits the von Willebrand factor -binding function of GPIb-IX and GPIb-IX-mediated platelet adhesion under flow without affecting GPIb-IX-independent platelet activation. MPαC inhibits platelet adhesion to LPS-stimulated endothelial cells in vitro and alleviates LPS-induced thrombosis in glomeruli in mice. Importantly, MPαC reduces mortality in LPS-challenged mice, suggesting a protective effect of this inhibitor during endotoxemia. Interestingly, MPαC, but not the integrin antagonist, Integrilin, alleviated LPS-induced thrombocytopenia. CONCLUSIONS: These data indicate an important role for the platelet adhesion receptor GPIb-IX in LPS-induced thrombosis and thrombocytopenia, and suggest the potential of targeting GPIb as an antiplatelet strategy in managing endotoxemia.

Dopamine D3 receptor Ser9Gly and catechol-o-methyltransferase Val158Met polymorphisms and acute pain in sickle cell disease.

BACKGROUND: Pain in sickle cell disease (SCD) is characterized by episodes of acute pain, primarily responsible for acute health care utilization, and persistent chronic pain. Pain severity and frequency vary significantly among patients with SCD. In this study, we investigated the possible contribution of monoamine gene polymorphisms to pain variation. METHODS: Adult subjects with SCD completed PAINReportIt, a computerized McGill Pain Questionnaire, from which we calculated the Composite Pain Index. Utilization data were obtained from the medical record and biweekly telephone calls for 12 months. Utilization is defined as admissions to the emergency department and/or the acute care center resulting from a sickle cell pain crisis. We performed genotyping for catechol-O-methyltransferase (COMT) Val158Met (rs4680) and dopamine D3 receptor (DRD3) Ser9Gly (rs6280) polymorphisms, which were analyzed for associations with pain phenotypes. RESULTS: Binary logistic models revealed that DRD3 Ser9Gly heterozygote patients were more likely not to have an acute pain crisis (odds ratio [OR] [95% confidence interval {CI}], 4.37 [1.39-22.89]; P = 0.020), which remained so when demographic variables were considered (OR [95% CI], 4.53 [1.41-28.58]; P = 0.016). COMT Val158Met Met allele showed lower probability for zero utilization (OR [95% CI], 0.32 [0.12-0.83]; P = 0.020) than the Val allele. In the negative binomial regression analysis, subjects with COMT Met/Met genotype had utilization incident rate ratio (95% CI) of 2.20 (1.21-3.99) over those with Val/Val (P = 0.010). CONCLUSIONS: These exploratory findings suggest that DRD3 Ser9Gly and COMT Val158Met may contribute to pain heterogeneity in SCD, as suggested by the different rates of acute pain crisis. Specifically, SCD patients with the DRD3 homozygote genotypes, COMT 158 Met allele or Met/Met genotype, are more likely to have acute care utilization, an indicator of acute pain. These results, however, will need to be further examined in future large prospective studies.

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease.

ABSTRACT: Pain is the most common symptom experienced by patients with sickle cell disease (SCD) throughout their lives and is the main cause of hospitalization. Despite the progress that has been made towards understanding the disease pathophysiology, major gaps remain in the knowledge of SCD pain, the transition to chronic pain, and effective pain management. Recent evidence has demonstrated a vital role of gut microbiota in pathophysiological features of SCD. However, the role of gut microbiota in SCD pain is yet to be explored. We sought to evaluate the compositional differences in the gut microbiota of transgenic mice with SCD and nonsickle control mice and investigate the role of gut microbiota in SCD pain by using antibiotic-mediated gut microbiota depletion and fecal material transplantation (FMT). The antibiotic-mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in mice with SCD. Fecal material transplantation from mice with SCD to wild-type mice resulted in tactile allodynia (0.95 ± 0.17 g vs 0.08 ± 0.02 g, von Frey test, P < 0.001), heat hyperalgesia (15.10 ± 0.79 seconds vs 8.68 ± 1.17 seconds, radiant heat, P < 0.01), cold allodynia (2.75 ± 0.26 seconds vs 1.68 ± 0.08 seconds, dry ice test, P < 0.01), and anxiety-like behaviors (Elevated Plus Maze Test, Open Field Test). On the contrary, reshaping gut microbiota of mice with SCD with FMT from WT mice resulted in reduced tactile allodynia (0.05 ± 0.01 g vs 0.25 ± 0.03 g, P < 0.001), heat hyperalgesia (5.89 ± 0.67 seconds vs 12.25 ± 0.76 seconds, P < 0.001), and anxiety-like behaviors. These findings provide insights into the relationship between gut microbiota dysbiosis and pain in SCD, highlighting the importance of gut microbial communities that may serve as potential targets for novel pain interventions.