Intrathecal administration of conditioned serum from different species resolves Chemotherapy-Induced neuropathic pain in mice via secretory exosomes.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-ß1, and resolvins D1/D2. Intrathecal injection of anti-TGF-ß1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.

Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.

BACKGROUND & AIMS: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. METHODS: Pruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a. RESULTS: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates. CONCLUSIONS: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.

A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect.

Genetic variation in melanocortin-1 receptor (MC1R) is a known contributor to disease-free red hair in humans. Three loss-of-function single-nucleotide variants (rs1805007, rs1805008 and rs1805009) have been established as strongly correlated with red hair. The contribution of other loss-of-function MC1R variants (in particular rs1805005, rs2228479 and rs885479) and the extent to which other genetic loci are involved in red hair colour is less well understood. Here, we used the UK Biobank cohort to capture a comprehensive list of MC1R variants contributing to red hair colour. We report a correlation with red hair for both strong-effect variants (rs1805007, rs1805008 and rs1805009) and weak-effect variants (rs1805005, rs2228479 and rs885479) and show that their coefficients differ by two orders of magnitude. On the haplotype level, both strong- and weak-effect variants contribute to the red hair phenotype, but when considered individually, weak-effect variants show a reverse, negative association with red hair. The reversal of association direction in the single-variant analysis is facilitated by a distinguishing structure of MC1R, in which loss-of-function variants are never found to co-occur on the same haplotype. The other previously reported hair colour genes' variants do not substantially improve the MC1R red hair colour predictive model. Our best model for predicting red versus other hair colours yields an unparalleled area under the receiver operating characteristic of 0.96 using only MC1R variants. In summary, we present a comprehensive statistically derived characterization of the role of MC1R variants in red hair colour and offer a powerful, economical and parsimonious model that achieves unsurpassed performance.

Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch.

BACKGROUND: Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice. METHODS: In silico structure-based similarity search of 1.5 million compounds followed by docking to the Nav1.7 voltage sensor of Domain 4 and molecular dynamics simulation was performed. Patch clamp experiments in Nav1.7-expressing human embryonic kidney 293 cells and in mouse and human dorsal root ganglion neurons were conducted to test sodium current inhibition. Formalin-induced inflammatory pain model, paclitaxel-induced neuropathic pain model, histamine-induced itch model, and mouse lymphoma model of chronic itch were used to confirm in vivo activity of the selected compound. RESULTS: After in silico screening, nine compounds were selected for experimental assessment in vitro. Of those, four compounds inhibited sodium currents in Nav1.7-expressing human embryonic kidney 293 cells by 29% or greater (P < 0.05). Compound 9 (3-(1-benzyl-1H-indol-3-yl)-3-(3-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)propanamide, referred to as DA-0218) reduced sodium current by 80% with a 50% inhibition concentration of 0.74 µM (95% CI, 0.35 to 1.56 µM), but had no effects on Nav1.5-expressing human embryonic kidney 293 cells. In mouse and human dorsal root ganglion neurons, DA-0218 reduced sodium currents by 17% (95% CI, 6 to 28%) and 22% (95% CI, 9 to 35%), respectively. The inhibition was greatly potentiated in paclitaxel-treated mouse neurons. Intraperitoneal and intrathecal administration of the compound reduced formalin-induced phase II inflammatory pain behavior in mice by 76% (95% CI, 48 to 100%) and 80% (95% CI, 68 to 92%), respectively. Intrathecal administration of DA-0218 produced acute reduction in paclitaxel-induced mechanical allodynia, and inhibited histamine-induced acute itch and lymphoma-induced chronic itch. CONCLUSIONS: This study's computer-aided drug discovery approach yielded a new Nav1.7 inhibitor that shows analgesic and anti-pruritic activity in mouse models.

Sustained stimulation of ß2- and ß3-adrenergic receptors leads to persistent functional pain and neuroinflammation.

Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ß2- and ß3-adrenergic receptors (ß2- and ß3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ß2- and ß3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The ß2AR antagonist ICI118551 and ß3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1ß, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ß2- and ß3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

Genomics of Cardiovascular Measures of Autonomic Tone.

The autonomic nervous system exerts broad control over the involuntary functions of the human body through complex equilibrium between sympathetic and parasympathetic tone. Imbalance in this equilibrium is associated with a multitude of cardiovascular outcomes, including mortality. The cardiovascular static state of this equilibrium can be quantified using physiological parameters such as heart rate (HR), blood pressure, and by spectral analysis of HR variability. Here, we review the current state of knowledge of the genetic background of cardiovascular measurements of autonomic tone. For most parameters of autonomic tone, a large portion of variability is explained by genetic heritability. Many of the static parameters of autonomic tone have also been studied through candidate-gene approach, yielding some insight into how genotypes of adrenergic receptors affect variables such as HR. Genome-wide approaches in large cohorts similarly exist for static variables such as HR and blood pressure but less is known about the genetic background of the dynamic and more specific measurements, such as HR variability. Furthermore, because most autonomic measures are likely polygenic, pathway analyses and modeling of polygenic effects are critical. Future work will hopefully explain the control of autonomic tone and guide individualized therapeutic interventions.

Association of Epidemiologic Factors and Genetic Variants Influencing Hypothalamic-Pituitary-Adrenocortical Axis Function With Postconcussive Symptoms After Minor Motor Vehicle Collision.

OBJECTIVES: To determine the influence of epidemiologic factors and the influence of genetic variants affecting FKBP5, a protein known to modulate hypothalamic-pituitary-adrenocortical axis function, on the severity of somatic symptoms commonly termed "postconcussive" 6 and 12 months after motor vehicle collision (MVC). METHODS: European Americans 18 to 65 years of age who presented to one of eight emergency departments (EDs) after MVC were enrolled. Exclusion criteria included hospital admission. Blood samples were collected in the ED for genotyping. Participants completed evaluations including an adapted Rivermead Post-Concussive Symptoms Questionnaire in the ED and at 6 weeks, 6 months, and 1 year. Repeated-measures analysis of covariance was used to evaluate the association between epidemiologic factors (sociodemographic, pre-MVC health, collision characteristics, head injury, peritraumatic pain, and stress), FKBP5 genetic variants, and postconcussive symptom severity. RESULTS: Among 943 patients recruited in the ED, follow-up was completed on 835 (88%) at 6 months and 857 (90%) at 1 year. Self-reported head impact during collision was not associated with chronic postconcussive symptom severity. After correction for multiple testing, three FKBP5 single-nucleotide polymorphisms (rs3800373, rs7753746, and rs9380526) predicted chronic postconcussive symptom severity, with an average symptom severity of 1.10 (95% confidence interval = 0.96-1.24), 1.36 (1.21-1.51), and 1.55 (1.23-1.88) for one, two, or three copies of minor allele at rs3800373 (p = .001). Similar effect sizes were observed for the minor alleles of rs7753746 and rs9380526. CONCLUSIONS: Postconcussive symptoms after minor MVC are not generally related to the severity of mild brain injury. This study shows that neurobiologic stress systems may play a role in the pathogenesis of postconcussive symptoms.

Persistent Pain Among Older Adults Discharged Home From the Emergency Department After Motor Vehicle Crash: A Prospective Cohort Study.

STUDY OBJECTIVE: Motor vehicle crashes are the second most common form of trauma among older adults. We seek to describe the incidence, risk factors, and consequences of persistent pain among older adults evaluated in the emergency department (ED) after a motor vehicle crash. METHODS: We conducted a prospective longitudinal study of patients aged 65 years or older who presented to one of 8 EDs after motor vehicle crash between June 2011 and June 2014 and were discharged home after evaluation. ED evaluation was done through in-person interview; follow-up data were obtained through mail-in survey or telephone call. Pain severity (0 to 10 scale) overall and for 15 parts of the body were assessed at each follow-up point. Principal component analysis was used to assess the dimensionality of the locations of pain data. Participants reporting pain severity greater than or equal to 4 attributed to the motor vehicle crash at 6 months were defined as having persistent pain. RESULTS: Of the 161 participants, 72% reported moderate to severe pain at the ED evaluation. At 6 months, 26% of participants reported moderate to severe motor vehicle crash-related pain. ED characteristics associated with persistent pain included acute pain severity; pain located in the head, neck, and jaw or lower back and legs; poor self-rated health; less formal education; pre-motor vehicle crash depressive symptoms; and patient's expected time to physical recovery more than 30 days. Compared with individuals without persistent pain, those with persistent pain were substantially more likely at 6-month follow-up to have also experienced a decline in their capacity for physical function (73% versus 36%; difference=37%; 95% confidence interval [CI] 19% to 52%), a new difficulty with activities of daily living (42% versus 17%; difference=26%; 95% CI 10% to 43%), a 1-point or more reduction in overall self-rated health on a 5-point scale (54% versus 30%; difference=24%; 95% CI 6% to 41%), and a change in their living situation to obtain additional help (23% versus 8%; difference=15%; 95% CI 2% to 31%). CONCLUSION: Among older adults discharged home from the ED post-evaluation after a motor vehicle crash, persistent pain is common and frequently associated with functional decline and disability.

A noninvasive hemoglobin monitor in the pediatric intensive care unit.

BACKGROUND: Critically ill pediatric patients frequently require hemoglobin monitoring. Accurate noninvasive Hb (SpHb) would allow practitioners to decrease anemia from repeated blood draws, traumatic blood draws, and a decreased number of laboratory Hb (LabHb) medical tests. The Food and Drug Administration has approved the Masimo Pronto SpHb and associated Rainbow probes; however, its use in the pediatric intensive care unit (PICU) is controversial. In this study, we define the degree of agreement between LabHb and SpHb using the Masimo Pronto SpHb Monitor and identify clinical and demographic conditions associated with decreased accuracy. MATERIALS AND METHODS: We performed a prospective, observational study in a large PICU at an academic medical center. Fifty-three pediatric patients (30-d and 18-y-old), weighing >3 kg, admitted to the PICU from January-April 2013 were examined. SpHb levels measured at the time of LabHb blood draw were compared and analyzed. RESULTS: Only 83 SpHb readings were obtained in 118 attempts (70.3%) and 35 readings provided a result of "unable to obtain." The mean LabHb and SpHb were 11.1 g/dL and 11.2 g/dL, respectively. Bland-Altman analysis showed a mean difference of 0.07 g/dL with a standard deviation of ±2.59 g/dL. Pearson correlation is 0.55, with a 95% confidence interval between 0.38 and 0.68. Logistic regression showed that extreme LabHb values, increasing skin pigmentation, and increasing body mass index were predictors of poor agreement between SpHb and LabHb (P < 0.05). Separately, increasing body mass index, hypoxia, and hypothermia were predictors for undetectable readings (P < 0.05). CONCLUSIONS: The Masimo Pronto SpHb Monitor provides adequate agreement for the trending of hemoglobin levels in critically ill pediatric patients. However, the degree of agreement is insufficient to be used as the sole indicator for transfusion decisions and should be used in context of other clinical parameters to determine the need for LabHb in critically ill pediatric patients.

High-dose dexmedetomidine for noninvasive pediatric procedural sedation and discharge readiness.

BACKGROUND: The University of North Carolina's (UNC) Pediatric Sedation Service adopted a noninvasive procedural sedation protocol that uses dexmedetomidine in children based on review of literature that reported fast recovery times and low morbidity. This study aimed to compare dexmedetomidine discharge readiness times observed at UNC with those previously published with a hypothesis that the discharge times at UNC are longer than those previously published. A secondary aim was to evaluate the safety profile of the protocol. METHODS: Pediatric outpatients (6 months-18 years) who received dexmedetomidine per protocol for a noninvasive procedure or study from January 2011 through April 2012 were included in this retrospective chart review. A total of 615 patient encounters were evaluated. Patients received bolus doses of 2 µg·kg(-1) over 10 min for up to three doses followed by a 1 µg·kg(-1) ·h(-1) infusion (group 1) or a 1.5 µg·kg(-1) ·h(-1) infusion (group 2). Primary outcomes included time to sedation, time to arousal, and time to discharge. RESULTS: No significant differences between the dosing groups were noted. Time to discharge was significantly shorter for group 1 (79 min) than for group 2 (101 min). The range of discharge times at UNC was 78.7-100.9 min compared to previous studies that report recovery times of 24.8-35.2 min. CONCLUSION: Dexmedetomidine arousal and discharge times observed at UNC were longer than anticipated when compared to literature. The safety profile of the drug was comparable to prior studies.

Simulator training enhances resident performance in transesophageal echocardiography.

BACKGROUND: Standardized training via simulation as an educational adjunct may lead to a more rapid and complete skill achievement. The authors hypothesized that simulation training will also enhance performance in transesophageal echocardiography image acquisition among anesthesia residents. METHODS: A total of 42 clinical anesthesia residents were randomized to one of two groups: a control group, which received traditional didactic training, and a simulator group, whose training used a transesophageal echocardiography-mannequin simulator. Each participating resident was directed to obtain 10 commonly used standard views on an anesthetized patient under attending supervision. Each of the 10 selected echocardiographic views were evaluated on a grading scale of 0 to 10, according to predetermined criteria. The effect of the intervention was assessed by using a linear mixed model implemented in SAS 9.3 (SAS Institute Inc., Cary, NC). RESULTS: Residents in the simulation group obtained significantly higher-quality images with a mean total image quality score of 83 (95% CI, 74 to 92) versus the control group score of 67 (95% CI, 58 to 76); P = 0.016. On average, 71% (95% CI, 58 to 85) of images acquired by each resident in the simulator group were acceptable for clinical use compared with 48% (95% CI, 35 to 62) in the control; P = 0.021. Additionally, the mean difference in score between training groups was the greatest for the clinical anesthesia-1 residents (difference 24; P = 0.031; n = 7 per group) and for those with no previous transesophageal echocardiography experience (difference 26; P = 0.005; simulator n = 13; control n = 11). CONCLUSION: Simulation-based transesophageal echocardiography education enhances image acquisition skills in anesthesiology residents.

Higher Cardiovagal Baroreflex Sensitivity Predicts Increased Pain Outcomes After Cardiothoracic Surgery.

Excessive postoperative pain can lead to extended hospitalization and increased expenses, but factors that predict its severity are still unclear. Baroreceptor function could influence postoperative pain by modulating nociceptive processing and vagal-mediated anti-inflammatory reflexes. To investigate this relationship, we conducted a study with 55 patients undergoing minimally invasive cardiothoracic surgery to evaluate whether cardiovagal baroreflex sensitivity (BRS) can predict postoperative pain. We assessed the spontaneous cardiovagal BRS under resting pain-free conditions before surgery. We estimated postoperative pain outcomes with the Pain, Enjoyment, and General Activity scale and pressure pain thresholds on the first (POD1) and second (POD2) postoperative days and persistent pain 3 and 6 months after hospital discharge. We also measured circulating levels of relevant inflammatory biomarkers (C-reactive protein, albumin, cytokines) at baseline, POD1, and POD2 to assess the contribution of inflammation to the relationship between BRS and postoperative pain. Our mixed-effects model analysis showed a significant main effect of preoperative BRS on postoperative pain (P = .013). Linear regression analysis revealed a significant positive association between preoperative BRS and postoperative pain on POD2, even after adjusting for demographic, surgical, analgesic treatment, and psychological factors. Moreover, preoperative BRS was linked to pain interfering with general activity and enjoyment but not with other pain parameters (pain intensity and pressure pain thresholds). Preoperative BRS had modest associations with postoperative C-reactive protein and IL-10 levels, but they did not mediate its relationship with postoperative pain. These findings indicate that preoperative BRS can independently predict postoperative pain, which could serve as a modifiable criterion for optimizing postoperative pain management. PERSPECTIVE: This article shows that preoperative BRS predicts postoperative pain outcomes independently of the inflammatory response and pain sensitivity to noxious pressure stimulation. These results provide valuable insights into the role of baroreceptors in pain and suggest a helpful tool for improving postoperative pain management.

A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt+/- mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund's adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Immunotherapies in chronic pain through modulation of neuroimmune interactions.

It is generally believed that immune activation can elicit pain through production of inflammatory mediators that can activate nociceptive sensory neurons. Emerging evidence suggests that immune activation may also contribute to the resolution of pain by producing distinct pro-resolution/anti-inflammatory mediators. Recent research into the connection between the immune and nervous systems has opened new avenues for immunotherapy in pain management. This review provides an overview of the most utilized forms of immunotherapies (e.g., biologics) and highlight their potential for immune and neuronal modulation in chronic pain. Specifically, we discuss pain-related immunotherapy mechanisms that target inflammatory cytokine pathways, the PD-L1/PD-1 pathway, and the cGAS/STING pathway. This review also highlights cell-based immunotherapies targeting macrophages, T cells, neutrophils and mesenchymal stromal cells for chronic pain management.

Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice.

Temporomandibular disorder (TMD) pain that involves inflammation and injury in the temporomandibular joint (TMJ) and/or masticatory muscle is the most common form of orofacial pain. We recently found that transient receptor potential vanilloid-4 (TRPV4) in trigeminal ganglion (TG) neurons is upregulated after TMJ inflammation, and TRPV4 coexpresses with calcitonin gene-related peptide (CGRP) in TMJ-innervating TG neurons. Here, we extended these findings to determine the specific contribution of TRPV4 in TG neurons to TMD pain, and examine whether sensory neuron-TRPV4 modulates TMD pain via CGRP. In mouse models of TMJ inflammation or masseter muscle injury, sensory neuron-Trpv4 conditional knockout (cKO) mice displayed reduced pain. Coexpression of TRPV4 and CGRP in TMJ- or masseter muscle-innervating TG neurons was increased after TMJ inflammation and masseter muscle injury, respectively. Activation of TRPV4-expressing TG neurons triggered secretion of CGRP, which was associated with increased levels of CGRP in peri-TMJ tissues, masseter muscle, spinal trigeminal nucleus, and plasma in both models. Local injection of CGRP into the TMJ or masseter muscle evoked acute pain in naïve mice, while blockade of CGRP receptor attenuated pain in mouse models of TMD. These results suggest that TRPV4 in TG neurons contributes to TMD pain by potentiating CGRP secretion. PERSPECTIVE: This study demonstrates that activation of TRPV4 in TG sensory neurons drives pain by potentiating the release of pain mediator CGRP in mouse models of TMJ inflammation and masseter muscle injury. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.

Association of DASH diet with cardiovascular risk factors in youth with diabetes mellitus: the SEARCH for Diabetes in Youth study.

BACKGROUND: We have shown that adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is related to blood pressure in youth with type 1 and type 2 diabetes mellitus. We explored the impact of the DASH diet on other cardiovascular disease risk factors. METHODS AND RESULTS: Between 2001 and 2005, data on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein particle density, apolipoprotein B, body mass index, waist circumference, and adipocytokines were ascertained in 2130 youth aged 10 to 22 years with physician-diagnosed diabetes mellitus. Dietary intake was assessed by food frequency questionnaire, categorized into the DASH food groups, and assigned an adherence score. Among youth with type 1 diabetes mellitus, higher adherence to the DASH diet was significantly and inversely associated with low-density lipoprotein/high-density lipoprotein ratio and A(1c) in multivariable-adjusted models. Youth in the highest adherence tertile had an estimated 0.07 lower low-density lipoprotein/high-density lipoprotein ratio and 0.2 lower A(1c) levels than those in the lowest tertile adjusted for confounders. No significant associations were observed with triglycerides, low-density lipoprotein particle density, adipocytokines, apolipoprotein B, body mass index Z score, or waist circumference. Among youth with type 2 diabetes mellitus, associations were observed with low-density lipoprotein particle density and body mass index Z score. CONCLUSIONS: The DASH dietary pattern may be beneficial in the prevention and management of cardiovascular disease risk in youth with diabetes mellitus.

µ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer.

BACKGROUND: Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the µ-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival. METHODS: A total of 2,039 women ages 23-74 yr (38% African-American, 62% European-American, 55% postmenopausal) diagnosed with breast cancer between 1993-2001 were followed through 2006. Genotyping was performed using the TaqMan platform (Applied Biosystems Inc., Foster City, CA). Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models were used to examine the association between each genotype and survival. RESULTS: After Bonferroni correction for multiple testing, patient genotype at A118G was associated with breast cancer-specific mortality at 10 yr. Women with one or more copies of the G allele had decreased breast cancer-specific mortality (P < 0.001). This association was limited to invasive cases only; effect size appeared to increase with clinical stage. Cox regression model adjusted for age and ethnicity also showed decreased mortality in A/G and G/G genotypes compared with A/A genotype (hazard ratio = 0.57 [0.38, 0.85] and 0.32 [0.22, 0.49], respectively; P = 0.006). CONCLUSIONS: These results suggest that opioid pathways may be involved in tumor growth. Further studies examining the association between genetic variants influencing opioid system function and cancer survival are warranted.

Older US emergency department patients are less likely to receive pain medication than younger patients: results from a national survey.

STUDY OBJECTIVE: The purpose of this study is to determine whether older adults presenting to the emergency department (ED) with pain are less likely to receive pain medication than younger adults. METHODS: Pain-related visits to US EDs were identified with reason-for-visit codes from 7 years (2003 to 2009) of the National Hospital Ambulatory Medical Care Survey. The primary outcome was the administration of an analgesic. The percentage of patients receiving analgesics in 4 age groups was adjusted for measured covariates, including pain severity. RESULTS: Pain-related visits accounted for 88,031 (46.9%) ED visits by patients aged 18 years or older during the 7-year period. There were 7,585 pain-related ED visits by patients aged 75 years or older, representing an estimated 3.65 million US ED visits annually. In comparing survey-weighted unadjusted estimates, pain-related visits by patients aged 75 years or older were less likely than visits by patients aged 35 to 54 years to result in administration of an analgesic (49% versus 68.3%) or an opioid (34.8% versus 49.3%). Absolute differences in rates of analgesic and opioid administration persisted after adjustment for sex, race/ethnicity, pain severity, and other factors and multiple imputation of missing pain severity data, with visits by patients aged 75 years and older being 19.6% (95% confidence interval 17.8% to 21.4%) less likely than visits by patients aged 35 to 54 years to receive an analgesic and 14.6% (95% confidence interval 12.8% to 16.4%) less likely to receive an opioid. CONCLUSION: Patients aged 75 years and older with pain-related ED visits are less likely to receive pain medication than patients aged 35 to 54 years.