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1.  Central Processing of Noxious Somatic Stimuli in Patients With Irritable Bowel Syndrome Compared With Healthy Controls 
The Clinical journal of pain  2010;26(2):104-109.
To compare a central analgesic mechanism known as diffuse noxious inhibitory controls (DNIC) using somatic test stimuli and somatic conditioning stimuli, (CS) in irritable bowel syndrome (IBS) patients and healthy controls.
Participants were 48 premenopausal females (27 with IBS), mean age of 29 years. The phasic heat test stimulus (peak temperature, 50°C) was applied to the left palm. The DNIC effect, which measured reductions in average pain ratings (APR) during counter irritation (submersion of the participant’s right hand in painful 12°C circulating water) compared with baseline, was compared between groups. In addition, a second, counterbalanced, CS protocol (right hand submerged in nonpainful 32°C circulating water) was performed. Differences in APR between the 2 counter-irritation protocols were compared between groups to control for nonspecific effects known to influence DNIC. Psychologic measures and cardiovascular reactivity were also assessed.
IBS patients demonstrated smaller DNIC than controls (P=0.011, repeated measures analysis of variance), and greater state-anxiety, depression, catastrophizing, and anger-out expression (P<0.05). Group differences in DNIC were enhanced after controlling for nonspecific effects occurring during the nonpainful CS, and for psychologic measures (P=0.001, repeated measures analysis of covariance). There were no group differences in age, cardiovascular reactivity, APR, or pain ratings for the 12°C CS.
These data demonstrate deficient DNIC in IBS. This is the first study to adequately control for alternative explanations of pain reduction during counterirritation. Only by controlling for nonspecific effects can evidence of deficient DNIC be attributed to dysregulation in endogenous analgesic mechanisms.
PMCID: PMC4321817  PMID: 20090435
diffuse noxious inhibitory controls; DNIC; pain; irritable bowel syndrome
4.  Study Protocol, Sample Characteristics, and Loss to Follow-Up: The OPPERA Prospective Cohort Study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.06.006.
When studying incidence of pain conditions such as temporomandibular disorders (TMDs), repeated monitoring is needed in prospective cohort studies. However, monitoring methods usually have limitations and, over a period of years, some loss to follow-up is inevitable. The OPPERA prospective cohort study of first-onset TMD screened for symptoms using quarterly questionnaires and examined symptomatic participants to definitively ascertain TMD incidence. During the median 2.8-year observation period, 16% of the 3,263 enrollees completed no follow-up questionnaires, others provided incomplete follow-up, and examinations were not conducted for one third of symptomatic episodes. Although screening methods and examinations were found to have excellent reliability and validity, they were not perfect. Loss to follow-up varied according to some putative TMD risk factors, although multiple imputation to correct the problem suggested that bias was minimal. A second method of multiple imputation that evaluated bias associated with omitted and dubious examinations revealed a slight underestimate of incidence and some small biases in hazard ratios used to quantify effects of risk factors. Although “bottom line” statistical conclusions were not affected, multiply-imputed estimates should be considered when evaluating the large number of risk factors under investigation in the OPPERA study.
These findings support the validity of the OPPERA prospective cohort study for the purpose of investigating the etiology of first-onset TMD, providing the foundation for other papers investigating risk factors hypothesized in the OPPERA project.
PMCID: PMC3855654  PMID: 24275220
Temporomandibular joint disorders; cohort studies; population statistics; epidemiologic methods; proportional hazards models
5.  Psychological Factors Associated with Development of TMD: the OPPERA Prospective Cohort Study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.06.009.
Case-control studies have consistently associated psychological factors with chronic pain in general and with temporomandibular disorders (TMD) specifically. However, only a handful of prospective studies has explored whether pre-existing psychological characteristics represent risk factors for first-onset TMD. The current findings derive from the prospective cohort study of the Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 3,263 TMD-free participants completed a battery of psychological instruments assessing general psychological adjustment and personality, affective distress, psychosocial stress, somatic symptoms, and pain coping and catastrophizing. Study participants were then followed prospectively for an average of 2.8 years to ascertain cases of first-onset of TMD, and 2,737 provided follow-up data and were considered in the analyses of TMD onset. In bivariate and demographically-adjusted analyses, several psychological variables predicted increased risk of first-onset TMD, including reported somatic symptoms, psychosocial stress, and affective distress. Principal component analysis of 26 psychological scores was used to identify latent constructs, revealing four components: stress and negative affectivity, global psychological and somatic symptoms, passive pain coping, and active pain coping. In multivariable analyses, global psychological and somatic symptoms emerged as the most robust risk factor for incident TMD. These findings provide evidence that measures of psychological functioning can predict first-onset of TMD. Future analyses in the OPPERA cohort will determine whether these psychological factors interact with other variables to increase risk for TMD onset and persistence.
PMCID: PMC3855656  PMID: 24275225
temporomandibular disorders; psychological risk factors; chronic pain; somatic symptoms; psychosocial stress
6.  Clinical orofacial characteristics associated with risk of first-onset TMD: the OPPERA prospective cohort study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.07.018.
Case-control studies have documented clinical manifestations of chronic temporomandibular disorders (TMD), whereas clinical predictors of TMD development are largely unknown. We evaluated 41 clinical orofacial characteristics thought to predict first-onset TMD in a prospective cohort study of U.S. adults aged 18-44 years. During the median 2.8-year follow-up period, 2,737 people completed quarterly screening questionnaires. Those reporting symptoms were examined and 260 people were identified with first-onset TMD. Univariate and multivariate Cox regression models quantified associations between baseline clinical orofacial measures and TMD incidence. Significant predictors from baseline self-report instruments included oral parafunctions, prior facial pain and its life-impact, TMJ noises and jaw locking, and non-specific orofacial symptoms. Significant predictors from the baseline clinical examination were pain on jaw opening and pain from palpation of masticatory, neck, and body muscles. Examiner assessments of TMJ noise and tooth wear facets did not predict incidence. In multivariate analysis, non-specific orofacial symptoms, pain from jaw opening and oral parafunctions predicted TMD incidence. The results indicate that only a few orofacial examination findings influenced TMD incidence, and only to a modest degree. More pronounced influences were found for self-reported symptoms, particularly those that appeared to reflect alterations to systems beyond the masticatory tissues.
PMCID: PMC3855658  PMID: 24275222
temporomandibular disorders; cohort studies; trauma; parafunction; pain
7.  General health status and incidence of first-onset temporomandibular disorder: OPPERA prospective cohort study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.06.001.
Temporomandibular disorders (TMD) overlap with other health conditions but no study has examined which of these conditions increase the risk of developing first-onset TMD. The authors prospectively evaluated the relationship between health status at enrollment and subsequent incidence of TMD in 2,722 men and women. Participants aged 18–44 years had no history of TMD and were clinically free of TMD when enrolled in 2006–08 at four U.S. study sites in the OPPERA prospective cohort study. First-onset examiner-classified TMD developed in 260 people over a median 2.8 years of follow-up. Cox regression estimated the association between health conditions and TMD incidence while accounting for potential confounders. Incidence of first-onset TMD was 50% higher for people with lower back pain (adjusted hazard ratio [AHR] = 1.50, 95% confidence limits [95% CL]: 1.08, 2.10) and 75% higher for people with genital pain symptoms (AHR = 1.75 [95% CL: 1.04, 2.93]) than people without a history of these pain disorders. Digit ratio, a marker of intra-uterine exposure to sex hormones, was significantly associated with TMD incidence. Other independent predictors of first-onset TMD were sleep disturbance and cigarette smoking. These findings reveal multiple-influences of health status on incidence of first-onset TMD.
PMCID: PMC3855662  PMID: 24275223
Temporomandibular Joint Disorders; Prospective Cohort Studies; Comorbidity; Epidemiology
8.  Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.09.004.
Genetic risk factors are believed to combine with environmental exposures and contribute to risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios (HRs) were computed as measures of association between 2,924 single nucleotide polymorphisms (SNPs) and TMD incidence. After correction for multiple testing, no single SNP was significantly associated with risk of onset TMD. However, several SNPs exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (FDR=0.05, 0.1, or 0.2) for association with intermediate phenotypes shown to be predictive of TMD onset. Non-specific orofacial symptoms were associated with voltage-gated sodium channel, type 1 alpha subunit (SCN1A, rs6432860, p=2.77×10−5) and angiotensin-I converting enzyme 2 (ACE2, rs1514280, p=4.86×10−5), global psychological symptoms with prostaglandin-endoperoxide synthase 1 (PTGS1, rs3842803, p=2.79×10−6), stress and negative affectivity with amyloid-β (A4) precursor protein (APP, rs466448, p=4.29×10−5), and heat pain temporal summation with multiple PDZ domain protein (MPDZ, rs10809907, p=3.05×10−5). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD.
PMCID: PMC3855664  PMID: 24275226
temporomandibular disorders; genetic risk factors; incidence; chronic pain; intermediate phenotypes
9.  Summary of Findings from the OPPERA Prospective Cohort Study of Incidence of First-Onset Temporomandibular Disorders: Implications and Future Directions 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.09.010.
Papers in this volume investigate when and how putative risk factors influence development of first-onset, painful temporomandibular disorders (TMD). The results represent first findings from the OPPERA prospective cohort study which monitored 2,737 men and women aged 18–44 years recruited at four U.S. study sites. During a median 2.8 year follow-up period, 260 participants developed TMD. The average incidence rate of 4% per annum was influenced by a broad range of phenotypic risk factors including sociodemographic characteristics, health status, clinical orofacial factors, psychological functioning, pain sensitivity and cardiac autonomic responses. A novel method of multivariable analysis used random forest models to simultaneously evaluate contributions of all 202 phenotypic variables. Variables from the health status domain made the greatest contribution to TMD incidence, followed closely by psychological and clinical orofacial domains. However, only a few measures of pain sensitivity and autonomic function contributed to TMD incidence, and their effects were modest. Meanwhile, age and study site were independent predictors of TMD incidence, even after controlling for other phenotypes. Separate analysis of 358 genes that regulate pain found several novel genetic associations with intermediate phenotypes which, themselves, are risk factors for TMD, suggesting new avenues to investigate biological pathways contributing to TMD.
PMCID: PMC3857103  PMID: 24275219
Temporomandibular Disorders; Cohort Studies; Epidemiology; Psychological Factors; Clinical Pain; Comordid Conditions; Pain Sensitivity; Genetics
10.  Signs and Symptoms of First-Onset TMD and Sociodemographic Predictors of Its Development: The OPPERA Prospective Cohort Study 
The journal of pain : official journal of the American Pain Society  2013;14(12 0):10.1016/j.jpain.2013.07.014.
Although cross-sectional studies of temporomandibular disorders (TMDs) often report elevated prevalence in young women, they do not address the risk of its development. Here we evaluate sociodemographic predictors of TMD incidence in a community-based prospective cohort study of U.S. adults. Symptoms and pain-related disability in TMD cases are also described. People aged 18 to 44 years with no history of TMD were enrolled at 4 study sites when they completed questionnaires about sociodemographic characteristics. During the median 2.8-year follow-up period, 2,737 participants completed quarterly screening questionnaires. Those reporting symptoms were examined clinically and 260 had first-onset TMD. Additional questionnaires asked about severity and impact of their symptoms. Univariate and multivariate Cox regression models quantified associations between sociodemographic characteristics and TMD incidence. First-onset TMD developed in 3.9% of participants per annum, typically producing mild to moderate levels of pain and disability in cases. TMD incidence was positively associated with age, whereas females had only slightly greater incidence than males. Compared to whites, Asians had lower TMD incidence whereas African Americans had greater incidence, although the latter was attenuated somewhat after adjusting for satisfaction with socioeconomic circumstances.
In this study of 18- to 44-year-olds, TMD developed at a higher rate than reported previously for similar age groups. TMD incidence was positively associated with age but weakly associated with gender, thereby differing from demographic patterns of prevalence found in some cross-sectional studies. Experiences related to aging merit investigation as etiologic influences on development of TMD.
PMCID: PMC3857109  PMID: 24275221
Temporomandibular joint disorders; prospective cohort studies; demography; socioeconomic factors; population characteristics
11.  Pain Sensitivity and Autonomic Factors Associated with Development of TMD: the OPPERA Prospective Cohort Study 
Multiple studies report that individuals with chronic temporomandibular disorder (TMD) have enhanced sensitivity to experimental pain. Additionally, chronic TMD cases show altered autonomic function, including elevated heart rate and reduced heart rate variability. However, causal inferences regarding the association between TMD and pain sensitivity and autonomic function cannot be drawn from these cross-sectional observations. The prospective OPPERA study examines whether measures of pain sensitivity or cardiac autonomic function provide predictive value in TMD incidence. A cohort of 2,737 initially TMD-free people was followed for up to 5.2 years, during which time 260 developed first-onset TMD. Fourteen of 39 experimental pain measures produced significant hazard ratios, such that greater pain sensitivity was associated with greater TMD incidence. A single autonomic measure – heart rate at rest – was also associated significantly with greater TMD incidence. In contrast, using the same measures of pain sensitivity and cardiac autonomic function, we previously reported a larger group of variables that was significantly associated with chronic TMD in the OPPERA case-control study. Future studies should investigate whether premorbid pain sensitivity or autonomic function more specifically predicts risk of developing chronic TMD than first-onset TMD.
PMCID: PMC3955992  PMID: 24275224
Quantitative Sensory Testing; Temporomandibular Joint Disorders; orofacial pain; heat pain; pressure pain; cardiovascular measures
12.  Multivariable modeling of phenotypic risk factors for first-onset TMD: the OPPERA prospective cohort study 
Incidence of temporomandibular disorders (TMD) was predicted with multivariable models that used putative risk factors collected from initially TMD-free individuals in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. The 202 baseline risk factors included sociodemographic and clinical characteristics, measures of general health status, experimental pain sensitivity, autonomic function, and psychological distress. Study participants (n=2,737) were then followed prospectively for a median of 2.8 years to ascertain cases of first-onset TMD. Lasso regression and random forest models were used to predict incidence of first-onset TMD using all of the aforementioned measures. Variable importance scores identified the most important risk factors, and their relationship with TMD incidence was illustrated graphically using partial dependence plots. Two of the most important risk factors for elevated TMD incidence were greater numbers of comorbid pain conditions and greater extent of non-specific orofacial symptoms. Other important baseline risk factors were pre-existing bodily pain, heightened somatic awareness, and greater extent of pain in response to examiners’ palpation of the head, neck and body. Several demographic variables persisted as risk factors even after adjusting for other OPPERA variables, suggesting that environmental variables not measured in OPPERA may also contribute to first-onset TMD.
PMCID: PMC4036699  PMID: 24275218
chronic pain; multivariable analysis; data mining; OPPERA; temporomandibular disorders
13.  Facial pain with localized and widespread manifestations: separate pathways of vulnerability 
Pain  2013;154(11):10.1016/j.pain.2013.07.009.
Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically-relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically-homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2,925 SNPs and two subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD; and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P=0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P=0.0014). A risk index representing combined effects of six SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio = 2.7, P=1.3×10−9), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio = 1.6, P=0.014). A risk index representing combined effects of eight SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P=1.9×10−8), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background.
PMCID: PMC3808468  PMID: 23867732
Temporomandibular disorder; human genetics; serotonergic receptor; case-control study
14.  The relationship between resting arterial blood pressure and acute postoperative pain in endodontic patients 
Journal of orofacial pain  2012;26(4):321-327.
Several lines of evidence support a functional interaction between the cardiovascular and pain regulatory systems. Elevated resting blood pressure is consistently associated with reduced responsiveness to experimental pain stimuli in healthy normotensive subjects. This prospective observational study was designed to evaluate the relationship between preoperative resting arterial blood pressure and postoperative pain in patients undergoing non-surgical endodontic treatment (also known as root canal therapy).
Written informed consent was obtained from normotensive patients seeking treatment for teeth with a preoperative diagnosis of pulpal necrosis and periradicular periodontitis. Preoperative resting blood pressure was recorded and non-surgical root canal therapy was initiated using a standardized protocol. Patients recorded their preoperative and postoperative pain intensity on a 100mm visual analog scale for up to 7 days after the procedure. A linear regression model was used to predict postoperative VAS intensity using preoperative pain and blood pressure values as covariates. Pearson correlations were calculated to assess the relationship between the measures of preoperative blood pressure and both preoperative and postoperative pain.
After controlling for preoperative pain, significant correlations were observed between preoperative systolic blood pressure and postoperative pain (p < .05) as well as between preoperative pulse pressure and postoperative pain (p< .005) on day 1.
This study provides further evidence of a functional interaction existing between the cardiovascular and trigeminal pain regulatory systems. Understanding this complex relationship may lead to enhanced pain management strategies.
PMCID: PMC4208728  PMID: 23110272
Pain; Cardiovascular system; Orofacial; Endodontics; Blood pressure
15.  From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia 
Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal–regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia.
This article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia.
PMCID: PMC4196675  PMID: 24524846
Acupuncture analgesia; extracellular signal–regulated kinase; skin tissues; mouse pain model
17.  Multisystem Dysregulation in Painful Temporomandibular Disorders 
Multiple physiological and psychological regulatory domains may contribute to the pathophysiology of pain in temporomandibular disorder (TMD) and other bodily pain conditions. The purpose of this study was to evaluate the relationship between multisystem dysregulation and the presence of TMD pain, as well as the presence of different numbers of comorbid pain conditions in TMD. Secondary data analysis was conducted in 131 non-TMD (without comorbid pain) controls, 14 TMD subjects without comorbid pain, 78 TMD subjects with 1 comorbid pain, and 67 TMD subjects with multiple comorbid pain conditions who participated in a TMD genetic study. Twenty markers from sensory, autonomic, inflammatory, and psychological domains were evaluated. The results revealed that 1) overall dysregulation in multiple system domains (OR [odds ratio] = 1.6, 95% confidence interval [CI] = 1.4–1.8), particularly in the sensory (OR = 1.9, 95% CI = 1.3–2.9) and the psychological (OR = 2.1, 95% CI = 2.1–2.7) domains, were associated with increased likelihood of being a painful TMD case; and 2) dysregulations in individual system domains were selectively associated with the increased odds of being a TMD case with different levels of comorbid persistent pain conditions. These outcomes indicate that heterogeneous multisystem dysregulations may exist in painful TMD subgroups, and multidimensional physiological and psychological assessments can provide important information regarding pathophysiology, diagnosis, and management of pain in TMD patients.
The concurrent assessment of multiple physiological and psychological systems is critical to our understanding of the pathophysiological processes that contribute to painful TMD and associated comorbid conditions, which will ultimately guide and inform appropriate treatment strategies that address the multisystem dysregulation associated with complex and common persistent pain conditions.
PMCID: PMC3770463  PMID: 23721875
Temporomandibular disorders; multisystem dysregulation; comorbid pain conditions; headache
18.  Preclinical episodes of orofacial pain symptoms and their association with healthcare behaviors in the OPPERA prospective cohort study. 
Pain  2013;154(5):750-760.
The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial- and recurrent-symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 people aged 18-44 years with lifetime absence of TMD when enrolled completed 25,103 quarterly (three-monthly) questionnaires during amedian 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance and analgesic usage and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with healthcare and analgesic use. One third of people developed TMD symptoms and for one quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at anannual rate of 18.8 episodes per 100 people. The annual rate more than doubled for first-recurrence and doubled again for second-or-subsequent recurrence such that, one year after first recurrence, 71% of people experienced second recurrence. The overall rate increased with age and was greater in African-Americans and lower in Asians relative to Whites. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache and body pain were associated with increases of ~10% in probability of analgesic usage and healthcare attendance. Yet, even when TMD, headache and body pain occurred concurrently, 27% of people neither attended healthcare nor used analgesics.
PMCID: PMC3652580  PMID: 23531476
temporomandibular disorder; epidemiology; pain symptoms; prospective cohort study; health behavior
19.  Chronic HPA Axis Response to Stress in Temporomandibular Disorder 
Perceived stress is associated with temporomandibular disorder (TMD), but whether cortisol levels are elevated in individuals with TMD is unknown. We hypothesized that cortisol concentration, a biomarker of hypothalamic-pituitary-adrenal (HPA) axis function, was elevated in TMD cases relative to controls, and that perceived stress was positively correlated with cortisol concentration.
In this case control study, TMD case status was determined by examiners using TMD Research Diagnostic Criteria. Participants (n=116) aged 18 to 59 years were recruited from within a 50 mile radius of the University of North Carolina at Chapel Hill. Following examination, cases (n=45) and controls (n=71) completed the 14-item Perceived Stress Scale using a reference interval of the past 3 months. Approximately 100 strands of hair were cut from the posterior vertex segment of their scalp. The 3 centimeters of hair most proximal to the scalp was analyzed with a commercially available salivary cortisol enzyme immunoassay adapted for hair cortisol. This length corresponds to the last 3 months of systemic HPA axis activity.
TMD cases perceived higher stress than controls (p=0.001). However, hair cortisol concentration was lower in TMD cases than controls (p<0.001). The correlation coefficient revealed a weak negative relationship (r=−0.188) between perceived stress and hair cortisol concentration (p=0.044). In analysis stratified by case status, the relationship of perceived stress and hair cortisol concentration was non-significant for cases (p=0.169) and controls (p=0.498).
Despite greater perceived stress, TMD cases had lower hair cortisol concentrations than controls and the 2 measures of stress were weakly and negatively correlated.
PMCID: PMC3992383  PMID: 23986140
Temporomandibular joint disorders; Epidemiology; Factor; psychosocial; Hormones; hypothalamic pituitary regulating
20.  Molecular Assays for Characterization of Alternatively Spliced Isoforms of the Mu Opioid Receptor (MOR) 
Mu-opioid receptor (MOR) belongs to a family of heptahelical G-protein-coupled receptors (GPCRs). Studies in humans and rodents demonstrated that the OPRM1 gene coding for MOR undergoes extensive alternative splicing afforded by the genetic complexity of OPRM1. Evidence from rodent studies also demonstrates an important role of these alternatively spliced forms in mediating opiate analgesia via their differential signaling properties. MOR signaling is predominantly Giα coupled. Release of the α subunit from G-protein complex results in the inhibition of adenylyl cyclase/cAMP pathway, whereas release of the βγ subunits activates G-protein-activated inwardly rectifying potassium channels and inhibits voltage-dependent calcium channels. These molecular events result in the suppression of cellular activities that diminish pain sensations. Recently, a new isoform of OPRM1, MOR3, has been identified that shows an increase in the production of nitric oxide (NO) upon stimulation with morphine. Hence, there is a need to describe molecular techniques that enable the functional characterization of MOR isoforms. In this review, we describe the methodologies used to assay key mediators of MOR activation including cellular assays for cAMP, free Ca2+, and NO, all of which have been implicated in the pharmacological effects of MOR agonists.
PMCID: PMC3991784  PMID: 20336438
Alternative splicing; OPRM1; Opioid; Calcium; cAMP; Nitric oxide; Fluo-4; Fluo-3; GPCR; FSK; Capsaicin
21.  The phenotypic and genetic signatures of common musculoskeletal pain conditions 
Nature reviews. Rheumatology  2013;9(6):340-350.
Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and ‘psychological’ measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.
PMCID: PMC3991785  PMID: 23545734
22.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
PMCID: PMC3694490  PMID: 23583978
23.  Relationship between Temporomandibular Disorders, Widespread Palpation Tenderness and Multiple Pain Conditions: A Case - Control Study 
The multiple bodily pain conditions in temporomandibular disorders (TMD) have been associated with generalized alterations in pain processing. The purpose of this study was to examine the relationship between the presence of widespread body palpation tenderness (WPT) and the likelihood of multiple comorbid pain conditions in TMD patients and controls. This case-control study was conducted in 76 TMD subjects with WPT, 83 TMD subjects without WPT, and 181 non-TMD matched control subjects. The study population was also characterized for clinical pain, experimental pain sensitivity, and related psychological phenotypes. Results showed that (1) TMD subjects reported an average of 1.7 comorbid pain conditions compared to 0.3 reported by the control subjects (p<0.001); (2) Compared to control subjects, the odds ratio (OR) for multiple comorbid pain conditions is higher for TMD subjects with WPT [OR 8.4 (95% CI 3.1–22.8) for TMD with WPT versus OR 3.3 (95% CI 1.3–8.4) for TMD without WPT]; (3) TMD subjects with WPT presented with reduced pressure pain thresholds (PPTs) in both cranial and extra-cranial regions compared to TMD subjects without WPT; and (4) TMD subjects with WPT reported increased somatic symptoms. These findings suggest that pain assessment outside of the orofacial region may prove valuable for the classification, diagnosis, and management of TMD patients.
PMCID: PMC3475612  PMID: 23031401
TMD; temporomandibular disorders; palpation tenderness; multiple pain conditions; comorbid
24.  Reliability and Reproducibility of Novel Methodology for Assessment of Pressure Pain Sensitivity in Pelvis 
Vestibulodynia, the most common type of chronic vulvovaginal pain, impairs the psychological, physical health of nearly 10% of women at some point in their lifetime. The aim of this investigation was to establish reliable standardized methodologies for assessment of pain sensitivity in vulvar mucosa and pelvic musculature. We enrolled 34 women with vestibulodynia and 21 pain-free controls. The participants underwent a nuanced exam that consisted of palpation of precisely located vulvar mucosal and pelvic muscle sites. These measurements remained highly stable when participants were reexamined after two weeks, with high within-examiner correlation. Vestibulodynia patients reported greater sensitivity than pain-free controls at the majority of examination sites, particularly at mucosal sites on the lower vestibule. The pain threshold measures at the lower mucosal sites were also associated with the participants’ self-reported pain levels during intercourse. These mucosal pain threshold measurements were used to discriminate between vestibulodynia cases and controls with high sensitivity and specificity. This data supports the feasibility of contemporaneous assessment of vulvar mucosa and underlying musculature in the pelvic region, offering the hope of a more precise case definition for vestibulodynia and related disorders.
PMCID: PMC3495612  PMID: 22958875
Pelvic Pain; Musculoskeletal Pain; Reliability; Vulvodynia
25.  Pain modality- and sex-specific effects of COMT genetic functional variants 
Pain  2013;154(8):1368-1376.
The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to inter-individual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality-specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3’UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female versus male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.
PMCID: PMC3700530  PMID: 23701723

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