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1.  Differential expression of the alternatively-spliced OPRM1 isoform MOR-1K in HIV-infected subjects 
AIDS (London, England)  2014;28(1):19-30.
We previously examined the expression of specific C-terminal μ-opioid receptor (MOR) splice variants in human central nervous system cell types and HIV-infected brain tissue from subjects with neurocognitive impairment ± HIV encephalitis (HIVE). In the present study, we examined the N-terminal splice variant MOR-1K which mediates excitatory cellular signaling.
Methods and Results
We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C-terminal MOR splice variants using RT-PCR. Expression of MOR-1K mRNA was also increased in HIV-infected subjects with combined neurocognitive impairment and HIVE compared to the other groups. MOR-1K expression correlated with the level of subject neurocognitive impairment whereas the pool of C-terminal MOR splice variants did not. HIVE was also associated with increased expression of the inflammatory mediators MCP-1, MCP-2, and RANTES, but not the host HIV co-receptors CXCR4 and CCR5 or the CD4 receptor, using qRT-PCR. Network analysis of microarray data from these same subjects revealed filamin A (FLNA) as a possible interaction partner with MOR-1K, and FLNA gene expression was also found to be upregulated in HIVE using qRT-PCR. Overexpression of filamin A in HEK293 cells redistributed MOR-1K from intracellular compartments to the cell surface.
These results suggest that HIVE, and neurocognitive impairment depending on its severity, are associated with enhanced MOR-1K signaling through both increased expression and trafficking to the cell surface, which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS.
PMCID: PMC3939043  PMID: 24413261
μ opioid receptor; splice variant; HIV; gene regulation; neural cell type; neurocognition; HIV encephalitis
2.  Translational research in the genomic era: OPPERA study 
Molecular Pain  2014;10(Suppl 1):O1.
PMCID: PMC4304348  PMID: 25521492
5.  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
6.  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
7.  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
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.  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
15.  Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure 
Pain  2013;154(8):1419-1426.
Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity six weeks after two common trauma exposures. The study included data from two prospective emergency department-based cohorts: a discovery cohort (n=949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n=53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain six weeks after trauma exposure were assessed using a 0–10 numeric rating scale. After adjustment for multiple comparisons, six FKBP5 polymorphisms showed significant association (minimum p <0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain six weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent post-traumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.
PMCID: PMC3699900  PMID: 23707272
16.  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
17.  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
18.  Correlation of transcription of MALAT-1, a novel noncoding RNA, with deregulated expression of tumor suppressor p53 in small DNA tumor virus models 
Journal of cancer therapy  2013;4(3):10.4236/jct.2013.43094.
Although metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies, little is known about its function or regulation. We therefore examined the relationship between MALAT-1 expression and candidate modulators such as DNA tumor virus oncoproteins human papillomavirus (HPV)-16 E6 and E7, BK virus T antigen (BKVTAg), mouse polyoma virus middle T antigen (MPVmTAg) and tumor suppressor genes p53 and pRb. Using suppressive subtractive hybridization (SSH) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays, MALAT-1 was shown to be increased in viral oncongene-expressing salivary gland biopsies from humans and mice. The results also indicated that MALAT-1 transcripts and promoter activity were increased in vitro when viral oncongene-expressing plasmids were introduced into different cell types. These same viral oncogenes in addition to increasing MALAT-1 transcription have also been shown to inhibit p53 and/or pRb function. In p53 mutant or inactive cell lines MALAT-1 was also shown to be highly upregulated. We hypothesize that there is a correlation between MALAT-1 over-expression and p53 deregulation. In conclusion, we show that disruption of p53, by both polyoma and papilloma oncoproteins appear to play an important role in the up-regulation of MALAT-1. MALAT-1 might therefore represent a biomarker for p53 deregulation within malignancies.
PMCID: PMC3808111  PMID: 24163781
p53; MALAT-1; transcription; BK virus; polyoma virus; papillomavirus; HPV
19.  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
20.  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
21.  Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients 
Increasing evidence suggests that stress system activation after burn injury may contribute to burn-related pain. If this is the case, then genetic variations influencing the function of important stress system components, such as the enzyme catechol-O-methyltransferase (COMT), may predict pain severity after thermal burn injury.
We evaluated the association between COMT genotype and pain intensity in 57 individuals hospitalized after thermal burn injury. Consenting participants at four burn centers were genotyped and completed daily 0-10 numeric rating scale pain assessments on two consecutive days including evaluation of waking, least, and worst pain. The association between COMT genotype and individual pain outcomes was calculated using a linear mixed model adjusting for sociodemographic and burn injury characteristics.
Overall pain (combination of least, worst, and waking pain scores) was significantly higher in patients with a COMT pain vulnerable genotype (6.3 (.4) vs. 5.4 (.4), p=.037). Individuals with a COMT pain vulnerable genotype also had significantly higher “least pain” scores (3.8 (.5) vs. 2.6 (.4), p=.017) and significantly higher pain on awakening (6.8 (.5) vs. 5.3 (.4), p=.004). Differences in worst pain according to genotype group were not significant. COMT pain vulnerable genotype was a stronger predictor of overall pain severity than burn size, burn depth, or time from admission to pain interview assessment.
These findings suggest that genetic factors influencing stress system function may have an important influence on pain severity after burn injury. Further studies of genetic predictors of pain after burn injury are needed.
PMCID: PMC3319634  PMID: 22210062
catechol-O-methyltransferase; burn; pain; stress
22.  Study methods, recruitment, socio-demographic findings and demographic representativeness in the OPPERA study 
This paper describes methods used in the project “Orofacial Pain Prospective Evaluation and Risk Assessment” (OPPERA) and evaluates socio-demographic characteristics associated with temporomandibular disorders (TMD) in the OPPERA case-control study. Representativeness was investigated by comparing socio-demographic profiles of OPPERA participants with population census profiles of counties near study sites and by comparing age- and gender-associations with TMD in OPPERA and the 2007-09 US National Health Interview Survey. Volunteers aged 18-44 years were recruited at four US study sites: 3,263 people without TMD were enrolled into the prospective cohort study; 1,633 of them were selected as controls for the baseline case-control study. Cases were 185 volunteers with examiner-classified TMD. Distributions of some demographic characteristics among OPPERA participants differed from census profiles, although there was less difference in socio-economic profiles. Odds of TMD was associated with greater age in this 18-44 year range; females had three times the odds of TMD as males; and relative to non-Hispanic-Whites, other racial groups had one-fifth the odds of TMD. Age- and gender-associations with chronic TMD were strikingly similar to associations observed in the US population. Assessments of representativeness in this demographically diverse group of community volunteers suggest that OPPERA case-control findings have good internal validity.
PMCID: PMC3666856  PMID: 22074749
Temporomandibular Joint Disorders; Case-Control Studies; Demography; Socioeconomic Factors; Population Characteristics
23.  Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity 
Nature medicine  2012;18(4):595-599.
Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary1. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da2,3. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.
PMCID: PMC3350463  PMID: 22447075
24.  Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia 
Arthritis and Rheumatism  2012;64(2):584-593.
Fibromyalgia (FM) represents a complex disorder characterized by widespread pain and tenderness and frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome, but few specific genetic variants have been identified to date and still require replication. In this study, a large scale candidate gene approach was used to examine over 350 genes for association with FM.
Four hundred ninety-six FM patients were included in the study as cases with a total of 348 chronic pain-free controls. Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing over 350 genes known to be involved in biological pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression.
Significant differences in allele frequencies between cases and controls were observed for three genes: GABRB3 (rs4906902, p = 3.65×10−6), TAAR1 (rs8192619, p = 1.11×10−5) and GBP1 (rs7911, p = 1.06×10−4). These three genes, and seven other genes with suggestive evidence for association, were examined in a second, independent cohort of FM patients and controls genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4 genes.
Variation in these genes may serve as a basis for development of new diagnostic approaches, and these genes’ products may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.
PMCID: PMC3237946  PMID: 21905019
25.  Excess Risk of Temporomandibular Disorder Associated with Cigarette Smoking in Young Adults 
Evidence suggests that the effect of cigarette smoking on chronic pain is stronger in younger than older adults. This case control study investigated whether age modified an effect of smoking on temporomandibular disorder (TMD) in 299 females aged 18–60 years. It also investigated the extent to which this relationship was explained by psychological profile, inflammatory response and allergy. Cases were defined using the Research Diagnostic Criteria for Temporomandibular Disorders based on clinical examination. Psychological profile was evaluated using standardized instruments. Inflammatory response was evaluated with 11 cytokines isolated in plasma. History of allergy conditions was self-reported. Odds ratios (OR) for the effect of smoking were calculated using binary logistic regression. Stratified analyses and the likelihood ratio test examined effect modification by smoking. Compared to non-smokers, ever smokers aged <30 years had higher odds of TMD (OR =4.14, 95% CI: 1.57, 11.35) than older adults (OR =1.23, 95% CI: 0.55, 2.78) (P (effect modification) =0.038). Adjustment for psychological profile, cytokines and history of allergy-like conditions attenuated the effect by 45% to statistical non-significance. The main finding was reproduced with secondary analyses of two nationally-representative surveys of adults conducted in the U.S. and Australia.
PMCID: PMC3249502  PMID: 22036516
Epidemiology; case-control study; temporomandibular joint disorder; psychological stress; allergy and hypersensitivity, cytokines

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