GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos.

Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10-8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.

Estrogen-Induced Monocytic Response Correlates with TMD Pain: A Case Control Study.

Temporomandibular disorders (TMD) are a set of conditions characterized by pain and dysfunction in the temporomandibular joint and muscles of mastication. These pain conditions are associated with considerable morbidity, societal costs, and reduced quality of life. The prevalence varies between 4% and 10%, with females at higher risk, and a higher prevalence occurs during reproductive years. The increased prevalence of TMD in females and low prevalence in childhood reinforce that sex hormones, like estrogen, play an important, complex role in the pathophysiology of these disorders. The goal of this study was to determine whether women with TMD exhibit a monocytic hyperinflammatory response compared with control women, and to examine associations of monocytic inflammatory responses with clinical pain. Eighteen women, aged 18 to 35 y, were seen during their follicular menstrual phase. A blood sample was collected, a clinical questionnaire about pain history was administered, and a Research Diagnostic Criteria (RDC) exam was performed. Extracted monocytes were stimulated with the toll-like receptor (TLR)-4 ligand, lipopolysaccharide (LPS), in the presence and absence of estrogen, and the levels of IL6 expression evaluated. Women with TMD showed a systemic hyperinflammatory phenotype, manifested by an increased monocytic release of cytokines after an inflammatory insult, and this was further increased by estrogen. In addition, monocytes from participants who self-reported more pain on the VAS scale produced higher levels of IL6 compared with those from participants who self-reported lower pain sensitivity. These data suggest that an estrogen-induced hyperinflammatory phenotype in women with TMD may at least in part contribute to heightened clinical pain, perhaps via central sensitization.

Differences in suprathreshold heat pain responses and self-reported sleep quality between patients with temporomandibular joint disorder and healthy controls.

The purpose of this study was to examine differences in heat pain threshold (HPTh) and heat pain tolerance (HPTo) between temporomandibular joint disorder (TMJD) patients and healthy controls. Using suprathreshold heat pain, this study also examined between-group (i.e. TMJD vs. healthy controls) differences in hyperalgesia and temporal summation (TS) of heat pain. Lastly, whether between-group differences in these heat pain outcomes were mediated by self-reported sleep quality was also tested. A total of 119 participants (41% TMJD) completed the current study. HPTh and HPTo responses were assessed at the ventral forearm with an ascending method of limits, while hyperalgesia and TS responses were assessed at the dorsal forearm at temperatures of 46, 48 and 50 °C. Prior to completion of heat pain procedures, participants completed the Pittsburgh Sleep Quality Index. Significant between-group differences in HPTh and HPTo were not observed. TMJD patients demonstrated significantly greater hyperalgesia than healthy controls at 46 °C only, but there were no differences for TS. Furthermore, TMJD patients reported significantly poorer sleep quality compared with healthy controls. Data analysis revealed a significant simple mediation effect whereby the presence of TMJD was strongly associated with poorer self-reported sleep quality, which, in turn, was related to enhanced hyperalgesia at 46 °C. These findings support the hypothesis that the thermal hyperalgesia demonstrated by TMJD patients may be related to poor quality of their self-reported sleep. The ability of interventions that improve sleep quality to also affect pain sensitivity is currently the topic of ongoing investigation.

Evaluation of menstrual cycle effects on morphine and pentazocine analgesia.

Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08mg/kg) or pentazocine (0.5mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic, and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model analyses of variance. NOC women showed slightly greater heat pain sensitivity in the follicular vs luteal phase, while the reverse pattern emerged for OC women (P=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (P<0.05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs the luteal phase (P=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (P=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. Limited menstrual cycle effects on baseline pain responses were observed; however, morphine analgesia and side effects were greater during the follicular phase.

Genetic contributions to pain: a review of findings in humans.

Pain represents the major motivating factor for which individuals seek healthcare, and pain responses are characterized by substantial inter-individual differences. Increasing evidence suggests that genetic factors contribute significantly to individual differences in responses to both clinical and experimental pain. The purpose of this review article was to summarize the current literature regarding genetic contributions to pain, highlighting findings relevant to oral pain where available. A brief discussion of methodologic considerations is followed by a review of findings regarding genetic influences on clinical pain. Next, the literature examining genetic contributions to experimental pain responses is presented, emphasizing genetic associations that have been replicated in multiple cohorts. It is hoped that an enhanced understanding of genetic contributions to pain responses will ultimately improve diagnosis and treatment of clinical pain conditions.