RNA sequencing of the thalamus and rostral ventral medulla in rats with chronic orofacial pain.

Diagnosing and treating chronic orofacial pain is challenging due to its complex structure and limited understanding of its causes and mechanisms. In this study, we used RNA sequencing to identify differentially expressed genes (DEGs) in the rostral ventral medulla (RVM) and thalamus of rats with persistent orofacial pain, aiming to explore its development. DEGs were functionally analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results showed a significant association between immune response and pain in this model. Key DEG mRNA expression trends were further validated using real-time quantitative polymerase chain reaction (RT-PCR), confirming their crucial roles in chronic orofacial pain. After injecting complete Freund's adjuvant (CFA) into the bilateral temporomandibular joint cavity for 14 days, we observed 293 upregulated genes and 14 downregulated genes in the RVM, and 1086 upregulated genes and 37 downregulated genes in the thalamus. Furthermore, we identified 27 common DEGs with altered expression (upregulation) in both the thalamus and RVM, including Cd74, C3, Cxcl13, C1qb, Itgal, Fcgr2b, C5ar1, and Tlr2, which are pain-associated genes. Protein-protein interaction (PPI) analysis using Cytoscape revealed the involvement of Toll-like receptors, complement system, differentiation clusters, and antigen presentation-related proteins in the interaction between the thalamus and RVM. The results of this study show that the immune system seems to have a more significant influence on chronic orofacial pain. There may be direct or indirect influence between the thalamus and RVM, which may participate in the regulation of chronic orofacial pain.

Association between oxidative stress and chronic orofacial pain and potential druggable targets: Evidence from a Mendelian randomization study.

BACKGROUND: Oxidative stress indicators affect chronic orofacial pain (COFP), but how to reduce these effects is uncertain. OBJECTIVES: 11 oxidative stress biomarkers were collected as exposures, while four forms of COFP were chosen as outcomes for Mendelian randomization (MR) study. METHODS: The effect estimates between oxidative stress and COFP were calculated using inverse variance-weighted MR (IVW-MR). Then, functional mapping and annotation (FUMA) was utilized in order to carry out SNP-based functional enrichment analyses. In addition, the IVW-MR method was applied to combine effect estimates when using genetic variants associated with oxidative stress biomarkers as an instrument for exploring potential druggable targets. RESULTS: The results indicated that oxidative stress biomarkers (causal OR of uric acid (UA), 0.998 for myofascial pain, 95% CI 0.996-1.000, p < .05; and OR of glutathione transferase (GST), 1.002 for dentoalveolar pain, 95% CI 1.000-1.003, p < .05) were significantly linked with the probability of COFP. Functional analysis also demonstrated that UA and myofascial pain genes were prominent in nitrogen and uracil metabolism, while GST and dentoalveolar pain genes were enriched in glutathione metabolism. Also, the study provided evidence that solute carrier family 2 member 9 (SLC2A9) and glutathione S-transferase alpha 2 (GSTA2) cause discomfort in the myofascial pain (OR = 1.003, 95% CI 1.000-1.006; p < .05) and dentoalveolar region (OR = 1.001, 95% CI 1.000-1.002; p < .05), respectively. CONCLUSIONS: In conclusion, this MR study indicates that genetically predicted myofascial pain was significantly associated with decreased UA and dentoalveolar pain was significantly associated with increased GST level. SLC2A9 inhibitor and GSTA2 inhibitor were novel chronic orofacial pain therapies and biomarkers, but clinical trials are called to examine if these oxidative biomarkers have the protective effect against orofacial pain, and further research are needed to explore the underlying mechanisms.

Genetic influence on treatment outcomes in patients with pain-related temporomandibular disorders.

BACKGROUND: Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain-related temporomandibular disorders (TMDp). OBJECTIVE: Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. METHODS: Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain-free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. RESULTS: Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p < .025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain-free mouth opening while dominant homozygous exhibited improvement (p < .025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p = .003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain-free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. CONCLUSION: Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response.

Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain.

The information provided from the papers reviewed here about the role of epigenetics in chronic craniofacial neuropathic pain is critically important because epigenetic dysregulation during the development and maintenance of chronic neuropathic pain is not yet well characterized, particularly for craniofacial pain. We have noted that gene expression changes reported vary depending on the nerve injury model and the reported sample collection time point. At a truly chronic timepoint of 10 weeks in our model of chronic neuropathic pain, functional groupings of genes examined include those potentially contributing to anti-inflammation, nerve repair/regeneration, and nociception. Genes altered after treatment with the epigenetic modulator LMK235 are discussed. All of these differentials are key in working toward the development of diagnosis-targeted therapeutics and likely for the timing of when the treatment is provided. The emphasis on the relevance of time post-injury is reiterated here.

NGF-Induced Upregulation of CGRP in Orofacial Pain Induced by Tooth Movement Is Dependent on Atp6v0a1 and Vesicle Release.

The nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) play a crucial role in the regulation of orofacial pain. It has been demonstrated that CGRP increases orofacial pain induced by NGF. V-type proton ATPase subunit an isoform 1 (Atp6v0a1) is involved in the exocytosis pathway, especially in vesicular transport in neurons. The objective was to examine the role of Atp6v0a1 in NGF-induced upregulation of CGRP in orofacial pain induced by experimental tooth movement. Orofacial pain was elicited by ligating closed-coil springs between incisors and molars in Sprague-Dawley rats. Gene and protein expression levels were determined through real-time polymerase chain reaction, immunostaining, and fluorescence in situ hybridization. Lentivirus vectors carrying Atp6v0a1 shRNA were used to knockdown the expression of Atp6v0a1 in TG and SH-SY5Y neurons. The release of vesicles in SH-SY5Y neurons was observed by using fluorescence dye FM1-43, and the release of CGRP was detected by Enzyme-Linked Immunosorbent Assy. Orofacial pain was evaluated through the rat grimace scale. Our results revealed that intraganglionic administration of NGF and Atp6v0a1 shRNA upregulated and downregulated CGRP in trigeminal ganglia (TG) and trigeminal subnucleus caudalis (Vc), respectively, and the orofacial pain was also exacerbated and alleviated, respectively, following administration of NGF and Atp6v0a1 shRNA. Besides, intraganglionic administration of NGF simultaneously caused the downregulation of Atp6v0a1 in TG. Moreover, the release of vesicles and CGRP in SH-SY5Y neurons was interfered by NGF and Atp6v0a1 shRNA. In conclusion, in the orofacial pain induced by experimental tooth movement, NGF induced the upregulation of CGRP in TG and Vc, and this process is dependent on Atp6v0a1 and vesicle release, suggesting that they are involved in the transmission of nociceptive information in orofacial pain.

Chronic Orofacial Pain: Models, Mechanisms, and Genetic and Related Environmental Influences.

Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes.

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

OBJECTIVE: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. METHODS: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. RESULTS: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. INTERPRETATION: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168-180.

CGRP Induces Differential Regulation of Cytokines from Satellite Glial Cells in Trigeminal Ganglia and Orofacial Nociception.

Neuron-glia interactions contribute to pain initiation and sustainment. Intra-ganglionic (IG) secretion of calcitonin gene-related peptide (CGRP) in the trigeminal ganglion (TG) modulates pain transmission through neuron-glia signaling, contributing to various orofacial pain conditions. The present study aimed to investigate the role of satellite glial cells (SGC) in TG in causing cytokine-related orofacial nociception in response to IG administration of CGRP. For that purpose, CGRP alone (10 µL of 10-5 M), Minocycline (5 µL containing 10 µg) followed by CGRP with one hour gap (Min + CGRP) were administered directly inside the TG in independent experiments. Rats were evaluated for thermal hyperalgesia at 6 and 24 h post-injection using an operant orofacial pain assessment device (OPAD) at three temperatures (37, 45 and 10 °C). Quantitative real-time PCR was performed to evaluate the mRNA expression of IL-1ß, IL-6, TNF-α, IL-1 receptor antagonist (IL-1RA), sodium channel 1.7 (NaV 1.7, for assessment of neuronal activation) and glial fibrillary acidic protein (GFAP, a marker of glial activation). The cytokines released in culture media from purified glial cells were evaluated using antibody cytokine array. IG CGRP caused heat hyperalgesia between 6⁻24 h (paired-t test, p < 0.05). Between 1 to 6 h the mRNA and protein expressions of GFAP was increased in parallel with an increase in the mRNA expression of pro-inflammatory cytokines IL-1ß and anti-inflammatory cytokine IL-1RA and NaV1.7 (one-way ANOVA followed by Dunnett's post hoc test, p < 0.05). To investigate whether glial inhibition is useful to prevent nociception symptoms, Minocycline (glial inhibitor) was administered IG 1 h before CGRP injection. Minocycline reversed CGRP-induced thermal nociception, glial activity, and down-regulated IL-1ß and IL-6 cytokines significantly at 6 h (t-test, p < 0.05). Purified glial cells in culture showed an increase in release of 20 cytokines after stimulation with CGRP. Our findings demonstrate that SGCs in the sensory ganglia contribute to the occurrence of pain via cytokine expression and that glial inhibition can effectively control the development of nociception.

Peripheral and orofacial pain sensation is unaffected by the loss of p39.

Abstract: Cdk5 is a key neuronal kinase necessary for proper brain development, which has recently been implicated in modulating nociception. Conditional deletion of Cdk5 in pain-sensing neurons attenuates pain responses to heat in both the periphery and orofacial regions. Cdk5 activity is regulated by binding to the activators p35 and p39, both of which possess a cyclin box. Our previous examination of the nociceptive role of the well-characterized Cdk5 activator p35 using mice that either lack or overexpress this regulatory subunit demonstrated that Cdk5/p35 activity affects mechanical, chemical, and thermal nociception. In contrast, the nociceptive role of Cdk5's other less-studied activator p39 is unknown. Here, we report that the knockout of p39 in mice did not affect orofacial and peripheral nociception. The lack of any algesic response to nociceptive stimuli in the p39 knockout mice contrasts with the hypoalgesic effects that result from the deletion of p35. Our data demonstrate different and nonoverlapping roles of Cdk5 activators in the regulation of orofacial as well as peripheral nociception with a crucial role for Cdk5/p35 in pain signaling.

Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.

BACKGROUND: Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. METHODS: The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. RESULTS: pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1ß upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1ß inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1ß in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1ß upregulation. CONCLUSIONS: CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1ß pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.

To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.

COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial.

Propranolol is a nonselective ß-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase (COMT) gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of COMT, and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within COMT genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly (P = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction (P = 0.035). Cumulative response curves confirmed greater (P = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol's efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of COMT's role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).

Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy.

This article discusses the pathophysiology of temporomandibular disorders (TMD)-related pain and its treatment with analgesic drugs. Temporomandibular disorders are comprised of a group of conditions that result in temporomandibular joint pain (arthralgia, arthritis) and/or masticatory muscle pain (myofascial TMD). In at least some patients with TMD, a peripheral mechanism contributes to this pain. However, there is often a poor correlation between the severity of TMD-related pain complaints and evidence of definitive tissue pathology. This has led to the concept that pain in some patients with TMD may result from altered central nervous system pain processing and further that this altered pain processing may be attributable to specific genes that are heritable. Psychosocial stressors are also thought to contribute to the development of TMD-related pain, particularly masticatory muscle pain. Finally, substantially more women suffer from TMD than men. Although there are arguably multiple reasons for sex-related differences in the prevalence of TMD, one candidate for the increased occurrence of this disorder in women has been suggested to be the female sex hormone oestrogen. Analgesic drugs are an integral part of the primary treatment for TMD-related pain and dysfunction with more that 90% of treatment recommendations involving use of medications. The most commonly used agents include non-steroidal anti-inflammatory drugs, corticosteroids, muscle relaxants, anxiolytics, opiates and tricyclic antidepressants, however, evidence in support of the effectiveness of these drugs is lacking. Continued research into the pathophysiology of TMD-related pain and the effectiveness of analgesic treatments for this pain is required.

Effect of Genetic Polymorphisms on Pain Sensitivity in the Orofacial Region: A Systematic Review.

AIMS: To systematically review the literature to assess whether genetic polymorphisms affect orofacial pain sensitivity in healthy individuals and in patients with chronic orofacial pain disorders. METHODS: Electronic searches were conducted to identify observational studies and clinical trials investigating the association between genetic polymorphisms and orofacial pain sensitivity in healthy individuals and/or patients with chronic orofacial pain disorders. Searches were carried out in PubMed, Embase, and Scopus databases using Medical Subject Headings and free terms. RESULTS: Seven studies fulfilled the eligibility criteria: four analyzed healthy subjects, two included chronic orofacial pain patients, and one included samples of healthy subjects and patients with neuropathic pain. The results showed that genes associated with mechanical and thermal pain sensitivity were mostly related to opioid, catecholaminergic, inflammatory, and dopaminergic pathways. CONCLUSION: Genetic polymorphisms related to opioid, catecholaminergic, inflammatory, and dopaminergic pathways were associated with sensitivity to thermal and pressure stimuli in the orofacial region. Therefore, genetic factors should be taken into account for an accurate interpretation of orofacial pain sensitivity. These results will allow for a better understanding of the etiopathogenesis of chronic pain affecting the orofacial region, and consequently for finding new therapeutic targets.

The role of RNA editing of the serotonin 2C receptor in a rat model of oro-facial neuropathic pain.

We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post-injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post-injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem-spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis.

Are post-traumatic stress disorder symptoms and temporomandibular pain associated? Findings from a community-based twin registry.

AIMS: To determine whether symptoms of post-traumatic stress disorder (PTSD) are related to the pain of temporomandibular disorders (TMD) in a community-based sample of female twin pairs, and if so, to ascertain whether the association is due to the presence of chronic widespread pain (CWP) and familial/genetic factors. METHODS: Data were obtained from 630 monozygotic and 239 dizygotic female twin pairs participating in the University of Washington Twin Registry. PTSD symptoms were assessed with the Impact of Events Scale (IES), with scores partitioned into terciles. TMD pain was assessed with a question about persistent or recurrent pain in the face, jaw, temple; in front of the ear; or in the ear during the past 3 months. CWP was defined as pain located in 3 body regions during the past 3 months. Random-effects regression models, adjusted for demographic features, depression, CWP, and familial/genetic factors, were used to examine the relationship between the IES and TMD pain. RESULTS: IES scores were significantly associated with TMD pain (P < .01). Twins in the highest IES tercile were almost 3 times more likely than those in the lowest tercile to report TMD pain, even after controlling for demographic factors, depression, and CWP. After adjustment for familial and genetic factors, the association of IES scores with TMD pain remained significant in dizygotic twins (Ptrend = .03) but was not significant in monozygotic twins (Ptrend = .30). CONCLUSION: PTSD symptoms are strongly linked to TMD pain. This association could be partially explained by genetic vulnerability to both conditions but is not related to the presence of CWP. Future research is needed to understand the temporal association of PTSD and TMD pain and the genetic and physiological underpinnings of this relationship.

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.

Pulp Sensitivity: Influence of Sex, Psychosocial Variables, COMT Gene, and Chronic Facial Pain.

INTRODUCTION: The purpose of this study was to evaluate the associations of variability in pulp sensitivity with sex, psychosocial variables, the gene that encodes for the enzyme catechol-O-methyltransferase (COMT), and chronic painful conditions (temporomandibular disorders [TMDs]). METHODS: The study was composed of 97 subjects (68 women and 29 men aged 20-44 years). The electric (electric pulp tester) and cold (refrigerant spray) stimuli were performed on mandibular lateral incisors. The results were expressed as pain threshold values for electric pulp stimulation (0-80 units) and as pain intensity scores (visual numeric scale from 0-10) for cold stimulation. The Research Diagnostic Criteria for TMD were used to assess TMD, depression, and somatization. DNA extracted from peripheral blood was genotyped for 3 COMT polymorphisms (rs4680, rs6269, and rs165774) using the real-time TaqMan method. Multivariate linear regression was used to investigate the joint effect of the predictor variables (clinical and genetic) on pulp sensitivity (dependent variables). RESULTS: Threshold responses to electric stimuli were related to female sex (P < .01) and the homozygous GG genotype for the rs165774 polymorphism (P < .05). Pain intensity to cold stimuli was higher in TMD patients (P < .01) and tended to be higher in women. Multivariate linear regression identified sex and the rs165774 COMT polymorphism as the determinants of electric pain sensitivity, whereas TMD accounts for the variability in the cold response. CONCLUSIONS: Our findings indicate that sex/a COMT gene variant and TMD as a chronic painful condition may contribute to individual variation in electric and cold pulp sensitivity, respectively.

Sex, Gender, and Orofacial Pain.

This review examines gender prevalence in orofacial pain to elucidate underlying factors that can explain such differences. This review highlights how gender affects (1) the association of hormonal factors and pain modulation; (2) the genetic aspects influencing pain sensitivity and pain perception; (3) the role of resting blood pressure and pain threshold; and (4) the impact of sociocultural, environmental, and psychological factors on pain.

Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients.

The purpose of this study was to investigate the possible association between estrogen receptor alpha (ERalpha) polymorphism and pain susceptibility in female symptomatic temporomandibular joint (TMJ) osteoarthritis (OA) patients. A patient group of 100 women, diagnosed as TMJ OA according to the research diagnostic criteria for temporomandibular disorders, were selected, and 74 women with no signs and symptoms of temporomandibular disorder were assigned to a control group. Pvu II and Xba I restriction fragment length polymorphisms were analyzed by direct haplotyping. The patient group was divided into three subgroups according to a visual analog scale (VAS): mild pain (0.05). TMJ OA patients carrying the PX haplotype were found to have a significantly higher risk of moderate or severe pain compared to those without the PX haplotype, suggesting that ERalpha polymorphism may be associated with pain susceptibility in female TMJ OA patients.