Pain of the orofacial region is the primary complaint for which patients seek treatment. Of all the orofacial pain conditions, one condition that possess a significant global health problem is temporomandibular disorder (TMD). Patients with TMD typically frequently complaints of pain as a symptom. TMD can occur due to complex interplay between peripheral and central sensitization, endogenous modulatory pathways, and cortical processing. For diagnosis of TMD pain a descriptive history, clinical assessment, and imaging is needed. However, due to the complex nature of pain an additional step is needed to render a definitive TMD diagnosis. In this review we explicate the role of different biomarkers involved in painful TMD. In painful TMD conditions, the role of biomarkers is still elusive. We believe that the identification of biomarkers associated with painful TMD may stimulate researchers and clinician to understand the mechanism underlying the pathogenesis of TMD and help them in developing newer methods for the diagnosis and management of TMD. Therefore, to understand the potential relationship of biomarkers, and painful TMD we categorize the biomarkers as molecular biomarkers, neuroimaging biomarkers and sensory biomarkers. In addition, we will briefly discuss pain genetics and the role of potential microRNA (miRNA) involved in TMD pain.

Inhibition of dendritic cell maturation and activation, together with abnormal functioning of cell-mediated immunity, has been reported in chronic spinal cord injury (SCI). The development of immune-based therapies could: 1) prevent or slow down limit further tissue damage in chronic SCI, and 2) promote tissue regeneration. To identify novel candidate molecular pathways mediating SCI-induced immune changes, we performed whole–genome microarray and molecular pathway analyses. Subjects with motor complete chronic SCI (> 2 years post-injury) and uninjured controls were selected from an ongoing study. Microarray analysis was performed with RNA extracted from circulating monocytes. Partek Genomic Suite (PGS) software was used to limit the 54,000 gene list to only those genes up-regulated or down-regulated by 2-fold or more in SCI compared with control. Pathway analyses were performed with Ingenuity Systems IPA software to identify biological pathways of interest involving differentially expressed genes. Genes of interest were then confirmed by quantitative PCR (qPCR). Six SCI subjects and five uninjured controls were included in the final analyses. A molecular pathway related to immune cell trafficking was identified as being significantly upregulated in the SCI subjects. Two genes in that network, transmembrane domain protein (TMEM)176A and TMEM176B, were notable for the magnitude of overexpression. Dendritic cells have been shown to mediate recovery and/or protective autoimmunity in central nervous system injuries and have the capacity to induce neuroprotection and neurogenesis in stroke patients. High TMEM176A and TMEM176B levels have been shown to prevent dendritic cell maturation and inhibit dendritic cell activity in the general population. Here, we report overexpression of both genes in SCI compared with control subjects. Thus, we propose that TMEM176A and TMEM176B are candidate genes involved in inhibiting protective immune responses in SCI. This study may support future research aimed at developing new targets for therapies to promote immune system-mediated neuroprotection and recovery in SCI.

Objective: To assess the association between ibuprofen use and the systemic inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL-6) in chronic Spinal Cord Injury (SCI). Study design: Prospective cohort study. Setting: Community dwelling individuals with SCI. Participants: 338 (278 male, 60 female) community dwelling individuals with chronic SCI (≥1-year post-injury). Interventions: None. Main outcome measures: CRP and IL-6 levels were quantified by ultra-sensitive ELISA assay. General linear models were used to assess associations between various clinical and demographic factors and CRP and IL-6 levels. Results: There were 50 active ibuprofen users and 288 non-users. After adjusting for clinical and demographic factors, ibuprofen users had significantly lower CRP levels (2.3 mg/L versus 3.5 mg/L, P = 0.04) and IL-6 levels (3.2 pg/ml versus 4.0 pg/ml, P = 0.04) compared to nonusers. Conclusions: Our study suggests that self-reported ibuprofen use may be negatively associated with CRP and IL-6 levels in chronic SCI after adjusting for known confounding factors, and suggests ibuprofen use may be an important, potential variable to consider in future studies focused on systemic inflammation in SCI. Future prospective studies require assessing frequency, duration, and dosage-dependent effects of ibuprofen on systemic markers of inflammation in chronic SCI. These findings may support future clinical trials to determine safety and efficacy of ibuprofen treatment for various outcomes in chronic SCI.

Neuropathic pain in spinal cord injury (SCI) is associated with inflammation in both the peripheral and central nervous system (CNS), which may contribute to the initiation and maintenance of persistent pain. An understanding of factors contributing to neuroinflammation may lead to new therapeutic targets for neuropathic pain. Moreover, novel circulating biomarkers of neuropathic pain may facilitate earlier and more effective treatment. MicroRNAs (miRNAs) are short, non-coding single-stranded RNA that have emerged as important biomarkers and molecular mediators in physiological and pathological conditions. Using a genome-wide miRNA screening approach, we studied differential miRNA expression in plasma from 68 healthy, community-dwelling adults with and without SCI enrolled in ongoing clinical studies. We detected 2367 distinct miRNAs. Of these, 383 miRNAs were differentially expressed in acute SCI or chronic SCI versus no SCI and 71 were differentially expressed in chronic neuropathic pain versus no neuropathic pain. We selected homo sapiens (hsa)-miR-19a-3p and hsa-miR-19b-3p for additional analysis based on p-value, fold change, and their known role as regulators of neuropathic pain and neuroinflammation. Both hsa-miR-19a-3p and hsa-miR-19b-3p levels were significantly higher in those with chronic SCI and severe neuropathic pain versus those with chronic SCI and no neuropathic pain. In confirmatory studies, both hsa-miR-19a-3p and hsa-miR-19b-3p have moderate to strong discriminative ability to distinguish between those with and without pain. After adjusting for opioid use, hsa-miR-19b-3p levels were positively associated with pain interference with mood. Because hsa-miR-19 levels have been shown to change in response to exercise, folic acid, and resveratrol, these studies suggest that miRNAs are potential targets of therapeutic interventions.

Many individuals with spinal cord injury live with debilitating chronic pain that may be neuropathic, nociceptive, or a combination of both in nature. Identification of brain regions demonstrating altered connectivity associated with the type and severity of pain experience may elucidate underlying mechanisms, as well as treatment targets. Resting state and sensorimotor task-based magnetic resonance imaging data were collected in 37 individuals with chronic spinal cord injury. Seed-based correlations were utilized to identify resting state functional connectivity of regions with established roles in pain processing: the primary motor and somatosensory cortices, cingulate, insula, hippocampus, parahippocampal gyri, thalamus, amygdala, caudate, putamen, and periaqueductal gray matter. Resting state functional connectivity alterations and task-based activation associated with individuals' pain type and intensity ratings on the International Spinal Cord Injury Basic Pain Dataset (0-10 scale) were evaluated. We found that intralimbic and limbostriatal resting state connectivity alterations are uniquely associated with neuropathic pain severity, whereas thalamocortical and thalamolimbic connectivity alterations are associated specifically with nociceptive pain severity. The joint effect and contrast of both pain types were associated with altered limbocortical connectivity. No significant differences in task-based activation were identified. These findings suggest that the experience of pain in individuals with spinal cord injury may be associated with unique alterations in resting state functional connectivity dependent upon pain type.