ABSTRACT
The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.
Subject(s)
Chronic Pain/metabolism , Epiregulin/genetics , Epiregulin/physiology , ErbB Receptors/physiology , Adolescent , Adult , Animals , Behavior, Animal , Case-Control Studies , Cohort Studies , Drosophila melanogaster , Female , Humans , Hyperalgesia/metabolism , Inflammation , Ligands , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mutation , Neurons/metabolism , Pain Management , Phosphorylation , Polymorphism, Single Nucleotide , Protein Binding , Signal Transduction , Young AdultABSTRACT
UNLABELLED: Genetic risk factors are believed to combine with environmental exposures and contribute to the 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 were computed as measures of association between 2,924 single-nucleotide polymorphisms and TMD incidence. After correction for multiple testing, no single single-nucleotide polymorphism was significantly associated with risk of onset TMD. However, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (.05, .1, or .2) for association with intermediate phenotypes shown to be predictive of TMD onset. Nonspecific orofacial symptoms were associated with voltage-gated sodium channel, type I, 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-ß (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. PERSPECTIVE: This article reports the findings of a large candidate gene association study of first-onset TMD and related intermediate phenotypes in the OPPERA Study. Although no genetic markers predicted TMD onset, several genetic risk factors for clinical, psychological, and sensory phenotypes associated with TMD onset were observed.
