Mechanisms for Orofacial Pain: Roles of Immunomodulation, Metabolic Reprogramming, Oxidative Stress and Epigenetic...

Background and Objectives: Orofacial pain corresponds to pain sensitization originating from the facial and oral regions, often accompanied by diagnostic complexity due to a multitude of contributory factors, leading to significant patient distress and impairment. Here, we have reviewed current mechanistic pathways and biochemical aspects of complex orofacial pain pathology, highlighting recent advancements in understanding its multifactorial regulation and signaling and thus providing a holistic approach to challenging it. Materials and Methods: Studies were identified from an online search of the PubMed database without any search time range. Results: We have discussed neuron-glia interactions and glial cell activation in terms of immunomodulatory effects, metabolism reprogramming effects and epigenetic modulatory effects, in response to orofacial pain sensitization comprising different originating factors. We have highlighted the fundamental role of oxidative stress affecting significant cellular pathways as well as cellular machinery, which renders pain pathology intricate and multidimensional. Emerging research on the epigenetic modulation of pain regulatory genes in response to molecular and cellular environmental factors is also discussed, alongside updates on novel diagnostic and treatment approaches. Conclusions: This review deliberates the integrative perspectives and implications of modulation in the immune system, glucose metabolism, lipid metabolism and redox homeostasis accompanied by mitochondrial dysfunction as well as epigenetic regulation accommodating the effect of dysregulated non-coding RNAs for an interdisciplinary understanding of pain pathology at the molecular level, aiming to improve patient outcomes with precise diagnosis offering improved pain management and treatment.