Ligand-gated ion channel P2X7 regulates hypoxia-induced factor-1α mediated pain induced by dental pulpitis in the medullary dorsal horn

Abstract

Dental pulpitis often induces severe pain, and the molecular immune response is remarkable in both peripheral and central nervous system. Accumulating evidence indicates that activated microglia in the medullary dorsal horn (MDH) contribute to dental pulpitis induced pain. The P2X7 receptor plays an important role in driving pain and inflammatory processes, and its downstream target hypoxia-induced factor-1α (HIF-1α) has a crucial role in maintaining inflammation. However, the relationship between P2X7 and HIF-1α in dental inflammatory pain remains unclear. This study demonstrated that the degree of inflammation in the dental pulp tissue became more severe in a time-dependent manner by establishing a rat dental pulpitis model via pulp exposure. Meanwhile, the expression of P2X7, HIF-1α, IL-1β, and IL-18 in the MDH increased most on the seventh day when the pain threshold was the lowest in the dental pulpitis model. Furthermore, lipopolysaccharides (LPS) increased P2X7-mediated HIF-1α expression in microglia. Notably, the suppression of P2X7 caused less IL-1β and IL-18 release and lower HIF-1α expression, and P2X7 antagonist Brilliant Blue G (BBG) could alleviate pain behaviors of the dental pulpitis rats. In conclusion, our results provide further evidence that P2X7 is a key molecule, which regulates HIF-1α expression and inflammation in dental pulpitis-induced pain.

Involvement of microglial P2X7 receptor in pain modulation

“…102 In addition, microglial P2X7R plays a pivotal role in dental pulpitis-induced pain by enhancing NLRP3 and hypoxia-induced factor-1α (HIF-1α) expression. 103,104 These findings highlight the role of microglial P2X7R in central Bmk I, a sodium channel activator and inflammation/pain mediator, was found to upregulate microglial P2X7R expression in the dorsal horn of the spinal cord through plantar injections, activating the p38 pathway and inducing substantial IL-1β production, ultimately suppressing inflammatory pain. 105 Similarly, in urological diseases like chronic prostatitis, characterized by painful symptoms, microglial activation in the posterior horn of spinal cord and heightened P2X7R expression were observed.…”

“…In a model of acute pulpal inflammatory pain induced by mustard oil, the P2X7R antagonists BBG and oxATP significantly alleviated MDH neuron central sensitization, while microglia inhibition using minocycline relieved pain 102 . In addition, microglial P2X7R plays a pivotal role in dental pulpitis‐induced pain by enhancing NLRP3 and hypoxia‐induced factor‐1α (HIF‐1α) expression 103,104 . These findings highlight the role of microglial P2X7R in central sensitization and underscore the need for further research into oral inflammatory pain mechanisms.…”

“… 102 In addition, microglial P2X7R plays a pivotal role in dental pulpitis‐induced pain by enhancing NLRP3 and hypoxia‐induced factor‐1α (HIF‐1α) expression. 103 , 104 These findings highlight the role of microglial P2X7R in central sensitization and underscore the need for further research into oral inflammatory pain mechanisms.…”

Combined Transcriptomic and Proteomic Profiling of the Mouse Anterior Cingulate Cortex Identifies Potential Therapeutic Targets for Pulpitis-Induced Pain

“…We established the pulpitis model by exposing pulp. , The mice were grouped into two groups. First, the mice were anesthetized with pentobarbital sodium (50 mg/kg) by intraperitoneal injection, positioned face up, and fixed to the operating board with adhesive tape.…”

Activation of GABAergic neurons in anterior cingulate cortex and their impacts on pulpitis-induced pain

“…The pulpitis pain model in mice was established through dental pulp exposure as previously [12][13] . Then, the pain-related behavior was assessed in both control and pulpitis groups on -1, 1, 3, 5, 7, 9, 11, 13, and 15 days post-model establishment (Fig.…”