Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Sensitization of peripheral and central nociceptive neurons along pain transmission pathway is essential to the genesis of chronic pain. Plastic events at transcriptional and translational levels in nociceptive dorsal root ganglion (DRG) neurons (nociceptors) contribute to persistent peripheral sensitization. Our long term go al focuses on role of neuroplasticity induced by inflammatory mediators in prolonged nociceptor sensitization and potentiation. Prostaglandin E2 (PGE2), a well-known inflammatory mediator enriched in injured tissue, not only sensitizes nociceptors, but also potentiates the sensitizing effects of other pain mediators such as transient potential receptor vanilloid-1 (TRPV1) at functional level. TRPV1 is an integrator of diverse noxious stimuli and involved in chronic pain of inflammatory and neuropathic origins. However, it remains unknown whether PGE2 potentiates TRPV1 activity by stimulating its transcription and translation in DRG neurons and whether PGE2-induced TRPV1 synthesis contributes to persistent nociceptor sensitization and potentiation. Our pilot data suggest that PGE2 is involved in TRPV1 up-regulation in DRG neurons after inflammation and nerve injury. Moreover, PGE2 exposure not only prolongs pain evoked by subsequent challenge of TRPV1 agonist capsaicin, but also increases TRPV1 levels in DRG neurons. These data let us hypothesize that facilitating TRPV1 synthesis in DRG neurons is a novel mechanism underlying PGE2 prolonged nociceptor sensitization and potentiation. In this research program, we will target three specific short term goals using multidisciplinary approaches in both in vitro and in vivo models.
Specific aim 1: Using molecular, neurochemical and morphological approaches, we will determine whether PGE2 induces TRPV1 synthesis at the gene and protein levels in DRG neurons in both in vitro and in vivo models and whether PGE2 contributes to TRPV1 up-regulation in animal models of prolonged sensitization pain, inflammatory pain and neuropathic pain.
Specific aim 2: Using selective Cdk5 inhibitor and siRNA technique, we will determine whether cyclin dependent kinase 5 (Cdk5) signaling mediates PGE2-induced TRPV1 synthesis in in vitro and in vivo DRG neurons.
Specific aim 3: Using electrophysiological, pharmacological and behavioral approaches, we will determine whether PGE2-induced TRPV1 synthesis is coupled to enhanced TRPV1 activity in cultured DRG neurons, whether PGE2-induced TRPV1 up-regulation contributes to prolonged sensitization pain in wild type rats and whether PGE2-prolonged sensitization pain is abolished in TRPV1 knockout rats.
Significance: The anticipated outcome will advance our understanding of a novel mechanism governing development of chronic pain, i. e, facilitating TRPV1 synthesis in DRG neurons contributes to PGE2 potentiated TRPV1 activity and prolonged nociceptor sensitization.