Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model.

Brain-derived neurotrophic factor (BDNF) exists in small to medium size neurons in adult rat dorsal root ganglion (DRG) and serves as a modulator at the first synapse of the pain transmission pathway in the spinal dorsal horn. Peripheral nerve injury increases BDNF expression in DRG neurons, an event involved in the genesis of neuropathic pain. In the present study, we tested the hypothesis that prostaglandin E2 (PGE2) over-produced in injured nerves contributes to the up-regulation of BDNF in DRG neurons. Two weeks after partial sciatic nerve ligation (PSNL), BDNF levels in the ipsilateral L4-L6 DRG of injured rats were significantly increased compared to the contralateral side. Perineural injection of a selective cyclooxygenase (COX2) inhibitor or a PGE2 EP4 receptor antagonist not only dose-dependently relieved PSNL elicited mechanical hypersensitivity, but also suppressed the increased BDNF levels in DRG neurons. PSNL shifted BDNF expression in the ipsilateral DRG from small to medium and larger size injured neurons. BDNF is mainly co-expressed with the EP1 and EP4 while moderately with the EP2 and EP3 receptor subtypes in naïve and PSNL rats. PSNL also shifted the expression of EP1-4 receptors to a larger size population of DRG neurons. In DRG explant cultures, a stabilized PGE2 analog 16,16 dimethyl PGE2 (dmPGE2) or the agonists of EP1 and EP4 receptors significantly increased BDNF levels and the phosphorylated protein kinase A (PKA), extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) and cAMP response element binding protein (CREB). The EP1 and EP4 antagonists, a sequester of nerve growth factor (NGF), the inhibitors of PKA and MEK as well as CREB small interfering RNA suppressed dmPGE2-induced BDNF. Taken together, EP1 and EP4 receptor subtypes, PKA, ERK/MAPK and CREB signaling pathways as well as NGF are involved in PGE2-induced BDNF synthesis in DRG neurons. Injured nerve derived-PGE2 contributes to BDNF up-regulation in DRG neurons following nerve injury. Facilitating the synthesis of BDNF in primary sensory neurons is a novel mechanism underlying the role of PGE2 in the genesis of neuropathic pain.