BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state

Background: Chronic pain is an important medical problem affecting hundreds of millions of people worldwide. Mechanisms underlying the maintenance of chronic pain states are poorly understood but the elucidation of such mechanisms have the potential to reveal novel therapeutics capable of reversing a chronic pain state. We have recently shown that the maintenance of a chronic pain state is dependent on an atypical PKC, PKM zeta, but the mechanisms involved in controlling PKM zeta in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKM zeta, and possibly other aPKCs, to maintain a centralized chronic pain state. Results: We first demonstrate that although other kinases play a role in the initiation of persistent nociceptive sensitization, they are not involved in the maintenance of this chronic pain state indicating that a ZIP-reversible process is responsible for the maintenance of persistent sensitization. We further show that BDNF plays a critical role in initiating and maintaining persistent nociceptive sensitization and that this occurs via a ZIP-reversible process. Moreover, at spinal synapses, BDNF controls PKM zeta and PKC lambda nascent synthesis via mTORC1 and BDNF enhances PKM zeta phosphorylaton. Finally, we show that BDNF signaling to PKM zeta and PKC lambda is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms. Conclusions: Hence, BDNF is a key regulator of aPKC synthesis and phosphorylation and an essential mediator of the maintenance of a centralized chronic pain state. These findings point to BDNF regulation of aPKC as a potential therapeutic target for the permanent reversal of a chronic pain state.