BDNF Regulates Atypical PKC at Spinal Synapses to Initiate and Maintain a Centralized Chronic Pain State

Abstract

BackgroundChronic 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, PKMζ, but the mechanisms involved in controlling PKMζ in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMζ, and possibly other aPKCs, to maintain a centralized chronic pain state.ResultsWe 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 PKMζ and PKCλ nascent synthesis via mTORC1 and BDNF enhances PKMζ phosphorylaton. Finally, we show that BDNF signaling to PKMζ and PKCλ is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms.ConclusionsHence, 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.

Atypical PKCs in memory maintenance: the roles of feedback and redundancy

“…Once the fraction of synapses potentiated as a result of L-LTP is determined, it would be possible to tune our model parameters to account for the actual U and D values as well. However, unlike previous models of a molecular switch that depend on post-translational modifications (Lisman 1985;Lisman and Zhabotinsky 2001;Miller et al 2005), here the total kinase concentration (K T ) is different in the U and D states, which is qualitatively consistent with experimental findings for aPKCs (Osten et al 1996;Kelly et al 2007;Melemedjian et al 2013).…”

“…1B) for 15 min. Significant evidence shows that the induction of L-LTP requires translation of new protein locally at dendrites (Bradshaw et al 2003;Tsokas et al 2005;Sutton and Schuman 2006;Costa-Mattioli et al 2009), and experimental protocols use time frames approximately consistent with that assumed in the model (Ling et al 2002;Melemedjian et al 2013). After induction of L-LTP, the total concentration of aPKCs increase, and the concentration of PKMz remains at this elevated level (Osten et al 1996;Kelly et al 2007).…”

“…Experiments have quantified increases, relative to the base levels, in aPKCs resulting from L-LTP (Kelly et al 2007;Melemedjian et al 2013); for our model to quantitatively match these results, we must take into account that only some synapses get potentiated after L-LTP. The empirical results are for hippocampal CA1 homogenates, which include both synapses that have and have not been potentiated, as well as nonsynaptic compartments.…”

“…The amount of aPKC increases after inducing L-LTP. Biochemical measurements indicate that aPKCs increase by nearly 75% in the hippocampal CA1 tissue homogenate after L-LTP induction (Kelly et al 2007) and in synaptoneurosomes after chemically induced L-LTP (Melemedjian et al 2013). 2.…”

“…PKMz is autonomously active, lacking the regulatory subunit that inhibits the activity of most other PKC isoforms. Electrophysiological and chemical protocols that induce L-LTP cause an increase in the concentration of two atypical PKCs (aPKCs): PKMz and PKCi/l (Kelly et al 2007;Melemedjian et al 2013). Furthermore, z inhibitory peptide (ZIP), a synthesized compound containing the auto-inhibitory sequence of the regulatory subunit of PKCz and PKCi/l, erases memory when injected in targeted areas such as hippocampus (spatial memory), insular cortex (taste memory), nucleus accumbens (addiction), and amygdala (fear memory) (Pastalkova 2006;Shema et al 2007;Serrano et al 2008;Li et al 2011;Shabashov et al 2011;Crespo et al 2012;Kwapis et al 2012).…”