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Review
. 2015:131:409-34.
doi: 10.1016/bs.pmbts.2014.11.010. Epub 2015 Jan 30.

Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain

Theodore J Price  1 , Kufreobong E Inyang  2
Affiliations
Review

Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain

Theodore J Price et al. Prog Mol Biol Transl Sci. 2015.

Abstract

Pain sensing neurons in the periphery (called nociceptors) and the central neurons that receive their projections show remarkable plasticity following injury. This plasticity results in amplification of pain signaling that is now understood to be crucial for the recovery and survival of organisms following injury. These same plasticity mechanisms may drive a transition to a nonadaptive chronic pain state if they fail to resolve following the termination of the healing process. Remarkable advances have been achieved in the past two decades in understanding the molecular mechanisms that underlie pain plasticity following injury. The mechanisms bear a striking resemblance to molecular mechanisms involved in learning and memory processes in other brain regions, including the hippocampus and cerebral cortex. Here those mechanisms, their commonalities and subtle differences, will be highlighted and their role in causing chronic pain will be discussed. Arising from these data is the striking argument that chronic pain is a disease of the nervous system, which distinguishes this phenomena from acute pain that is frequently a symptom alerting the organism to injury. This argument has important implications for the development of disease modifying therapeutics.

Keywords: AMPK; Atypical PKC; Axonal mRNA; BDNF; CREB; ERK; Hyperalgesic priming; IL-6; LTP; NGF; Opioid; PKMzeta; Reconsolidation; eIF4E; mTOR; trkB.

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Figures

Figure 1
Figure 1. Use of Microfluidic Devices to elucidate properties of distally localized mRNAs
The left panel shows a schematic of a microfluidic device while the middle panel shows an immunocytochemical image of DRG neurons in culture labeled with βIII-tubulin staining. DRG somas are found on the bottom side of the chamber and extend axons through the microfluidic barrier where they then elaborate extensive axonal arobrations on the axonal side. Properties of distally (e.g. axonal) localized mRNAs vs. those found restricted to cell bodies are listed on the right.
Figure 2
Figure 2. Translational control pathways involved in hyperalgesic priming
mTORC1 phosphorylates 4EBPs, negative regulators of eIF4F formation. This results in its dissociation from eIF4E, allowing the binding of eIF4E to eIF4G. Phosphorylation of eIF4E (via ERK/MNK1/2) or eIF4G (via mTORC1) enhances the formation of the eIF4F complex, promoting translation. Phosphorylation of CPEB by CamKIIα enhances translation efficiency by increasing the length of the poly A tail in mRNAs containing a CPE sequence. Taken together, eIF4F complex formation enhances cap-dependent translation, which is necessary for the induction of priming via translational control of gene expression in sensory afferents.
Figure 3
Figure 3. AMPK activation pathway
AMPK activation phosphorylates TSCs at Ser 1227 and 1345 leading to the inhibition of mTORC1. This is shown in the figure as an uncoupling of mTORC1 from Trk signaling via phosphorylation of TSC1/2 by AMPK. AMPK activation also phosphorylates Braf (Raf) at Ser 729 leading to inhibition of ERK signaling. Again, this is shown in the figure by an uncoupling of Raf/Mek signaling to ERK, MNK and eIF4E via phosphorylation of Raf at Ser 729. Finally, AMPK phosphorylates IRS1 at Ser 789 leading to further inhibition of tyrosine kinase receptor signaling.
Figure 4
Figure 4. The role of aPKCs and BDNF in hyperalgesic priming initiation and maintenance
Nociceptor activation leads to spinal BDNF release and a postsynaptic mTORC1-dependent translation of aPKC protein. These newly synthesized aPKCs are then phosphorylated by PDK1. Increased levels and phosphorylation of aPKCs are thought to be involved in initiating priming. Once priming is established (right panel), increased aPKC protein and phosphorylation leads to a constitutive increase in AMPAR trafficking to the postsynaptic membrane. This appears to be regulated by BDNF signaling via trkB with BDNF potentially being released from postsynaptic dendrites in the maintenance stage of priming. Presynaptic trkB may also be activated by increased BDNF action in primed animals. Once established, hyperalgesic priming can be permanently reversed by inhibition of aPKCs with ZIP, disruption of AMPAR trafficking with pep2M or via inhibition of trkB/BDNF signaling with ANA-12 or trkB-Fc, respectively.
Figure 5
Figure 5. Consolidation of late phase LTP (late-LTP) and reconsolidation
A) Following high frequency stimulation of afferent input (3 upward arrows), early-LTP (e-LTP in the figure) is induced and this consolidates to late-LTP (l-LTP in the figure) over the course of 30 – 60 minutes. Application of translation control inhibitors, such as anisomycin (red line), during early-LTP cause a failure of late-LTP consolidation. Likewise, aPKC inhibition with ZIP (green line) blocks consolidation of late-LTP. Vehicle application (blue line) has no impact on consolidation of late-LTP B) Once late-LTP is established administering translation inhibitors (e.g. anisomycin, red line) in the absence of high frequency stimulation of afferents fails to reverse late-LTP while ZIP application (green line) does induce late-LTP decay. Restimulation of afferents at high frequency during late-LTP (upward arrows) opens a reconsolidation window. Application of translation inhibitors such as anisomycin (red line) during this reconsolidation period leads to late-LTP decay, an effect that is presumably linked to reversal of a chronic pain state in similar behavioral pharmacology experiments.
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