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Protein Kinase C and the Chronification of Acute Pain

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Pathogenesis of Neuropathic Pain

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Abstract

This chapter examines the role of protein kinase in the neuroplastic changes that convert acute pain to chronic pain. For this reason, we do not only look at PKC alone, but also at its interaction with other important molecules in the process. We will attempt to understand chronification as mediated by protein kinase, discuss the proposed molecular mechanisms of chronification; and try to identify cause-specific prophylaxis against and treatments of this malady. The Protein kinase C (PKC) enzyme is known to play a critical role in several life functions. These functions include learning, memory, and the processing and maintenance of nociceptive messages in the CNS. The enzyme interacts with the G-protein coupled metabotropic receptor and phosphorylates serine and threonine residues on the intracellular C-termini of various receptor subunits. These termini are denoted numerically and vary from species-to-species but in general have been conserved throughout mammalian and non-mammalian evolution. The phosphorylation event impacts the trafficking of the receptor both into and out of the cell membrane at or near the region of the membrane known as the perisynaptic or postsynaptic density (PSD). This chapter will discuss the role of the phosphorylation event itself and the fate of the phosphorylation target element and the subsequent physiologic consequences.

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Author information

Authors and Affiliations

  1. Icahn School of Medicine at Mount Sinai, Department of Anesthesiology, Perioperative, and Pain Medicine, New York, NY, USA

    Benjamin Hyers

  2. University of Rochester School of Medicine and Dentistry, Medical Humanities, Department of Anesthesiology and Periopoerative Medicine, Rochester, NY, USA

    Donald S. Fleming

  3. University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, Rochester, NY, USA

    Daryl I. Smith

Authors
  1. Benjamin Hyers
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  2. Donald S. Fleming
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  3. Daryl I. Smith
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Corresponding author

Correspondence to Daryl I. Smith .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Rochester, Rochester, NY, USA

    Daryl I. Smith

  2. School of Medicine, University of Rochester, Rochester, NY, USA

    Hai Tran

Appendix

Appendix

Element

Comments/Characteristics

PKCγ

Visceral pain

IL-1β

IL-1beta reduces glial glutamate transporter activities through enhancing the endocytosis of both GLT-1 and GLAST glial glutamate transporters.

TRPV1

Sensitization

PKMζ

Critical role in generating/maintaining sensitivity produced by NGF

Critical for maintenance of hippocampal LTP

Only molecule implicated in perpetuating L-LTP maintenance.

Autonomously active, aPKC isoform; necessary/sufficient to maintain LTP and long-term memory

PKCε

Inhibition of PKCε reduced persistent inflammatory hypernociception,

Hyperalgesia and priming are PKCε and G(i) dependent; transition from acute to chronic pain, and development of mu-opioid receptor tolerance and dependence linked by common cellular mechanisms in the primary afferent

IGF and PKC

IGF-1 receptor activation after nerve injury enhances T-type channel current and DRG excitability; recruits a Gβγ-dependent PKCα pathway

Phorbol

Activates C1 domain proteins on PKC → Phosphorylation of Voltage Dependent Ca++Channels (VDCC)

NMDA-R

Possesses ion channel characteristic; activity is modulated by phosphorylation of NR1

DGKs

Converts DAG to Phosphatidic acid (deactivates); requires PSD-95 proteins for synaptic localization; regulates DAG signaling/ neurotransmitter release in LTD.

Bradykinin

Activates multiple kinases in dorsal horn → Potentiates Glutamatergic mediated hypersensitivity

BDNF

Binds specific TrkB receptors

Mediates PKMζ (and PKCλ)

Regulates PKMzeta, and aPKCs

Maintains centralized chronic pain state.

Critical role in initiating and maintaining persistent sensitization

Occurs via a ZIP-reversible process.

Controls synaptic PKMζ and PKCλ synthesis via mTORC1 and BDNF enhances PKMzeta phosphorylation

Sustains L-LTP through PKMzeta in a protein synthesis-independent manner

Promotes neuronal growth, development, synaptogenesis, differentiation, survival and neurogenesis following nerve injury

EAAT3

(Excitatory amino acid transporters)- Activity leads to re-uptake of AA neurotransmitters and” turn off” noxious impulse.

GABA-R

Activity inhibits nociception but increased PKC decreases GABA activity

Summary chart of potential PKC-mediating therapeutic elements

Inhibitors

Comments

Procyanidins

Suppress matrix metalloproteinase and reduce phosphorylation of PKCγ

Chelerythrine

Prevented protein kinase C activation in the hind paw after intraplantar injection of phorbol-myristate acetate

Attenuates remifentanil induced thermal and mechanical hyperalgesia

Quercetin (polyphenolic flavonoid)

Inhibits translocation of PKCepsilon from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats.

Inhibits excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, suppressed the high plasma histamine levels in paclitaxel-treated rats.

Raises thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice.

Suppresses increased expression of PKCε and TRPV1 in SC and DRG (paclitaxel-murine)

Melatonin

Inhibit PKCγ and NR1 activities in the spinal cord.

IL-10

Decreases the expression of IL-1β and inhibits PKC phosphorylation.

Myricetin(flavonoid)

Inhibited phosphorylation of p38 in the spinal cord induced by intrathecal cytokine administration

AP5 (2-amino-5-phosphopentanoic-acid)

AP5 reduces the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation. Blocks GluN2A-containing NMDARs (murine)

DGKζ

Terminates DAG signaling by converting DAG to Phosphatidic acid

ZIP

Microinjection into ACC attenuates upregulation of glutamate transmission and painful behaviors in STZ-injected rats.

BDNF inhibitor

Inhibition of PKMzeta reversed BDNF-dependent form of L-LTP

Pregabalin/gabapentin

Gabapentin decreased EAAT3 activity in a concentration-dependent manner. Inhibitory effect on the PKC-ERK1/2 signaling pathway

Bisindolylmaleimide

PKC inhibitor. Attenuates status epilepticus-induced reactive astrogliosis.

GF109203X

General protein kinase C (PKC) inhibitor. Possibly used to prevent the conversion from acute to chronic pain

Stuarosporine

General protein kinase C (PKC) inhibitor. Possibly used to prevent the conversion from acute to chronic pain

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Hyers, B., Fleming, D.S., Smith, D.I. (2022). Protein Kinase C and the Chronification of Acute Pain. In: Smith, D.I., Tran, H. (eds) Pathogenesis of Neuropathic Pain. Springer, Cham. https://doi.org/10.1007/978-3-030-91455-4_2

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  • DOI: https://doi.org/10.1007/978-3-030-91455-4_2

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