Transcriptional and posttranslational plasticity and the generation of inflammatory pain - PubMed (original) (raw)

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Transcriptional and posttranslational plasticity and the generation of inflammatory pain

C J Woolf et al. Proc Natl Acad Sci U S A. 1999.

Abstract

Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain reflects direct activation of specific receptors on nociceptor terminals by inflammatory mediators. Pain hypersensitivity is the consequence of early posttranslational changes, both in the peripheral terminals of the nociceptor and in dorsal horn neurons, as well as later transcription-dependent changes in effector genes, again in primary sensory and dorsal horn neurons. This inflammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathways phosphorylate membrane proteins, changing their function, and activate transcription factors, altering gene expression. Two distinct aspects of sensory neuron function are changed as a result of these processes, basal sensitivity, or the capacity of peripheral stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of certain inputs to generate prolonged alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes both potentiate the system and alter neuronal phenotype. Potentiation occurs as a result of the up-regulation in the dorsal root ganglion of centrally acting neuromodulators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those that induce stimulus-induced hypersensitivity. Alterations in phenotype includes the acquisition by A fibers of neurochemical features typical of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity, something only C fiber inputs normally can do. Elucidation of the molecular mechanisms responsible provides new opportunities for therapeutic approaches to managing inflammatory pain.

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Figures

Figure 1

Figure 1

State-dependent sensory processing in the somatosensory system. (A) The basal sensitivity of the system is normally such that only a high-intensity C or Aδ stimulus produces pain. (B) C fiber inputs induce immediate posttranslational changes in the dorsal horn, resulting in central sensitization and altering basal sensitivity such that low intensity stimuli result in pain. (C) Conditioning C fiber strength inputs induce activity-dependent transcriptional changes in the DRG and dorsal horn, resulting in a potentiated system augmenting responsiveness to subsequent C fiber inputs. (D) Inflammation results in both a potentiated system and phenotypic switches such that both C fiber and low-intensity Aβ fiber inputs can evoke central sensitization.

Figure 2

Figure 2

Posttranslational changes within dorsal horn neurons after release of transmitters from C fiber central terminals. These transmitters/neuromodulators act on receptors and ion channels in the dorsal horn to activate protein kinases that phosphorylate membrane-bound NMDA and AMPA receptors and alter their functional properties, increasing membrane excitability and thereby eliciting central sensitization.

Figure 3

Figure 3

Putative DRG activity- and signal molecule-dependent second-messenger cascades leading to transcription. Activity-dependent calcium flux through voltage-gated calcium channels may increase BDNF transcription via CREB phosphorylation on Ser-133. NGF acts via TrkA to activate the MAP kinase cascade through ras. Myc phosphorylation through this pathway can result in E box transactivation via its association with P Max. The preprotachykinin promoter contains multiple E box units and thus maybe regulated by these transcription factors. RSK2 links the MAP kinase cascade to CREB phosphorylation. ATP can stimulate the MAP kinase cascade via Pyk2.

Figure 4

Figure 4

Posttranslational changes in transduction mechanisms/ion channels at nociceptor peripheral terminals induced by inflammatory mediators increases sensitivity and reduces threshold (peripheral sensitization), which occurs as a result of changes in the transducer proteins themselves (e.g., VR1) and as a result of a PKC- and PKA-mediated phosphorylation of TTXr sodium channels. Both activity and retrograde transport of signal molecules can also induce transcriptional changes in the DRG, which increase transducer molecules (VR1), ion channels (SNS/SNS2), and synaptic neuromodulators (BDNF/substance P) both altering phenotype and potentiating the system.

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References

    1. Bessou P, Perl E R. J Neurophysiol. 1969;32:1025–1043. - PubMed
    1. Woolf C J. Nature (London) 1983;306:686–688. - PubMed
    1. Neumann S, Doubell T P, Leslie T A, Woolf C J. Nature (London) 1996;384:360–364. - PubMed
    1. Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D, Julius D. Nature (London) 1997;389:816–824. - PubMed
    1. Tominaga M, Caterina M J, Malmberg A B, Rosen T A, Gilbert H, Skinner K, Raumann B E, Basbaum A I, Julius D. Neuron. 1998;21:531–543. - PubMed

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