Intracellular signaling in primary sensory neurons and persistent pain

Abstract

During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Adelta-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-alpha, IL-1beta), PGE(2), bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Na(v)1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source.

Figure 1. Induction of nociceptor sensitization

Peripheral tissue injury or nerve damage leads to the production of various inflammatory mediators, such as TNF-α, PGE₂, bradykinin, and NGF. These mediators are released and stimulate the corresponding receptors on terminals, axons, or cell body of nociceptors. Activation of different receptors results in the activation of multiple protein kinase pathways, leading to rapid posttranslational regulation of TRPV1 and TTX-R Na⁺ channels. Hyperactivity of TRPV1 and TTX-R Na⁺ channels induces nociceptor sensitization and hyperalgesia.

Figure 2. Maintenance of nociceptor sensitization by transcriptional/translational regulation

Inflammatory mediators produced after peripheral tissue injury or nerve damage (as shown in Fig. 1), as well as spontaneous electrical activity, induce the activation MAPK pathways (p38, ERK, JNK) in different subsets of nociceptive primary sensory neurons. Activation of these pathways results in transcriptional regulation via transcription factors CREB, ELK-1, Jun, and ATF and translational regulation via translation initiation factors. Consequently, there is increased synthesis of ion channels such as TRPV1, TRPA1, TTX-R Na⁺ channels, P2X3, and Ca²⁺ channel α2δ subunit and neuromodulators such as BDNF, substance P, CGRP, TNF-α, and IL-1β. Persistent synthesis of these pronociceptive proteins in primary sensory neurons maintains hypersensitivity of nociceptors and thus maintains persistent pain.