Activation of JNK pathway in persistent pain

Abstract

The c-Jun N-terminal kinase (JNK) is a stress-activated member of MAP kinase family. JNK activation has been strongly implicated in inflammatory responses, neurodegeneration, and apoptosis. Recent evidence shows that JNK pathway is also transiently activated in primary sensory neurons after tissue or nerve injury, which is required for the development of hyperalgesia and allodynia. In particular, JNK is persistently activated in astrocytes of the spinal cord after nerve injury, and this activation can maintain central sensitization and mechanical allodynia. In this mini-review, we will provide evidence for the involvement of JNK pathway in regulating persistent pain sensitization. We will also discuss possible upstream signaling mechanisms that cause JNK activation and downstream signaling mechanisms by which JNK modulates pain sensitivity. Thus, targeting JNK pathway might be a useful strategy to treat both neurodegeneration and chronic pain.

Figure 1. Prevention of capsaicin-induced heat hyperalgesia by JNK inhibition

Hindpaw injection (intraplantar) of the JNK inhibitor SP600125 (5 μg in 20 μl) inhibits capsaicin-induced heat hyperalgesia. Capsaicin (15 μg in 5 μl) was injected into the same site of hindpaw 20 min after SP600125 injection. The heat hyperalgesia was measured using Hargreaves apparatus (radiant heat) and paw withdrawal latencies from 15 to 180 minutes after capsaicin stimulation were determined. *, P<0.05, compared to corresponding vehicle control (10% DMSO), n=6, t-test. The baseline paw withdrawal latency is adjusted to 12–15 seconds.

Figure 2. Signal transduction of the JNK pathway

JNK family consists of 3 genes: jnk1, jnk2, and jnk3. While JNK1 is the dominant form in the spinal cord (especially in astrocytes), other forms may exist in the DRG. The JNK pathway can be activated by the exposure of cells to a diversity of extracellular stimuli, such as stress (UV irradiation, heat shock), inflammatory cytokines (TNF-α, IL-1β), growth factors (bFGF, TGF), as well as by the activation of Toll-like receptors. The activated receptors are communicated to upstream kinases of the JNK/MAPK cascade, such as Cdc42, Rac1, PAK-1, p21Rho-GTPase. This MAPK cascade includes various members of the MAP3Ks (such as MLKs, ASK1, TAK1, MEKK1, and MEKK4) and the MAP2Ks MKK4 and MKK7 and leads to the activation of JNK. The activated JNKs translocate to the nucleus and phosphorylate a range of substrates, such as the transcription factors c-Jun, Elk-1, p53, ATF-2, c-Myc, and the NFAT family, leading to gene transcription. The protein products of these genes (e.g., TNF-α, IL-1β, COX1/2) will enhance pain sensitivity. In addition to transcriptional regulation, non-transcriptional regulation can also mediate JNK’s action on pain.