A JNK-Regulated and IL-1β-Dependent Astrocyte-Neuron Signaling Pathway in the Spinal Dorsal Horn is Essential for Stress-Induced Hyperalgesia.

Abstract

Various forms of mild stress may exacerbate pain in patients with chronic pain disorders, though the underlying mechanism remains unclear. Astrocyte activation in the spinal dorsal horn plays a predominant role in stress and pain. The present study investigated the neuron-astrocyte interactions in the spinal dorsal horn in post-traumatic stress disorder (PTSD)-induced hyperalgesia using a single-prolonged stress (SPS) model, a Complete Freund's Adjuvant (CFA) model and an SPS + CFA model. Animals were tested for mechanical withdrawal threshold (MWT) of the paw after SPS, CFA and SPS + CFA. SPS + CFA group induced significantly increased mechanical allodynia compared with the SPS or CFA group. We tested the hypothesis that IL-1β contributes to signaling between astrocytes and neurons in stress-induced hyperalgesia (SIH). Immunohistochemical data showed that there was an upregulation of glial fibrillary acidic proteins (GFAPs, a marker of astrocyte) and Fos (a marker of neuron) in SIH. Immunohistochemical data showed specific localization of IL-1β to astrocyte, but not to microglia and neurons and a neuronal localization of the IL-1β receptor (IL-1RI) with NMDAR2B (NR2B). Enzyme immunoassay analysis showed that IL-1β release was dependent on c-Jun N-terminal kinase (JNK) activation in astrocyte. The JNK inhibitor SP600125 suppressed IL-1β release. SP600125 and IL-1RI blockade with IL-1ra resulted in a restoration of behavioral nociceptive thresholds. Our results showed that the IL-1β-dependent, JNK-regulated astrocyte-neuron signaling pathway mediated the astroglia component of pain maintenance in SIH.