IL-1 Mediates Chronic Stress-Induced Hyperalgesia Accompanied by Microglia and Astroglia Morphological Changes in Pain-Related Brain Regions in Mice

Abstract

Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its role in a chronic restraint stress (CRS) mouse model. Female and male C57Bl/6J wild-type (WT) and IL-1αβ-deficient (knock-out: IL-1 KO) mice were exposed to 6 h of immobilization/day for 4 weeks. Mechanonociception, cold tolerance, behavioral alterations, relative thymus/adrenal gland weights, microglia ionized calcium-binding adaptor molecule 1 (IBA1) and astrocyte glial fibrillary acidic protein (GFAP) integrated density, number and morphological transformation in pain-related brain regions were determined. CRS induced 15–20% mechanical hyperalgesia after 2 weeks in WT mice in both sexes, which was significantly reduced in female but not in male IL-1 KOs. Increased IBA1+ integrated density in the central nucleus of amygdala, primary somatosensory cortex hind limb representation part, hippocampus cornu ammonis area 3 (CA3) and periaqueductal gray matter (PAG) was present, accompanied by a cell number increase in IBA1+ microglia in stressed female WTs but not in IL-1 KOs. CRS induced morphological changes of GFAP+ astrocytes in WT but not in KO mice. Stress evoked cold hypersensitivity in the stressed animals. Anxiety and depression-like behaviors, thymus and adrenal gland weight changes were detectable in all groups after 2 but not 4 weeks of CRS due to adaptation. Thus, IL-1 mediates chronic stress-induced hyperalgesia in female mice, without other major behavioral alterations, suggesting the analgesic potentials of IL-1 in blocking drugs in stress-related pain syndromes.

Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0

“…Further evidence was provided for the role of neuro-immune interactions and the inflammatory cytokine IL-1 in chronic stress-induced nocifensive behaviors and neuroinflammation in female mice. These results indicated the analgesic potentials of IL-1-blocking drugs in stress-related pain syndromes, such as fibromyalgia, which mainly affects women [8]. Dendritic cell activation was shown to be crucial in both the development and resolution of neuroinflammation via different cell types of the immune system (T and B lymphocytes, macrophages, mast cells) and the resident immune cells of the central nervous system.…”

Interactions and Trends of Interleukins, PAI-1, CRP, and TNF-α in Inflammatory Responses during the Perioperative Period of Joint Arthroplasty: Implications for Pain Management—A Narrative Review

“…Similarly, dorsal horn neurons in the spinal cord express receptors for these immune mediators, including pro-inflammatory cytokines such as IL-1β [47][48][49][50][51], TNF-α [52][53][54][55][56][57][58], IL-6 [59,60], and IL-17. The activation of these cytokine receptors on neurons influences neuronal function.…”