<p>Activation of hippocampal microglia in a murine model of cancer-induced pain</p>

Abstract

IntroductionPain is a common and debilitating comorbidity of metastatic breast cancer. The hippocampus has been implicated in nociceptive processing, particularly relating to the subjective aspect of pain. Here, a syngeneic mouse model was used to characterize the effects of peripheral tumors on hippocampal microglial activation in relation to cancer-induced pain (CIP).Materials and methodsMice were systemically treated with the colony-stimulating factor 1 receptor inhibitor Pexidartinib prior to intrafemoral (IF) or subcutaneous 4T1 carcinoma cell inoculation. Spontaneous and evoked nociceptive responses were quantitated throughout tumor development, and contralateral hippocampi were collected via endpoint microdissection for RNA analysis. Additionally, IF tumor-bearing animals were sacrificed on days 5, 10, 15, and 20 post 4T1 cell inoculation, and brain sections were immunofluorescently stained for Iba1, a marker of activated microglia.ResultsAblation of these neuroimmune cells with the CSF1R inhibitor Pexidartinib delayed the onset and severity of cancer-induced nociceptive behaviors in IF tumor-bearing animals, adding to the body of literature that demonstrates microglial contribution to the development and maintenance of CIP. Furthermore, in untreated IF tumor-bearing mice, nociceptive behaviors appeared to progress in parallel with microglial activation in hippocampal regions. Immunofluorescent Iba1+ microglia increased in the dentate gyrus and cornu ammonis 1 hippocampal regions in IF tumor-bearing animals over time, which was confirmed at the mRNA level using relevant microglial markers.ConclusionThis is the first experimental evidence to demonstrate the effects of peripheral tumor-induced nociception on hippocampal microglial activation. The increase in hippocampal microglia observed in the present study may reflect the emotional and cognitive deficits reported by patients with CIP.

PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus

“…The hippocampus is one of the key brain regions in pain signals modulating [15], particularly with respect to the affective aspect of pain perception [16,17] and abnormal emotional processes, including anxiety and depression [18]. Accumulating studies have suggested that chronic pain arising from peripheral nerve injury induces alterations in different areas of the brain including impaired hippocampal mossy fiber-CA3 synaptic plasticity and DG neurogenesis [19][20][21].…”

Cerebral Glutamate Alterations Using Chemical Exchange Saturation Transfer Imaging in a Rat Model of Lipopolysaccharide-Induced Sepsis

“…The pathological features of the hippocampal tissues were observed using an automated quantitative pathology imaging system (Leica, Wetzlar, Germany). H&E staining was performed as previously described [ 27 , 28 ].…”

“…Immunofluorescence staining was performed as previously described [ 27 , 29 , 30 ]. The sectioned tissues were deparaffinized in a dry oven at 60 °C and then rehydrated.…”

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

“…CPP, open field activity, flinching, guarding, weight bearing, gait analysis, vocalizations, burrowing (King et al, 2007;King et al, 2008;Ungard et al, 2014;Slosky et al, 2016;Gdowski et al, 2017;Remeniuk et al, 2018;Zhang et al, 2018;Buehlmann et al, 2019;Miladinovic et al, 2019;Sliepen et al,…”