MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

Abstract

Cancer induced bone pain (CIBP) remains one of the most intractable clinical problems due to poor understanding of its underlying mechanisms. Recent studies demonstrate the decline of inhibitory interneurons, especially GABAergic interneurons in the spinal cord, can evoke generation of chronic pain. It has also been reported that neuronal MHC-I expression renders neurons vulnerable to cytotoxic CD8 T cells and finally lead to neurons apoptosis in a variety neurological disorders. However, whether MHC-I could induce the apoptosis of GABAergic interneurons in spinal cord and contribute to the development of CIBP remains unknown. In this study, we investigated roles of MHC-I and underlying mechanisms in CIBP on a rat model. Our results showed that increased MHC-I expression on GABAergic interneurons could deplete GABAergic interneurons by inducing their apoptosis in the spinal dorsal horn of tumor-bearing rats. Pretreatment of MHC-I RNAi-lentivirus could prevent the apoptosis of GABAergic interneurons and therefore alleviated mechanical allodynia induced by tumor cells intratibial injection. Additionally, we also found that CD8 T cells were colocalized with MHC-I and GABAergic neurons and presented a significant and persistent increase in the spinal cord of tumor-bearing rats. Taken together, these findings indicated that MHC-I could evoke CIBP by promoting apoptosis of GABAergic interneurons in the dorsal horn, and this apoptosis was closely related to local CD8 T cells.

PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

“…Bone cancer pain (BCP) is one of the most severe type of chronic pain [28][29][30]. It was reported that up to 85% of patients with advanced prostate, breast, and lung cancer had bone metastasis [31][32][33]. Moreover, one-third of these patients experienced unbearable pain, which severely affected their quality of life.…”

Altered expression of target genes of spinal cord in different itch models compared with capsaicin assessed by RT-qPCR validation

“…2 μg of total RNA was extracted from mouse spinal cords (C1-C4, C5-C8 or lumbar segment) using TRIzol reagent (Invitrogen, USA) according to the manufacturer’s protocol and quantified using a spectrophotometer (BioPhotometer, Eppendorf, Hamburg, Germany)[ 27 , 46 – 49 ]. The threshold cycle (CT) was used to estimate the amount of target mRNA.…”

Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain

“…Among advanced cancer patients 75% suffer from severe pain owing to bone metastasis, which significantly affects their quality of life (Costantini et al, 2009;Zhou et al, 2015;Fu et al, 2016). Currently, the role of CaMKII in bone cancer pain (BCP) remains largely unknown.…”