Inhibition of microRNA-155 Reduces Neuropathic Pain During Chemotherapeutic Bortezomib via Engagement of Neuroinflammation

Abstract

As a chemotherapeutic agent, bortezomib (BTZ) is used for the treatment of multiple myeloma with adverse effect of painful peripheral neuropathy. Our current study was to determine the inhibitory effects of blocking microRNA-155 (miR-155) signal on BTZ-induced neuropathic pain and the underlying mechanisms. We employed real time RT-PCR and western blot analysis to examine the miR-155 and expression of pro − inflammatory tumor necrosis factor-α receptor (TNFR1) in the dorsal horn of the spinal cord. Its downstream signals p38-MAPK and JNK and transient receptor potential ankyrin 1 (TRPA1) were also determined. Mechanical pain and cold sensitivity were assessed by behavioral test. In result, inhibition of miR-155 significantly attenuated mechanical allodynia and thermal hyperalgesia in BTZ rats, which was accompanied with decreasing expression of TNFR1, p38-MAPK, JNK, and TRPA1. In contrast, miRNA-155 mimics amplified TNFR1-TRPA1 pathway and augmented mechanical pain and cold sensitivity. In addition, mechanical and thermal hypersensitivity induced by miRNA-155 mimics were attenuated after blocking TNFR1, p38-MAPK, JNK, and TRPA1. Overall, we show the key role of miR-155 in modifying BTZ-induced neuropathic pain through TNFR1-TRPA1 pathway, suggesting that miR-155 is a potential target in preventing neuropathic pain development during intervention of BTZ.

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

“…Similarly, inhibition of TNFR1-TRPA1 pathway in the dorsal horn has recently been reported, including the critical involvement of the microRNA (miR-155) in painful BIPN ( 207 ). In particular, inhibiting miR-155 signal in BTZ-treated rats displayed significantly reduced mechanical and cold sensitivity associated with the decreased TNFR1 and TRPA1 expression as well as the reduction of signals p38-MAPK and JNK in DHSC.…”

“…In particular, inhibiting miR-155 signal in BTZ-treated rats displayed significantly reduced mechanical and cold sensitivity associated with the decreased TNFR1 and TRPA1 expression as well as the reduction of signals p38-MAPK and JNK in DHSC. Interestingly, administration of miR-155 mimic interfered with TNFR1-TRPA1 signal and contributed to enhanced cold hypersensitivity and allodynia ( 207 ). Therefore, interfering with this complex pathway may provide an effective treatment of neuropathic pain in BTZ-treated patients.…”

MicroRNA-155-5p promotes neuroinflammation and central sensitization via inhibiting SIRT1 in a nitroglycerin-induced chronic migraine mouse model

“…A large body of evidence suggests that changes in miRNA expression in the dorsal root ganglia (DRG) and spinal cord in a neuropathic pain model are related to hyperalgesia [ 17 ]. A few studies have confirmed that the downregulation of miR-155 reduces pain thresholds and proinflammatory cytokines in several pain models [ 18 , 19 ]. A clinical study showed multi-fold higher miR-155 levels in circulating blood in migraine patients than in healthy controls [ 20 ], suggesting that miR-155 might participate in the pathological mechanism of migraine.…”

microRNA-Based Network and Pathway Analysis for Neuropathic Pain in Rodent Models

“…Numerous circuits and molecules were identified as potential biomarkers and regulators in NP. The renowned mediators contain the transient receptor potential (TRP) channels (Lu et al, 2017;Miao et al, 2019;Duan et al, 2020;Zhang and Chen, 2021), voltage-gated sodium channels (Na V s) (Chen et al, 2014;Lin et al, 2014;Shao et al, 2016;Su et al, 2017;Cai et al, 2018;Yang et al, 2019;Yan et al, 2020b;Ye et al, 2020;Sun et al, 2021), and voltage-gated calcium channels (CaVs) (Favereaux et al, 2011;Gandla et al, 2017;Peng et al, 2017). In DRG and SDH, TRP channels act as transducers for Frontiers in Molecular Biosciences | www.frontiersin.org selectively activating sensory neurons and conveying diverse kinds of stimuli involving chemical, mechanical, and thermal stimuli.…”

“…SDH and DRGs were collected for measurement. miR-30b-5p and miR-141-5p (Zhang and Chen, 2021) were down-regulated in chemotherapeutic drug-induced NP; miR-500 (Huang et al, 2016), miR-15b (Ito et al, 2017) and miR-155 (Miao et al, 2019;Duan et al, 2020) were upregulated. NP induced by cancer pain and diabetes are shown in Supplementary Table S6.…”