Artesunate Alleviates Paclitaxel-Induced Neuropathic Pain in Mice by Decreasing Metabotropic Glutamate Receptor 5 Activity and Neuroinflammation in Primary Sensory Neurons

Abstract

Experimental studies on the pathogenetic process of paclitaxel-induced neuropathic pain (PINP) have been initially carried out, but PINP still has no effective therapy. Recently reported studies have highlighted the involvement of glutamate receptors and neuroinflammation in peripheral and central nociceptive transmission in PINP. Artesunate is a first-line antimalarial drug with established efficacy in alleviating pain in a variety of pathologies. The current work assessed whether artesunate inhibits PINP by modulating metabotropic glutamate receptor 5 (mGluR5) and neuroinflammation in mice. The anti-hyperalgesic effect of artesunate was verified by assessing mechanical frequency and thermal latency in the paw withdrawal test as well as spontaneous pain. The expression levels of mGluR5, pain-related receptors and neuroinflammatory markers in dorsal root ganglion (DRG) were examined. In addition, treatment with CHPG and 2-methyl-6-(phenyl ethynyl) pyridine (MPEP) (mGluR5 agonist and antagonist, respectively) was performed to determine mGluR5’s role in the anti-hyperalgesic properties of artesunate. We demonstrated artesunate prevented PINP in a dose-dependent manner, while exerting a clear anti-hyperalgesic effect on already existing PINP. Artesunate normalized paclitaxel-related expression changes in DRG mGluR5, NR1, and GluA2, as well as six paclitaxel related neuroinflammation markers. Intrathecal application of MPEP treated PINP by reversing NR1 and GluA2 expression changes but had no effects on chemokines and inflammatory factors. Furthermore, artesunate treatment reversed acute pain following CHPG application. In conclusion, this study revealed that artesunate alleviates paclitaxel-induced hyperalgesia and spontaneous pain by decreasing DRG mGluR5 expression and neuroinflammation in the mouse model of PINP.

Peripheral mu-opioid receptor activation by dermorphin [D-Arg2, Lys4] (1–4) amide alleviates behavioral and neurobiological aberrations in rat model of chemotherapy-induced neuropathic pain

“…Spontaneous pain, which is not triggered by external stimuli, presents a considerable hurdle in the management of chemotherapy-induced neuropathic pain [ 33 ]. Patients suffering from spontaneous pain may experience a range of debilitating symptoms that significantly affect their quality of life.…”

Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application

“…These routes are most commonly used for pain management with analgesics [65]. However, beyond pain management, the intrathe-cal route is widely used for stem cell therapy [45,46,62,67,68], gene therapy [7,17,38,68], delivery of immune cells [63], sedation [41], protein therapy, insulin delivery [69], mineral delivery [70], chemical delivery [2,[70][71][72], and drug therapy using agonists [43,72,73], antagonists [43,64], antibiotics [70,74], and antiparasitic drugs [75] (Table 6). Intraspinal injection used in pain models can be divided into cancer pain models [68], including chemotherapy, induced pain models [5,75], and non-cancer pain models, such as models of arthritis [24], rheumatoid arthritis [72], diabetes-induced neuropathic pain [69,73], chronic pancreatitis-induced pain [19], spinal injury-induced pain [57,60], post-herpetic neuralgia [43], foraminal stenosis-induced pain [2,3], chronic DRG compression-induced pain [45], spared nerve injury [76], intrathecal capsaicin-induce...…”

Artesunate Mitigates Cognitive Deficits by Promoting Hippocampal Neural Stem/Progenitor Cells Proliferation and Neurogenesis in Cadmium-Exposed Mice

“…Recent study indicated that artesunate could promote osteoblast differentiation through miR-34a/DKK1/Wnt pathway [14]. Besides, artesunate alleviated paclitaxelinduced hyperalgesia and spontaneous pain by decreasing DRG mGluR5 expression and neuroin ammation in the mouse model of paclitaxel-induced neuropathic pain [15].Due to the permeability of BBB, artesunate is a promising candidate for therapy CNS disease more than the cerebral malaria. In CNS, artesunate reduced the severity of experimental autoimmune encephalomyelitis by inhibiting migration of pathogenic T cells to the CNS [16].…”