Osthole alleviates neuropathic pain in mice by inhibiting the P2Y1-receptor-dependent JNK signaling pathway

Abstract

There are many reports about natural products relieving neuralgia. Osthole is the main component of Angelica biserrata Yuan et Shan, a natural product that treats rheumatism through the elimination of inflammation and the alleviation of pain that has a long history in the clinic. The analgesic mechanism of osthole is complicated and confusing. Astrocytes have attracted increasing attention from pain researchers. Inhibitors targeting astrocytes are thought to be promising treatments for neuropathic pain. Whether osthole can alleviate neuropathic pain through astrocytes has not been elucidated in detail. In this study, CCI surgery was used to establish the neuropathic pain model in mice. The CCI mice were treated with osthole (5, 10, or 20 mg/kg/day) for 14 days in vivo. Mechanical allodynia and heat hyperalgesia were measured to evaluate the therapeutic effect of osthole. In mechanism research, the activation of astrocytes; the protein expression of P2Y1R and p-JNK in astrocytes; the release of inflammatory factors; the variations in mEPSPs and eEPSPs; and the levels of GluA1, GluN2B, pERK , p-CREB and c-Fos in neurons were observed. The P2Y1R inhibitor MRS2179 and the p-JNK inhibitor SP600125 were used to demonstrate how osthole works in neuropathic pain. In addition, astrocytes and neurons were used to estimate the direct effect of osthole on astrocyte-neuron interactions and signal transmission in vitro. Our findings suggest that osthole treatment obviously relieved mechanical allodynia and heat hyperalgesia in CCI mice. P2Y1R is involved in CCI-induced pain hypersensitivity, and P2Y1R is required for osthole-induced p-JNK downregulation in the spinal cord. Osthole inhibited astrocyte activation and reduced inflammatory factor expression. After osthole treatment, mEPSP frequency and eEPSP amplitude were decreased in spinal lamina I-II neurons. Downstream signaling molecules such as pGluA1, pGluN2B, pERK , p-CREB and c-Fos were also reduced very quickly in osthole-treated neuralgic mice. Our conclusion is that osthole alleviates neuropathic pain in mice via the P2Y1-receptor-dependent JNK signaling pathway in spinal astrocytes, and osthole could be considered a potential pharmacotherapy to alleviate neuropathic pain.

lncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis

“…Reactive astrocyte-mediated neuroinflammation in the spinal dorsal horn contributes to NP [ 30 ]. Several studies have confirmed that inactivating astrocytes alleviates NP [ 31 , 32 ]. LPS has been widely applied to activate glia in vitro [ 33 ].…”

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions

“…Up to now, none of the medications are effective in neuropathic pain and have been failed in terms of effectiveness and safety [ 13 , 14 ]. In this context, natural products that present fewer side effects emerge as interesting therapeutic resources for the development of new drugs for the management of chronic pain [ 15 , 16 , 17 ]. Therefore, the development and utilization of more effective analgesic agents of natural origin that suppressed neuropathic pain remain desired.…”

RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling

“…Having determined that RIP3 and JNK were involved in pain-related behavioral changes and inflammatory responses in CCI rats, we next applied qRT-PCR and Western blotting to evaluate the expression of RIP3 and JNK in the lumbar spinal cord 1 day before and 3, 7 or 14 days after CCI. Since c-Fos expression has been reported to increase during NP [ 34 ]., we employed c-Fos as a marker of NP. On days 3, 7 and 14 after surgery, RIP3 and JNK mRNA levels in the spinal cord were greater in the CCI+NaCl group than in the control group ( P < 0.05; Figure 3C ).…”

“…SP600125 treatment after CCI surgery reduced JNK expression but had little effect on RIP3 expression. The expression of c-Fos (a marker of NP [ 34 ]) was also upregulated in the spinal cord after CCI, similar to RIP3; however, c-Fos was downregulated after both GSK’872 and SP600125 treatment. Immunofluorescence experiments revealed the same RIP3 expression patterns as the Western blotting and qRT-PCR assays in the lumbar spinal cord.…”