p38 MAPK: A Potential Target of Chronic Pain

Lin, Xiaoxuan; Wang, M.; Zhang, J.; Xu, Rui‐hua

doi:10.2174/0929867321666140915143040

Cited by 72 publications

(43 citation statements)

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“…Although p38 inhibition is no longer under clinical investigation for RA, it has generated interest for a range of disorders involving dysregulated inflammation such as multiple sclerosis (62), chronic obstructive pulmonary disorder (COPD) (63), atherosclerosis (64, 65), diabetic cardiomyopathy (66), and neuropathic pain (67, 68). Our findings argue for careful analysis of the effects of p38 inhibitors on multiple potential compensatory pathways and on the background of multiple disease-relevant contexts to understand the full effects of drugs targeting p38 in inflammation-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

et al. 2018

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Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging, in part because of the complexities and interconnected nature of intracellular signaling networks, which complicate the effects of pharmacological interventions. Here, we characterized the signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. For example, p38 inhibitors, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NFκB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. CREB, a transcription factor that functions in part within a negative feedback loop in MAPK signaling, emerged as a key regulator of this context-dependence. CREB activation was induced predominately by p38 in response to inflammatory stimuli but by MEK in response to mitogenic stimuli; the effects of drugs targeting p38 or MEK were therefore markedly different in SFs cultured in mitogenic or inflammatory conditions. Together these findings illustrate how stimulatory context can alter pathway cross-talk even for a fixed network topology, suggest cross-talk by p38 in inflammatory contexts limited the benefit of p38 inhibitors in RA, and furthermore demonstrate the need for careful consideration of p38-targeted drugs in inflammation-related disorders.

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Section: Discussionmentioning

confidence: 99%

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

et al. 2018

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“…An increase in the levels of p-p38, the active form of p38, has been reported in inflammation and neuropathic pain [29–31]. Inflammatory pain could be treated by inhibition of the p38 MAPK signaling pathway [32,33]. SB203580, an inhibitor of p38 MAPK, can relieve mechanical allodynia and thermal hyperalgesia [34].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-16 Alleviates Inflammatory Pain by Targeting Ras-Related Protein 23 (RAB23) and Inhibiting p38 MAPK Activation

2016

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BackgroundThe purpose of our study was to determine the functional role of microRNA (miR)-16 in chronic inflammatory pain and to disclose its underlying molecular mechanism.Material/MethodsInflammatory pain was induced by injection of complete Freund’s adjuvant (CFA) to Wistar rats. The pWPXL-miR-16, PcDNA3.1- Ras-related protein (RAB23), and/or SB203580 were delivered intrathecally to the rats. Behavioral tests were detected at 0 h, 4 h, 1 d, 4 d, 7 d, and 14 d after CFA injection. After behavioral tests, L4–L6 dorsal spinal cord were obtained and the levels of miR-16, RAB23, and phosphorylation of p38 (p-p38) were evaluated by quantitative real-time PCR (qRT-PCR). In addition, luciferase reporter assay was performed to explore whether RAB23 was a target of miR-16, and qRT-PCR and Western blotting were used to confirm the regulation between RAB23 and miR-16.ResultsThe level of miR-16 was significantly decreased in the CFA-induced inflammatory pain. Intrathecal injection of miR-16 alleviates pain response and raised pain threshold. The level of RAB23 was significantly increased in the pain model, and intrathecal injection of RAB23 aggravated pain response. Luciferase reporter assay confirmed that RAB23 was a direct target of miR-16, and RAB23 was negatively regulated by miR-16. In addition, we found that simultaneous administration of SB203580 and miR-16 further alleviates pain response compared to only administration of miR-16.ConclusionsOur findings suggest that miR-16 relieves chronic inflammatory pain by targeting RAB23 and inhibiting p38 MAPK activation.

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“…Phosphorylation of p38 or extracellular signal-regulated kinase (ERK)-1/2, another MAPK, is necessary for the development and perpetuation of mechanical hypersensitivity, as observed in models of chronic neuropathic6 and acute-to-chronic postoperative pain 3,7,8. Although p38 inhibition has demonstrated some efficacy in neuropathic pain in humans,9,10 its role in this condition remains unclear 11…”

Section: Introductionmentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

Skopelja-Gardner

Saha

Alvarado-Vázquez

et al. 2017

JPR

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Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69±0.17 g baseline vs 0.13±0.08 g day 1), which resolved normally by postoperative day 12 (0.46±0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19±0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4±6 cells/0.1 mm2) than WT mice (8.7±1.2 cells/0.1 mm2) on postoperative day 1 (vs 5–6 cells/0.1 mm2 at baseline) that returned to baseline 12 days after surgery (10–12 cells/0.1 mm2). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5- and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7–12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2.

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p38 MAPK: A Potential Target of Chronic Pain

Cited by 72 publications

References 0 publications

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

MicroRNA-16 Alleviates Inflammatory Pain by Targeting Ras-Related Protein 23 (RAB23) and Inhibiting p38 MAPK Activation

Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

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