Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Abstract

p38 mitogen-activated protein kinase (MAPK) consists of two major isoforms: p38α and p38β; however, it remains unclear which isoform is more important for chronic pain development. Recently, we developed potent, long-lasting, and p38 MAPK subtype-specific antisense oligonucleotides (ASOs). We examined the therapeutic effects of isoform-specific ASOs in several chronic pain models following single intrathecal injection (300 µg/10 µl) in CD1 mice. In the chronic constriction injury (CCI) model, p38α MAPK ASO, given on post-operative day 5, reduced CCI-induced mechanical allodynia in male but not female mice. In contrast, mechanical allodynia after CCI in both sexes was not affected by p38β MAPK ASO. Intrathecal injection of p38α or p38β ASO resulted in a partial reduction (≈50%) of spinal p38α or p38β mRNA level, respectively, in both sexes at two weeks. In contrast, intrathecal injection of the ASOs did not affect p38α and p38β MAPK mRNA levels in dorsal root ganglia. Intrathecal p38α ASO also reduced postoperative pain (mechanical and cold allodynia) in male mice after tibia fracture. However, intrathecal p38α ASO had no effect on mechanical allodynia in male mice after paclitaxel treatment. Intrathecal p38α MAPK ASO pre-treatment also prevented TLR4-mediated mechanical allodynia and downregulated levels of p38α MAPK and phosphorylated p38 MAPK following intrathecal treatment of lipopolysaccharide. In summary, our findings suggest that p38α MAPK is the major p38 MAPK isoform in the spinal cord and regulates chronic pain in a sex and model-dependent manner. Intrathecal p38α MAPK ASO may offer a new treatment for some chronic pain conditions.

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

“…Neuropathic pain models that are associated with persistent LPA signaling and subsequent activation of MAPK cascades might be candidates for such an approach [42]. Indeed, a series of recent reports demonstrated that pharmacological intervention strategies that attenuate MAPK signaling pathways (either directly or indirectly) alleviate hyperalgesia in preclinical animal models of neuropathic pain [58][59][60][61]. In one of our earlier proteome studies, we have shown that LPA affects the abundance of a number of metabolic enzymes involved in glycolysis [20].…”

Sex-Dependent Mechanisms of Chronic Pain: A Focus on Microglia and P2X4R

“…In a separate study, a male-specific increase in phosphorylated p38-MAPK was also observed in microglia, and inhibition of p38-MAPK via intrathecal drug administration reduced PNI-and formalin-induced pain in male, but not female, rodents (Taves et al, 2016). It was later demonstrated that the key isoform driving pain in a sexdependent manner is p38 (Luo et al, 2018). Together, these data suggest that male microglia are uniquely prepared to mediate pain-inducing signaling.…”

Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice

“…Notably, microglia drive neuropathic pain and inflammatory pain in male animals (Rosen et al, 2017). Several microglial signaling molecules, including Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (MAPK), ATP receptor P2X4, and BDNF, exhibit sexually dimorphic functions in inflammatory and neuropathic pain (Sorge et al, 2011(Sorge et al, , 2015Taves et al, 2016;Luo et al, 2018;Mapplebeck et al, 2018;Inyang et al, 2019). Upstream activators of microglia, such as caspase-6, also display male-specific activity in the contexts of inflammatory and neuropathic pain (Berta et al, 2016;Chen et al, 2018).…”