Celecoxib alleviates oxaliplatin-induced hyperalgesia through inhibition of spinal ERK1/2 signaling

Abstract

Numerous pieces of evidence have revealed that oxaliplatin (OXA) evokes mechanical and cold hypersensitivity. However, the mechanism underlying these bothersome side effects needs to be further investigated. It is well known that cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinases (ERK1/2) signaling play crucial roles in several pain states. Our previous data showed that Akt2 in the dorsal root ganglion (DRG) participated in the regulation of OXA-induced neuropathic pain. But it is still unclear whether spinal ERK1/2 signaling is involved in the regulation of OXA-induced hyperalgesia, and the linkage between COX-2 and ERK1/2 signaling in mediating OXA-induced hyperalgesia also remains unclear. In this research, we investigated the possible mechanism of celecoxib, a COX-2 inhibitor, in OXA-induced neuropathic pain. Our results show that single dose of OXA (12 mg/kg) significantly attenuated both the tail withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) at days 4 after the OXA treatment. Administration of celecoxib (30 mg/kg/day) for 4 and 6 days inhibited the decrease in TWL and MWT, and each was significantly higher than that of the OXA+vehicle group and was equivalent to that of the vehicles group. OXA increased the expression of cyclooxygenase-2 (COX-2) mRNA and phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2) protein in the lumbar 4-5 (L4-5) spinal cord dorsal horn neurons. Administration of celecoxib for 7 days suppressed the increase in expression of COX-2 and pERK1/2 induced by OXA. Our findings suggested that COX-2 and ERK1/2 signaling in spinal cord contributed to the OXA-induced neuropathic pain.

DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain

“…In line with our previous findings 22 , we demonstrated that CXCR1/2 inhibition by DF2726A is effective in reducing p-STAT3, p-FAK and PI3K/p-cortactin activation induced by both taxane and platinum agents, by modulating pivotal markers of chemotherapy-associated neurotoxicity. The activation of COX2 and ERK1/2 pathways can further contribute to cellular damage and neuropathic pain 20,28,29 . Oxaliplatin treatment was reported to induce peripheral neuropathy by triggering the COX2 and p-ERK1/2 cascade pathways 20,28,30 .…”

Isobolographic Analyses of Proglumide–Celecoxib Interaction in Rats with Painful Diabetic Neuropathy

“…Meloxicam a selective COX‐2 inhibitor diminishes allodynia in diabetic animals [Kimura and Kontani, ; Bermudez‐Ocana et al, ]. Celecoxib also reduced oxaliplatin‐induced neuropathic pain in mice via inhibition of PI3K/Akt2 in dorsal root ganglion and ERK1/2 pathways in the spinal cord [Chen et al, ; Jiang et al, ]. The antihyperalgesic and antiallodynic activity of celecoxib in diabetic and non‐diabetic rats, is mediated by the opioid system [Rezende et al, ; Juarez‐Rojop et al, ] while celecoxib activates Kv7/MK + channels [Mi et al, ], blocks Na + and L‐type Ca 2+ channels [Park et al, ; Zhang et al, ] and activates cannabinoid‐1 receptors [Rezende et al, ] indicating that celecoxib plays an important role in attenuating hyperalgesia and tactile allodynia in diabetic rats.…”

Duloxetine, a Balanced Serotonin-Norepinephrine Reuptake Inhibitor, Improves Painful Chemotherapy-Induced Peripheral Neuropathy by Inhibiting Activation of p38 MAPK and NF-κB

“…The cold pain threshold test was repeated three times over 5-min intervals. The mean latency was used as the result (Chen et al, 2016; Kim et al, 2016).…”

“…Other studies have suggested that the inflammatory response is also an important factor in CIPN reduction (Boyette-Davis and Dougherty, 2011; Boyette-Davis et al, 2011). Recent studies showed that MAPKs and NF-κB signaling participate in development of OXA- and PTX-induced neuropathy (Li et al, 2015; Chen et al, 2016; Yeo et al, 2016). In addition, a previous study showed increased extracellular signal related kinase (ERK1/2) and p38 signaling in the DRG.…”