P2Y1 purinoceptor inhibition reduces extracellular signal-regulated protein kinase 1/2 phosphorylation in spinal cord and dorsal root ganglia: implications for cancer-induced bone pain

Abstract

It remains unclear as to whether P2Y1 purinergic receptor (P2Y1R) and the molecules that act downstream, such as extracellular signal-regulated protein kinase 1/2 (ERK1/2), are involved in the development of cancer-induced bone pain (CIBP) in vivo. Here, we investigated the role of the P2Y1R in the modulation of CIBP-associated nociception in spinal cord and dorsal root ganglia (DRG). A CIBP model was established by inoculating Walker 256 gland carcinoma cells into the tibia of female rats. Tactile allodynia and spontaneous pain were assessed using von Frey filaments and ambulatory scores. The results showed that both the paw withdrawal latency to tactile allodynia and the ambulatory score to spontaneous pain were significantly different between the CIBP group and the sham group on days 7 -9 post-inoculation (P < 0.01). Furthermore, rats in the CIBP group also showed a progressive increase in ambulatory score, which is different from the sham group (P < 0.01). Furthermore, P2Y1R mRNA and phosphorylated ERK1/2 ( p-ERK1/2) protein expression levels were increased in the spinal dorsal horn and DRG of the CIBP group relative to the sham group. However, intrathecal injection of the P2Y1R antagonist MRS2179 decreased P2Y1R mRNA and p-ERK1/2 protein expression in the spinal dorsal horn and DRG (P < 0.01). These results provide evidence that the inhibition of P2Y1R-mediated ERK1/2 phosphorylation in the spinal dorsal horn and DRG can attenuate nociception transmission.

Purinergic signalling and cancer

“…They showed further that the P2X7 receptor antagonist, A-438079, failed to alleviate the painrelated behaviours and concluded that P2X7 receptors play a negligible role in bone cancer pain. Evidence has been presented that P2Y 1 receptors in the spinal cord and DRG may mediate bone cancer pain through the ERK pathway [749].…”

Painful Boney Metastases

“…Intrathecal injection of the P2Y1R antagonist MRS2179 decreased P2Y1R mRNA and p-ERK1/2 protein expression in the spinal dorsal horn and DRG (P ＜ 0.01), as well as pain-related behavior including tactile allodynia, spontaneous pain, and ambulatory-evoked pain [94]. These results provide supporting evidence that the inhibition of P2Y1R-mediated ERK1/2 phosphorylation in the spinal dorsal horn and DRG can attenuate nociception transmission [94].…”

“…However, due to the superior efficacy of their newer agent, denosumab (AMG-162) -a fully human monoclonal antibody that specifically neutralizes RANKLthereby inhibiting bone resorption, and concerns regarding deleterious OPG-mediated protection from TRAIL mediated apoptosis in cancer cells, Amgen ceased further clinical development of AMGN-0007 [92]. [94]. Intrathecal injection of the P2Y1R antagonist MRS2179 decreased P2Y1R mRNA and p-ERK1/2 protein expression in the spinal dorsal horn and DRG (P ＜ 0.01), as well as pain-related behavior including tactile allodynia, spontaneous pain, and ambulatory-evoked pain [94].…”

Purinergic signalling in the musculoskeletal system

“…P2X7 receptor activation also induces cell death and cell surface CD23 (the low affinity IgE receptor) shedding from lymphocytes in human RPMI 8226 multiple myeloma cells [461]. A recent paper has presented evidence that P2Y 1 receptor signalling in the spinal cord and DRG may mediate bone cancer pain through the ERK pathway [462].…”