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.