rhodamine 123 mg The activation of the ERK pathway participa

The activation of the ERK pathway participates in the transmission of pain signaling by sensitizing primary afferents (Ji et al., 2009, Lai et al., 2011). Thus, the blockade of ERK activation in the primary sensory rhodamine 123 mg can reduce the mechanical hypersensitivity and the thermal hypersensitivity in inflammatory pain. The phosphorylation of the MAPK indicates its activation. IL-10 can inhibit the phosphorylation of the MAPK signaling pathway in the neuropathic pain (Zheng et al., 2014). The down-regulation of IL-10 may enhance the phosphorylation of the MAPK signaling pathway in HIV-associated neuropathic pain. It was reported that the activation of the P2X3 receptor follows the activation of the ERK1/2-mediated signal transduction pathways and induces pain (Liu et al., 2014, Lai et al., 2011; Barbieri et al., 2008). Our data showed that the IOD ratio of p-ERK1/2 to ERK1/2 in the gp120 group was higher than that in the sham group. For this reason, ERK phosphorylation in the DRG is related to the gp120-induced P2X3 receptor-mediated hyperalgesia in the gp120-treated rats. The IOD ratios of p-ERK1/2 to ERK1/2 in the gp120+ A317491-treated rats were significantly decreased compared to the gp120 group. Our studies revealed that the P2X3 antagonist A317491 inhibited both the up-regulation of the P2X3 receptor and the phosphorylation of ERK1/2 in the DRG of the gp120-treated rats. The inhibition of the P2X3 receptor decreased the activation of ERK1/2 in the DRG to relieve mechanical hyperalgesia and thermal hyperalgesia in gp120-treated rats. ATP is an important mediator involved in immuno-neural interactions and can transmit sensory information from the periphery to the CNS (Burnstock, 2009, Burnstock, 2013, Burnstock, 2014, Sperlágh et al., 1995, Sperlágh et al., 1997, Sperlágh et al., 1998, Vizi et al., 1997). The P2X3 receptor can be expressed in DRG neurons(Chizh and Illes, 2001). Our results indicated that P2X3 agonist α,βme-ATP-activated currents in DRG neurons cultured with gp120 were higher than those in controls. The inhibitory effect of A317491 on α,βme-ATP-induced currents in DRG neurons cultured with gp120 was larger than that for controls. These results revealed that the activation of the P2X3 receptor in gp120-treated neurons was increased in comparison with that in control neurons. A317491 blockade of the P2X3 receptor decreased neuronal firing in the DRG and relieved pain behavior in the gp120-treated rats. Our results for molecular docking of A317491 on gp120 protein indicated that A317491 could affect gp120. As shown in Fig. 5, A317491could interact with the gp120 protein. Interaction energies for the docked-complexes were calculated by MOE 2012.10 and showed in Table 1. In Table 1, a higher value of negative interaction energy is an indicator of more efficient interaction between the gp120 and A317491. A317491 could bind to the gp120, lead to influencing the P2X3 activation induced by gp120. Therefore, A317491 may be acted in the gp120 protein to inhibit the gp120 initiated the P2X3 activation, decrease the sensitizing DRG primary afferents and reduce the signal transmission of neuropathic pain in gp120-treated rats. In conclusion, this study showed that peripheral nerve exposure to HIV gp120 increased the expression of the P2X3 receptor in the DRG of the gp120-treated model rats. Up-regulation of P2X3 receptor in the DRG consequently promoted the release of pro-inflammatory cytokines (IL-1β and TNF-α) and inhibited the release of an anti-inflammatory cytokine (IL-10). IL-1β and TNF-α increased the sensitization of neurons in the DRG, resulting in gp120-induced neuropathic pain behaviors (the mechanical hyperalgesia and the thermal hyperalgesia). The P2X3 antagonist A317491 decreased the up-regulated expression of the P2X3 receptor and the enhanced currents of DRG neurons treated with gp120. The inhibition of P2X3 receptor in the DRG decreased the release of pro-inflammatory cytokines, increased the release of an anti-inflammatory cytokine and lessened the phosphorylation of ERK1/2 in the DRG of the gp120-treated rats. A317491 could bind to the gp120, lead to influencing the P2X3 activation induced by gp120. In short, the inhibition of the P2X3 receptor relieved mechanical hyperalgesia and thermal hyperalgesia in gp120-treated rats.