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    • Adenosine triphosphatase ATP is a signaling molecule in acut

    2021-10-27

    Adenosine triphosphatase (ATP) is a signaling molecule in acute pain and chronic pain(Burnstock, 2009, Burnstock, 2013, Burnstock, 2014, Chizh and Illes, 2001). It is also known that presynaptic A1 receptors are involved in the inhibition of transmitter release (Vizi and Knoll, 1976). Extracellular ATP can activate the ionotropic P2X receptors on the DRG neurons(Burnstock, 2009, Burnstock, 2013, Burnstock, 2014, Chizh and Illes, 2001, Khakh and North, 2012). P2X receptors are expressed by neurons of the DRG [18]. P2X3 receptor is involved in transmitting persistent, chronic neuropathic and inflammatory pain(Burnstock, 2013, Gao et al., 2011, Mehta et al., 2014, Skaper et al., 2010, Xu et al., 2012). The interaction of the HIV surface protein gp120 with macrophages stimulates increased ATP release, and P2X receptors are required for HIV entry into macrophages (Hazleton et al., 2012, Lee et al., 2012). Stimulation of P2X3 receptors results in an increase of transmitter release (Sperlágh et al., 1995). ATP signaling is involved in the regulation of inflammatory responses during acute viral infection(Lee et al., 2012). Purinergic receptors have an important role in the macrophages’ immune response to pathogens, inflammation, and cellular damage. The blocking of purinergic receptors leads to a significant reduction in HIV replication in macrophages(Hazleton et al., 2012, Lee et al., 2012). Therefore, the P2X3 receptor may be related to HIV-associated neuropathic pain. However, the effects of the P2X3 receptor on HIV-gp120-associated neuropathic pain in rats are not clear. In this study, we investigated the role of the P2X3 receptor in gp120-induced neuropathology in rat primary afferent fibers.
    Materials and methods
    Results
    Discussion To clarify the mechanisms of HIV-associated pain, we performed experiments to identify the relevant factors that result in HIV-associated neuropathic pain. The peripheral gp120 application can induce the mechanical withdrawal threshold (MWT) (Zheng et al., 2011, Herzberg and Sagen, 2001, Wallace et al., 2007). This indicates that HIV-1 gp120 is a potential pathogenically relevant factor for HIV-associated neuropathic pain (Hao, 2013, Yuan et al., 2014, Zheng et al., 2011) Our study showed that the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) in the peripheral gp120 application model were reduced compared to those in the control group. Meanwhile, our results also revealed that the rq 1 levels of P2X3 mRNA and protein in the DRG in the HIV-1 gp120 treatment group were significantly higher than those in the sham group and the control group. The P2X3 receptor is related to neuropathic pain and inflammatory pain (Burnstock, 2013, Mehta et al., 2014, Skaper et al., 2010, Sperlagh et al., 2006) Therefore, the increased levels of the P2X3 receptor in the DRG are involved in the pathogenic mechanism of HIV-associated pain and may, at least in part, be responsible for the development of the neuropathic pain. The P2X3 antagonist A317491 decreased the expression levels of the P2X3 receptor and relieved the MWT in the gp120-treated rats, which indicated that the P2X3 receptor in the DRG participated in the signal transmission of HIV-associated pain. ATP as a transmitter can be released from the injured cells and sensory nerve endings (Burnstock, 2013, Burnstock, 2014, Sperlágh et al., 1995, Sperlágh et al., 1997, Sperlágh et rq 1 al., 1998, Puchalowicz. et al., 2014, Vizi et al., 1997). ATP can activate the P2X3 receptor in the DRG neurons (Gao et al., 2011, Xu et al., 2012). The activation of the P2X3 receptor may release proinflammatory cytokines that increase abnormal neuronal excitability and contribute to neuropathic pain. HIV gp120 stimulates the nervous system to release pro-inflammatory cytokines by direct and indirect effects (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). Pro-inflammatory cytokines, including IL-1β and TNF-α, have an important role in the initiation and maintenance of neuropathic pain. TNF-α can activate TNF-α R in DRG neurons and enhance neuronal excitability (Illes et al., 2012). Our results showed that the expression levels of the IL-1β protein and TNF-α R were augmented in the DRG of the gp120-treated rats. Thus, the up-regulation of IL-1β protein and TNF-α R in the DRG may induce abnormal neuronal excitability in the DRG. The abnormal neuronal excitability in the DRG induced hyperalgesia in the gp120-treated rats. IL-10 has anti-inflammatory effects(Zheng et al., 2014). The expression levels of IL-10 in the DRG of the gp120-treated rats were reduced in this experiment. Down-regulated anti-inflammatory cytokines (IL-10) can aggravate HIV-associated neuropathic pain. The P2X3 antagonist A317491 may decrease the up-regulated expression of the P2X3 receptor in the DRG and, in turn, reduce the release of pro-inflammatory cytokines in the DRG and increase the release of anti-inflammatory cytokines. Our data indicated that the MWT in gp120-induced A317491-treated rats with neuropathic pain was higher than the gp120 group. Therefore, the inhibition of the P2X3 receptor relieved pain behavior in the gp120-treated rats.