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    • Adenosine triphosphate ATP is thought to be a crucial

    2022-07-19

    Adenosine triphosphate (ATP) is thought to be a crucial molecule in acute pain signaling in the DRG, as well as in the development and maintenance of chronic pain (Burnstock, 2009, Burnstock, 2013, Burnstock, 2014, Chizh and Illes, 2001). Extracellular ATP activates the ionotropic P2X receptors (Burnstock, 2009, Burnstock, 2013, Burnstock, 2014, Chizh and Illes, 2001, Khakh and North, 2012), which are expressed by neurons of the DRG (Burnstock, 2009). The P2X7 receptor has important functions in the immune system (Burnstock, 2013, Mehta et al., 2014, Skaper et al., 2010); studies show that the severity of the inflammatory response is decreased in P2X7 receptor gene knockout phenotypes (Mehta et al., 2014, Skaper et al., 2010). The P2X7 receptor is important for the induction and maintenance of neuropathic and inflammatory pain (Burnstock, 2013, Liu et al., 2015, Skaper et al., 2010, Sperlagh et al., 2006). It was reported that the interaction of the HIV surface protein gp120 with macrophages stimulates increased ATP release (Hazleton et al., 2012, Lee et al., 2012). P2X receptors are required for HIV entry into macrophages (Hazleton et al., 2012). ATP signaling via the P2X7 receptor plays a key role in the regulation of inflammatory responses during acute viral infection (Lee et al., 2012). It is possible that the P2X7 receptor is involved in HIV-associated neuropathic pain. However, no studies have been performed to assess the effects of the P2X7 receptor on HIV gp120-associated pain behaviors and neuropathology in a rat model. In this study, we investigated the effects of the P2X7 receptor and its antagonist on pain behaviors and gp120-induced neuropathology in rat primary afferent fibers.
    Materials and methods
    Results
    Discussion The pathogenic mechanisms of HIV-associated pain remain poorly understood. To elucidate these mechanisms, it is important to identify the HIV-related factors that result in chronic pain. HIV-1 gp120 is a potential pathogenically relevant factor of HIV-associated neuropathic pain (Hao, 2013, Yuan et al., 2014, Zheng et al., 2011). The MWT and TWL in the peripheral gp120 application model were reduced compared with that in the control group, consistent with previous reports (Herzberg and Sagen, 2001, Wallace et al., 2007, Zheng et al., 2011). But the limitation is that the single dose gp120 was applied in the study, we could not get any dose-dependant relationship between gp120 dose and hyperalgesia. Our work shows that in the DRG, which is the primary afferent sensory ganglia of pain transmission, the Alamethicin levels of P2X7 mRNA and protein in the HIV-1 gp120 treatment group were significantly higher than those in the sham group. The P2X7 receptor is involved in inflammatory pain and neuropathic pain (Burnstock, 2013, Mehta et al., 2014, Skaper et al., 2010, Sperlagh et al., 2006). Our data indicate that the P2X7 receptor in the DRG may also be involved in HIV-associated neuropathic pain. The increased levels of the P2X7 receptor in the DRG are related to the pathogenic mechanisms of HIV-associated pain and may, at least in part, be responsible for the development of neuropathic pain. The P2X7 antagonist BBG inhibited the expression levels of the P2X7 receptor and relieved the MWT and TWL in the gp120-treated rats, indicating that the P2X7 receptor in the DRG participates in the transmission of the nociceptive signal induced by HIV gp120 infection. Damage and noxious stimulation induce ATP release by injured cells and sensory nerve endings (Burnstock, 2013, Burnstock, 2014, Puchalowicz et al., 2014). ATP can activate the P2X7 receptor in DRG neurons, leading to the release of pro-inflammatory cytokines that increase abnormal neuronal excitability and contribute to pain. HIV gp120 also has direct and indirect effects on nerves by stimulating the nervous system to release pro-inflammatory cytokines (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). It is well known that pro-inflammatory cytokines, including IL-1β and TNFα, have an important role in the initiation and maintenance of neuropathic pain. Our results show that the expression levels of P2X7 mRNA and protein were increased in the gp120-treated rats, accompanied by upregulated IL-1β protein. TNFα can activate TNFα-R in DRG neurons and enhance neuronal excitability (Illes et al., 2012). Meanwhile, our data show that the expression levels of TNFα-R were augmented in the DRG of the gp120-treated rats. Thus, the upregulation of IL-1β and TNFα-R proteins in the DRG may induce abnormal neuronal excitability in the DRG, thereby enhancing hyperalgesia in the gp120-treated rats. Expression levels of IL-10, an anti-inflammatory factor (Zheng et al., 2014), in the DRG of the gp120-treated rats were decreased in this experiment. Downregulated anti-inflammatory cytokines (such as IL-10) can aggravate HIV-associated neuropathic pain. The P2X7 antagonist BBG may decrease the expression of the P2X7 receptor in the DRG, and in turn reduce the release of pro-inflammatory cytokines in the DRG and increase the release of the anti-inflammatory cytokine. Our results show that the MWT and TWL in gp120-induced BBG-treated rats was higher than that in the gp120 group. Therefore, the inhibition of the P2X7 receptor relieved pain behavior in the gp120-treated rats.