ATP as a transmitter can be released from injured
ATP as a transmitter can be released from injured opioid receptors and sensory nerve endings (Sperlágh et al., 1995, Sperlágh et al., 1997, Sperlágh et al., 1998, Burnstock, 2013, Burnstock, 2014). ATP can activate the P2X3 receptor in the DRG neurons (Gao et al., 2011a; Xu et al., 2012). In DRG neurons cultured with gp120, P2X3 agonist α,βme-ATP-activated currents were higher than in controls. The peripheral sensitization of primary DRG neurons is the key event in the onset of chronic pain conditions (Richardson and Vasko, 2002, Basbaum et al., 2009). HIV-1 gp120 protein triggers rapid and sustained enhancement of the excitability of rat primary DRG neurons. Peripheral sensitization is enhanced after exposure to inflammatory mediators such as ATP (Barclay et al., 2002, Richardson and Vasko, 2002, Basbaum et al., 2009, Ford, 2012, Burnstock, 2013). After DRG neurons were co-cultured with gp120 and nano curcumin, α,βme-ATP-induced currents were significantly decreased compared with those in DRG neurons that were only cultured with gp120. These results revealed that nano curcumin treatment reduced the activation of the P2X3 receptor in gp120-treated neurons. Nano curcumin treatment decreased neuronal firing in the DRG neurons mediated by the P2X3 receptor and relieved pain behaviors in the gp120-treated rats. As shown in Fig. 5, curcumin could interact with the hP2X3. Interaction energies for the docked-complexes were calculated by AutoDock 4 and showed in Table 1. In Table 1, a higher value of negative interaction energy is an indicator of more efficient interaction between the hP2X3 and curcumin. Therefore, curcumin may be acted as the inhibitor of P2X3 receptor.
In conclusion, this study showed that peripheral nerve exposure to HIV gp120 increased mechanical hyperalgesia and thermal hyperalgesia accompanied by upregulated expression of the P2X3 receptor in the DRG of the gp120-treated model rats. Nano curcumin treatment decreased the upregulated expression of the P2X3 receptor in gp120-treated model rats and enhanced the currents of P2X3 activation in DRG neurons treated with gp120. After the inhibition of the P2X3 receptor in the DRG, nano curcumin treatment decreased the phosphorylation of ERK1/2 in the DRG of gp120-treated rats. Therefore, nano curcumin treatment may inhibit P2X3 activation, decrease the sensitization of DRG primary afferents and relieve mechanical hyperalgesia and thermal hyperalgesia in gp120-treated rats.
Introduction Chronic pain is a common symptom in people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), affecting>60% of HIV-1-infected patients (Hao, 2013, Parker et al., 2014, Schutz and Robinson-Papp, 2013). Chronic pain dramatically reduces the quality of life of HIV-1/AIDS patients and is one of the primary reasons patients seek medical assistance (Kamerman et al., 2012, Keltner et al., 2014, Maratou et al., 2009, Verma et al., 2005). HIV-1 proteins have been shown to induce pain behaviors when introduced into animal models; glycoprotein 120 (gp120) is an HIV-1 protein that may cause HIV-associated neuropathic pain (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). Distal symmetrical polyneuropathy (DSP) is one of the most common neurologic complications associated with HIV (Maratou et al., 2009, Schutz and Robinson-Papp, 2013). The dorsal root ganglia (DRG) transmit noxious stimuli from the periphery to the central nervous system and DRG afferent fibers are distributed to both central and peripheral terminals (Basbaum et al., 2009). Complications in HIV-associated neuropathic pain also include spontaneous pain and evoked pain (Freeman et al., 2014, Verma et al., 2005). Peripheral administration of gp120 enhances thermal hyperalgesia and mechanical allodynia in rats (Hao, 2013, Herzberg and Sagen, 2001, Kamerman et al., 2012, Maratou et al., 2009, Milligan et al., 2000, Oh et al., 2001, Wallace et al., 2007). HIV-1 gp120 interactions with the peripheral nerve may be involved in the generation of peripheral neuropathic pain in humans. The understanding of how HIV-1 gp120 leads to chronic pain is essential for the development of effective therapy.