The activation of the ERK pathway
The activation of the ERK pathway may participate in the sensitization of primary afferents in pain transmission (Ji et al., 2009, Lai et al., 2011); the blockade of ERK activation in the DRG can decrease mechanical and heat hypersensitivity in inflammatory pain. IL-10 can inhibit phosphorylation of the MAPK signaling pathway to modulate neuropathic pain (Zheng et al., 2014), and downregulation of IL-10 may induce phosphorylation of the MAPK signaling pathway. Further, activation of the P2X7 receptor is involved in the activation of the ERK1/2-mediated signal transduction pathways (Barbieri et al., 2008, Okumura et al., 2008, Sperlagh et al., 2006). The P2X7 agonist, BzATP, induces ERK phosphorylation, and the P2X7 antagonist, BBG, inhibits the BzATP-induced ERK activation (Okumura et al., 2008, Sperlagh et al., 2006). Our data show that the IOD ratio of p-ERK1/2 to ERK1/2 in the gp120 group was higher than that in the sham group, suggesting that ERK phosphorylation in the DRG is involved in the gp120-induced P2X7 receptor-mediated hyperalgesia in the gp120-treated rats. The IOD ratio of p-ERK1/2 to ERK1/2 in the gp120+ BBG-treated rats was significantly decreased compared with that in the gp120 group. The ATP released from the damaged transcription factor can phosphorylate ERK and induce pain (Seino et al., 2006). Our study indicates that BBG inhibited the upregulation of the P2X7 receptor and decreased the phosphorylation and activation of ERK1/2 in the DRG of the gp120-treated rats, consequently relieving the mechanical hyperalgesia of the gp120-treated rats.
ATP plays a key role in the relay of sensory information from the periphery to the CNS and is also an important mediator in immuno-neural interactions (Burnstock, 2009, Burnstock, 2013, Burnstock, 2014). The P2X7 receptor can be expressed in DRG neurons (Chizh and Illes, 2001), and our results indicate that P2X7 agonist BzATP-activated currents in DRG neurons cultured with gp120 were higher than those in control neurons. These data support the idea that the upregulation of IL-1β protein and TNFα-R augmented the abnormal neuronal excitability in the DRG. The inhibitory effect of BBG on BzATP-induced currents in DRG neurons cultured with gp120 was larger than that for control, suggesting that the activation of the P2X7 receptor in gp120-treated neurons was increased in comparison with that in control neurons. Therefore, BBG blockade of P2X7 receptor decreases neuronal firing in the DRG, likely contributing to pain relief in the gp120-treated rats. Taken together, the comparison of all patch clamp recording data from control and gp120-treated neurons demonstrates that the activation of the P2X7 receptor participates in sensitizing primary afferents in pain transmission signaling in gp120-treated rats.
Conclusion This study shows that peripheral nerve exposure to HIV gp120 increased mechanical hyperalgesia, thermal hyperalgesia as well as expression of the P2X7 receptor in the DRG of gp120-treated model rats. Upregulation of the P2X7 receptor in the DRG further 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 induced the sensitization of neurons in the DRG, resulting in gp120-induced neuropathic pain behavior. The P2X7 antagonist BBG decreased the upregulation and activation of the P2X7 receptor, and reduced the release of pro-inflammatory cytokines, increased the release of an anti-inflammatory cytokine, inhibited neuronal firing, and decreased the phosphorylation of ERK1/2 in the DRG of the gp120-treated rats. Therefore, inhibition of the P2X7 receptor relieved the mechanical hyperalgesia and thermal hyperalgesia in the gp120-treated rats.
Conflict of interest
Introduction Human immunodeficiency virus (HIV)-1 infection is associated with the neurological disorders that disturb sensory functions in HIV-1/acquired immunodeficiency syndrome (AIDS) patients. Chronic pain is one of the most common neuroAIDS disorders, affecting over 60% of HIV-1-infected patients (Hao, 2013, Parker et al., 2014, Schutz and Robinson-Papp, 2013). Chronic pain significantly decreases the quality of life of HIV-1/AIDS patients. HIV-1 proteins can induce pain behaviors when introduced into animal models. Glycoprotein 120 (gp120) is an HIV-1 protein and causes HIV-associated neuropathic pain (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). Distal symmetrical polyneuropathy (DSP) is the major neurological disorder in HIV/AIDS patients (Schutz and Robinson-Papp, 2013, Maratou et al., 2009). Symptoms of DSP include neuropathic pain, such as allodynia, hyperalgesia, and dysesthesia (Freeman et al., 2014, Verma et al., 2005, Schutz and Robinson-Papp, 2013, Mcarthur et al., 2005). The pathological features of DSP include injury to dorsal root ganglion (DRG) neurons (Schutz and Robinson-Papp, 2013). Peripheral neuropathy is the most common neurological complication of HIV-1 infection. The DRG afferent fibers are distributed to both central and peripheral terminals and transmit noxious stimuli from the periphery to the central nervous system(Basbaum et al., 2009). Thermal hyperalgesia and mechanical allodynia in rats are enhanced by the peripheral administration of gp120 (Hao, 2013, Maratou et al., 2009, Herzberg and Sagen, 2001, Kamerman et al., 2012, Milligan et al., 2000, Oh et al., 2001, Wallace et al., 2007). The pathogenic mechanisms underlying HIV neuropathic pain are uncertain.