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  • BRD4770 br AUTHOR CONTRIBUTIONS br ACKNOWLEDGMENTS br Introd

    2022-05-18


    AUTHOR CONTRIBUTIONS
    ACKNOWLEDGMENTS
    Introduction Chronic neuropathic pain is a common symptom in patients with human immunodeficiency virus (HIV)-1 infection. Glycoprotein 120 (gp120) is an HIV-1 protein that can cause pain behaviors in animal models (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). Concomitant with chronic pain manifestation, approximately 30% of HIV-1/AIDS patients develop clinically detectable peripheral neuropathy. Distal symmetrical polyneuropathy (DSP) is a major neurological disorder in HIV/AIDS patients (Schütz 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, Schütz and Robinson-Papp, 2013). Dorsal root ganglion (DRG) afferent fibers are distributed to both central and peripheral terminals as well as 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 peripheral administration of gp120 (Hao, 2013, Maratou et al., 2009, Herzberg and Sagen, 2001, Kamerman et al., 2012, Milligan et al., 2000, Wallace et al., 2007). At present, clinical interventions provide only symptomatic relief rather than a cure. Because the pathogenic mechanism of HIV-associated chronic pain is not yet clear, the understanding of how HIV-1 infection leads to chronic pain is very important for the development of effective therapies. Purinergic P2 receptors are activated by extracellular purine (ATP, ADP) and/or pyrimidine (UTP, UDP) nucleotides (Burnstock, 2013, Burnstock, 2014, Idzko et al., 2014, Magni and Ceruti, 2013). P2 receptors consist of metabotropic (i.e., G-protein-coupled) P2Y receptors and ionotropic P2X receptors (i.e., nucleotide-gated ion channels) (Burnstock, 2013, Burnstock, 2014, Idzko et al., 2014, Magni and Ceruti, 2013). ATP is released from both neurons and glial BRD4770 (Fields and Burnstock, 2006, Verderio and Matteoli, 2011, Sperlágh et al., 1995, Sperlágh et al., 1998, Sperlagh et al., 1997). Satellite glial cells (SGCs) are the most abundant cell type in DRG (Costa and Moreira, 2015, Hanani, 2005). After peripheral nerve injury, SGCs undergo structural changes and proliferate (Hanani, 2005, Jasmin et al., 2010). Neuron–glia interactions involve purinergic signaling (Fields and Burnstock, 2006, Rajasekhar et al., 2015, Verderio and Matteoli, 2011). SGCs of DRG express the P2Y12 receptor (Katagiri et al., 2012, Kobayashi et al., 2008, Kobayashi et al., 2013). The P2Y12 receptor participates in the transmission of nociceptive signals (Burnstock, 2013, Horváth et al., 2014, Katagiri et al., 2012, Magni and Ceruti, 2013). However, it is uncertain whether the P2Y12 receptor is involved in the pathogenic mechanisms underlying BRD4770 HIV neuropathic pain. In this experiment, our aim was to investigate the role of the P2Y12 receptor in HIV gp120-induced neuropathic pain.
    Materials and methods
    Results
    Discussion Chronic neuropathic pain is a common pain syndrome in patients with HIV-1 infection (Hao, 2013, Nasirinezhad et al., 2015, Yuan et al., 2014, Zheng et al., 2011). Although the severity and frequency of neuropathic pain are correlated with the progression of HIV-1 infection, neuropathic pain can appear at all stages of HIV-1 infection. The present study demonstrated that peripheral administration of gp120 enhanced thermal hyperalgesia and mechanical allodynia in rats. The results indicated that gp120 induced pathological changes in pain behaviors in animal models. DRG have an important role in sensory signaling under physiological and pathological conditions. The current experiments demonstrated that the P2Y12 receptor was increased in DRG of gp120-treated rats, leading to enhanced mechanical and thermal hyperalgesia. The P2Y12 receptor participates in the pathological processes of inflammatory and neuropathic pain (Burnstock, 2013, Katagiri et al., 2012, Magni and Ceruti, 2013). Thus, the P2Y12 receptor in DRG may be involved in nociceptive transmission of neuropathic pain in HIV gp120-treated rats. Our data also showed that down-regulation of P2Y12 reduced the expression levels of P2Y12 mRNA and protein, consequently rescuing MWT and TWL in gp120-treated rats. The results further indicated that the P2Y12 receptor has an important role in rat DRG in the transmission of nociceptive signals induced by HIV gp120.