Reactive Oxygen Species (ROS) are Critical for Morphine Exacerbation of HIV-1 gp120-Induced Pain
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Reactive Oxygen Species (ROS) are Critical for Morphine Exacerbation of HIV-1 gp120-Induced Pain Yuqiang Shi 1 & Subo Yuan 1 & Shao-Jun Tang 1 Received: 15 October 2019 / Accepted: 17 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Many HIV patients develop chronic pain and use opioid-derived medicine as primary analgesics. Emerging clinical evidence suggests that chronic use of opioid analgesics paradoxically heightens pain states in patients. This side effect of opioid analgesics has a significant negative impact on clinical practice, but the underlying pathogenic mechanism remains elusive. Using a mouse model of HIV-associated pain, we simulated the development of morphine exacerbation on pain and investigated potential underlying cellular and molecular pathways. We found that repeated morphine treatment promoted astrocyte activation in the spinal dorsal horn (SDH) and up-regulation of pro-inflammatory cytokines IL-1β and TNF-α. Furthermore, we observed that morphine administration potentiated mitochondrial reactive oxygen species (ROS) in the SDH of the HIV pain model, especially on astrocytes. Systemic application of the ROS scavenger phenyl-N-t-butyl nitrone (PBN) not only blocked the enhancement of gp120-induced hyperalgesia by morphine but also astrocytic activation and cytokine up-regulation. These findings suggest a critical role of ROS in mediating the exacerbation of gp120-induced pain by morphine. Keywords HIV-1 . gp120 . Pain . Opioid . Morphine . ROS . Mitochondria
Introduction According to the latest report from the World Health Organization, there were about 37.9 million people living with HIV/AIDS at the end of 2018 (https://www.who.int/newsroom/fact-sheets/detail/hiv-aids). Among them, about 30– 40%, including up to 75% of patients in advanced stages of HIV/AIDS, suffer from HIV-associated pain (Hewitt et al. 1997; Mirsattari et al. 1999; Evers et al. 2000). Chronic pain severely deteriorates the patient’s quality of life. Unfortunately, there is no specific and effective therapy to cure the pain syndrome. Opioid analgesics are widely used to treat chronic pain (Nafziger and Barkin 2018). Many HIV patients prescribed opioid analgesics to relieve pain (Smith 2011; Krashin et al. 2012) although the effectiveness of opioid analgesics is still controversial (Voon et al. 2017; Cunningham 2018). Although non-opioid analgesics such as gabapentin are becoming standard pain medicines (Attal et al. 2010), HIV patients are still more prevalence in using opioid analgesics, compared to * Shao-Jun Tang [email protected] 1
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
non-HIV patients (Edelman et al. 2013; Canan et al. 2019). The higher prevalence is probably contributed by multiple factors, including opioid abuse and responses to opioid analgesics in some HIV patients. Another important reason for practitioners to continue opioid analgesic prescription is to avoid withdraw symptoms. However, clinical data in
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