The Spinal Cell Atlas of Opioid-Targeted Inflammasomes in the HIV Pain Model: Mechanisms and Pathogenic Role

SUMMARY Opioid analgesics are still commonly prescribed to alleviate severe pain in patients with HIV-1/AIDS. However, chronic opioid treatment paradoxically leads to opioid-induced hyperalgesia (OIH), a heightened pain state that requires escalating dosages for opioids to be effective. This side effect directly contributes to opioid overdose and epidemics. Despite the common use of opioids, the mechanism underlying OIH in the context of HIV-induced pain remains unknown, which hinders the development of effective interventions. Recently, we found that morphine exacerbates pain in the HIV-1 gp120 pain model and causes neuroinflammation in the spinal dorsal horn (SDH), the pain processing center in the spinal cord. Emerging evidence indicates that inflammasomes play a critical role in controlling neuroinflammation during pain pathogenesis, including OIH. Our studies suggest that morphine induces neuroinflammatory phenotypes in the SDH, including glial activation (e.g., astrocytes), cytokine expression (e.g., IL-1ß), and inflammasome activation, and that the neuroinflammatory phenotypes are exacerbated in the gp120 pain models. We further demonstrate that Wnt5a signaling from neurons is essential for morphine to activate neuroinflammation and inflammasomes during OIH pathogenesis. Collectively, our preliminary data suggest that morphine targets inflammasomes in the SDH via neuronal Wnt5a signaling to regulate neuroinflammation during OIH development, and that HIV-1 gp120 enhances these effects of morphine. Hence, we hypothesize that morphine induces distinct cell distribution patterns of inflammasomes in the pain neural circuits, that Wnt5a signaling plays a critical role in setting up the cell maps of inflammasomes induced by morphine, and that inflammasomes compartmentalized in different cells cooperatively promote OIH pathogenesis. We also hypothesize that HIV-1 gp120 enhances these effects of morphine. To test the hypotheses, we will construct cell atlas of the opioid-targeted inflammasome in the spinal cord of HIV pain models (Aim 1), elucidate the role of Wnt5a signaling in the establishment of inflammasome cell maps (Aim 2), and determine the contribution of glial type-specific NLRP3 to OIH pathogenesis in the context of HIV-Associated pain. Results from this study will reveal the molecular mechanism and the pathogenic role of opioid-targeted inflammasomes in the CNS in the context of HIV-associated pain.