The role of NLRP3 inflammasome in opioid-induced neurochemical markers, therapeutic effects, and adverse effects in male mice.
Article
Rodriguez, Myosotys, Veeragoni, Dileepkumar, Carbajal, Candy et al. (2026). The role of NLRP3 inflammasome in opioid-induced neurochemical markers, therapeutic effects, and adverse effects in male mice.
. BRAIN BEHAVIOR AND IMMUNITY, 135 10.1016/j.bbi.2026.106528
Rodriguez, Myosotys, Veeragoni, Dileepkumar, Carbajal, Candy et al. (2026). The role of NLRP3 inflammasome in opioid-induced neurochemical markers, therapeutic effects, and adverse effects in male mice.
. BRAIN BEHAVIOR AND IMMUNITY, 135 10.1016/j.bbi.2026.106528
Repeated administration of opioids such as morphine and fentanyl activates glial cells, leading to the release of pro-inflammatory molecules through secretory pathways, including theNLRP3 inflammasome. NLRP3 activation is thought to contribute to neuroinflammation, opioid tolerance, and opioid-induced hyperalgesia (OIH), serving as a potential mechanism behind the reduced effectiveness and adverse consequences of long-term opioid analgesic therapy. The present study examined the influence of NLRP3 on neurochemical markers of inflammation and synaptic plasticity in the brain, as well as behavioral and physiological responses to morphine and fentanyl in C57BL/6J mice. Treatment with morphine or fentanyl, alone or combined, produced dose-dependent antinociception, respiratory depression, and psychostimulatory behavior while significantly increasing inflammatory cytokines IL-1β, IL-6, IL-18, and TNF-α, along with chemokines MCP-1 and RANTES. This response was linked to higher expressed levels of NLRP3, MAPKs, JNK and p38, and the transcription factor NF-kB, while reducing synaptic plasticity markers NMDAR, AMPA, and PSD-95. In animals treated with the selective NLRP3 inhibitor MCC950 alongside opioid exposure, levels of IL-6, IL-18, TNF-α, and NLRP3 in the brain decreased, and PSD-95 levels were restored. Behaviorally, MCC950 potentiated opioid-induced antinociception, respiratory depression, hyperlocomotion, and the rewarding effects of morphine in the conditioned place preference test, although it mitigated morphine acute antinociceptive tolerance and OIH. In summary, these initial results indicate that the NLRP3 pathway influences the release of opioid-related inflammatory molecules, affecting behaviors that increase the risk of opioid overdose.
