Abstract
We investigated the role that innate immunological signaling pathways, principally nod-like receptors (NLRs) and inflammasomes, in the manifestation of the contradictory outcomes associated with opioids, namely hyperalgesia, and tolerance. The utilization of opioids for pain management is prevalent; nonetheless, it frequently leads to an increased sensitivity to pain (hyperalgesia) and reduced efficacy of the medication (tolerance) over an extended period. This, therefore, represents a major challenge in the area of chronic pain treatment. Recent studies indicate that the aforementioned negative consequences are partially influenced by the stimulation of NLRs, specifically the NLRP3 inflammasome, and the subsequent assembly of the inflammasome. This process ultimately results in the generation of inflammatory cytokines and the occurrence of neuroinflammation and the pathogenesis of hyperalgesia. We also explored the putative downstream signaling cascades activated by NOD-like receptors (NLRs) and inflammasomes in response to opioid stimuli. Furthermore, we probed potential therapeutic targets for modifying opioid-induced hyperalgesia, with explicit emphasis on the activation of the NLRP3 inflammasome. Ultimately, our findings underscore the significance of conducting additional research in this area that includes an examination of the involvement of various NLRs, immune cells, and genetic variables in the development of opioid-induced hyperalgesia and tolerance. The present review provides substantial insight into the possible pathways contributing to the occurrence of hyperalgesia and tolerance in individuals taking opioids.
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Nasrin Zare conducted the design and coordination of the study, the literature searches, the quality rating, and drafted the manuscript. Fateme Sharafeddin, AmirMahdi Montazerolghaem, Nastaran Moradiannezhad, and Mohammaderfan Araghizadeh participated in the selection of reviews and the data extraction. The first draft of the manuscript was written by Nasrin Zare and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Zare, N., Sharafeddin, F., Montazerolghaem, A. et al. NLRs and inflammasome signaling in opioid-induced hyperalgesia and tolerance. Inflammopharmacol 32, 127–148 (2024). https://doi.org/10.1007/s10787-023-01402-x
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DOI: https://doi.org/10.1007/s10787-023-01402-x