Medicinal chemistry of terpenoids in chronic pain: Molecular pharmacology, neuroimmune modulation, and advanced drug delivery strategies

Chronic pain, including inflammatory and neuropathic pain, remains one of the largest public health issues in the world, characterized by enduring nociceptive signaling, dysregulation of the immune system, and sensitization of the central nervous system. In this regard, terpenoids are structurally diverse isoprene derivatives that are abundant in many medicinal plants. Terpenoids are emerging as a class of increasingly interesting bioactive compounds with a wide range of anti-inflammatory and analgesic activity. Compounds such as β-caryophyllene, D-limonene, α- and β-pinene, curcuminoids, turmerones and ginkgolides appear to have significant therapeutic potential, through multiple but interrelated modes of action, including inhibition of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), inhibition of cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS), and modulation of critical intracellular signaling pathways (NFκB, MAPK, JAK-STAT and Nrf2). Few terpenoids possess a receptor-specific mechanism, including (i) β-caryophyllene, which may selectively agonize the CB2 receptor, and (ii) ginkgolides, which might selectively antagonize the platelet-activating factor (PAF) receptor, demonstrating the potential for targeted therapeutic interventions with limited adverse events in the CNS. A variety of new drug delivery systems (e.g., nanotechnology-based carriers, lipid nanoparticles, and co-crystallization techniques) are being developed to overcome these barriers and improve the therapeutic effectiveness of terpenoid-based treatments for chronic pain. In general, Up-and-Coming systems for delivering terpenoids as therapeutics present a promising, dynamic new model for treating chronic pain. These potential therapeutic agents combine principles of natural product chemistry and modern pharmacology to inhibit inflammatory processes at the molecular level.