Mechanism-based nonopioid analgesic targets
Xiangsunze Zeng, … , Rasheen Powell, Clifford J. Woolf
Xiangsunze Zeng, … , Rasheen Powell, Clifford J. Woolf
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e191346. https://doi.org/10.1172/JCI191346.
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Review

Mechanism-based nonopioid analgesic targets

Abstract

Acute pain management has historically been dominated by opioids, whose efficacy is overshadowed by the risks of addiction, tolerance, and dependence, culminating in the global opioid crisis. To transcend this issue, we must innovate beyond opioid-based μ receptor treatments, identifying nonopioid analgesics with high efficacy and minimal adverse effects. This Review navigates the multifaceted landscape of inflammatory, neuropathic, and nociplastic pain, emphasizing mechanism-based analgesic targets tailored to specific pain conditions. We delve into the challenges and breakthroughs in clinical trials targeting ion channels, GPCRs, and other molecular targets. We also highlight the intricate crosstalk between different physiological systems and the need for multimodal interventions with distinct pharmacodynamics to manage acute and chronic pain, respectively. Furthermore, we explore emerging strategies, including gene therapy, stem cell therapy, cell type–specific neuromodulation, and AI-driven techniques for objective, unbiased pain assessment and research. These innovative approaches are poised to revolutionize pain management, paving the way for the discovery of safer and more effective analgesics.

Authors

Xiangsunze Zeng, Rasheen Powell, Clifford J. Woolf

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Figure 1

Molecular and circuit architecture of pain processing.

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Molecular and circuit architecture of pain processing. (A) Activating th...
(A) Activating the μ-opioid receptor (MOR) signaling system produces inhibitory effects on pain-initiating signal transmission but is also associated with adverse effects. See Table 1 for details. (B) Neural circuitry underlying nociceptive signal processing. Nociceptor afferents transmit signals from the periphery through the DRG to the spinal dorsal horn, where local interneurons (LINs) modulate the signals before relaying to higher-order brain structures via spinal projection neurons (SPNs). These structures include the parabrachial nucleus (PBN), periaqueductal gray (PAG), hypothalamus (HTh), thalamus (Th), prefrontal cortex (PFC), rostral anterior cingulate cortex (rACC), posterior insular cortex (PI), amygdala (Amy), and primary and secondary somatosensory cortices (S1, S2), constituting the ascending pathway (yellow). Descending pathways (blue) from the rACC, PAG, and rostral ventromedial medulla (RVM) modulate pain by inhibiting or facilitating spinal nociceptive transmission. The ventral tegmental area (VTA), nucleus accumbens (NAc), and PFC are implicated in the reward and abuse potential of opioids (red), whereas the PAG, RVM, and dorsal horn are primary sites for opioid-induced analgesia (green). (C) Peripheral tissue injury or pathogen invasion recruits immune cells that release proinflammatory cytokines, leading to heightened nociceptor excitability, which in turn drives neuropeptide release and amplifies inflammation. (D) Direct damage to nerves by injury or disease results in nociceptor hyperexcitability, demyelination, sympathetic nerve sprouting, and recruitment of peripheral immune cells to the site of injury that contribute to pain. Nonneuronal support cells secreting cytokines may exacerbate pain development. (E) Increases in ligand-gated ion channel activity, decreases in inhibitory GPCR signaling, loss of inhibitory LINs, and sprouting of nonnociceptive A fibers to the superficial dorsal horn can promote pain signaling. Recruitment of central immune cells (e.g., microglia and astrocytes) and a top-down regulation of serotonergic (5-HT), noradrenergic, and GABAergic projections via the bulbospinal tract also modulate CNS pain signals.