Papers of the Week

The heterotrimeric G protein-coupled serotonin receptor 5-HT receptor (5-HTR) mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, we evolved ST171, a bitopic 5-HTR agonist that revealed highly potent and functionally selective G signaling without G activation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo-electron microscopy structures of ST171 bound to 5-HTR in complex with the G protein compared to the canonical agonist befiradol bound to complexes of 5-HTR with G or G revealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein-coupled receptor drugs.

Microglial activation is linked to neuroinflammation in neuropathic pain. Recently, microglia-mediated synaptic pruning has received mounting attention. However, the exact role of spinal microglia in modulating neuropathic pain-associated neural circuits remains unclear. To investigate this question, we used pharmacological, optogenetic, and genetic manipulations combined with behavioral tests, confocal imaging, and patch-clamp studies in a murine spared nerve injury (SNI) model of neuropathic pain. We demonstrate that spinal microglia pruned inhibitory presynaptic terminals in SNI mice, contributing to the disinhibition of spinal protein kinase C γ (PKCγ) interneurons and facilitating neurotransmission from low-threshold Aβ fibers. Single-cell RNA sequencing revealed that SNI-associated microglial subpopulations exhibited high expression of liver X receptor, apolipoprotein E (), and complement C1q. Global knockout of , microglia-specific knockdown of , or treatment with anti-C1q monoclonal antibody reversed SNI-induced pruning of spinal inhibitory synapses, prevented the disinhibition of PKCγ interneurons, and reduced pain hypersensitivity. Our study suggests that destabilization of neural networks through microglia-mediated pruning of inhibitory synapses in the spinal cord contributes to the development of neuropathic pain in mice.

A number of neuropeptides including pituitary adenylate cyclase-activating polypeptide (PACAP) play an important role in the pathophysiology of migraine. Infusions of PACAP in patients with migraine can provoked migraine attacks. A placebo-controlled study with a monoclonal antibody directed against the PACAP-receptor failed to show efficacy. In a small, short, proof of concept study a monoclonal antibody directed against PACAP (Lu AG09222) showed efficacy in the reduction of monthly migraine days compared to placebo, but failed for the endpoint 50%-reduction in migraine days. The ongoing PROCEED-study is a double-blind, placebo-controlled, dose-finding study investigating four different doses of Lu AG09222 vs placebo for migraine prevention is expected to complete in the second half of 2025.

Chronic pain affects more than 50 million Americans, with women disproportionately affected by severe pain, pain interference, and overall disability. The development of chronic pain is multifactorial and often begins with an incident of acute pain associated with an injury or a surgical procedure that transitions to persistent pain lasting for months or years. Despite this, there are limited clinical studies investigating sex differences in predictors and biomarkers for the transition to chronic pain. Several preclinical animal models have been developed to gain a better understanding of the mechanisms for the transition to chronic pain, and several sex-specific mechanisms have been identified across multiple systems. These preclinical models generally involve a multiple-insult approach, in which a priming insult enhances sensitivity to a subsequent induction stimulus. There is emerging evidence from preclinical research for several male-specific and female-specific mechanisms, as well as several studies showing shared mechanisms. Here, we review the clinical and preclinical literature covering sex differences in the periphery and immune system, the central nervous system, and the endocrine system related to the transition to chronic pain. We further highlight gaps in the literature and provide recommendations for future research to understand sex-specific differences in the transition to chronic pain.

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.

Polyneuropathy remains a diagnostic and clinical challenge, with limited understanding of the mechanisms underlying painful and nonpainful phenotypes. While previous studies have examined various characteristics of these patients, the temporal and spatial dynamics of endogenous pain modulation remains not fully elucidated. In this study, offset analgesia (OA) and spatial summation of pain (SSp) were used as measures of pain modulation in individuals with distal symmetric polyneuropathy, stratified by the presence (n = 30) or absence of pain (n = 30), and compared with healthy controls (n = 30). All participants underwent quantitative sensory testing and assessments of OA and SSp using a thermal stimulator applied to the dorsum of the foot. Patients with painful polyneuropathy exhibited enhanced SSp compared with the pain-free polyneuropathy group and healthy controls (P < 0.05), and impaired OA compared with healthy controls (P < 0.05). The pain-free neuropathy group showed less efficient OA and a slightly enhanced SSp, but this finding did not reach significance. The data suggest that changes in spatial summation were primarily driven by heightened pain responses to nociceptive input from smaller areas, rather than larger ones. Notably, spatial summation and the effects of OA were found to be correlated, irrespective of pain diagnosis. These findings underscore specific impairments in endogenous pain modulation in individuals with painful neuropathy, thus advancing our understanding of its pathophysiological mechanisms. They further highlight the differential roles of spatial and temporal dynamics in pain modulation across various neuropathic populations, offering promising avenues for improved diagnostics and prognostics related to polyneuropathy-associated pain.

Nav1.8 voltage-gated sodium channels are strongly expressed in human primary pain-sensing neurons (nociceptors) and a selective Nav1.8 inhibitor VX-548 (suzetrigine) has shown efficacy for treating acute pain in clinical trials. Nociceptors also express other sodium channels, notably Nav1.7, raising the question of how effectively excitability of the neurons is reduced by inhibition of Nav1.8 channels alone. We used VX-548 to explore this question, recording from dissociated human dorsal root ganglion neurons at 37 °C. Applying VX-548 at 10 nM (about 25 times the IC determined using cloned human Nav1.8 channels at 37 °C) had only small effects on action potential threshold and upstroke velocity but substantially reduced the peak and shoulder. Counterintuitively, VX-548 shortened the refractory period-likely reflecting reduced potassium channel activation by the smaller, narrower action potential-sometimes resulting in faster firing. Generally, repetitive firing during depolarizations was diminished but not eliminated by VX-548. Voltage clamp analysis suggested two reasons that repetitive firing often remains in 10 to 100 nM VX-548. First, many neurons had such large Nav1.8 currents that even 99% inhibition leaves nA-level Nav1.8 current that could help drive repetitive firing. Second, Nav1.7 current dominated during initial spikes and could also contribute to repetitive firing. The ability of human neurons to fire repetitively even with >99% inhibition of Nav1.8 channels may help explain the incomplete analgesia produced by even the largest concentrations of VX-548 in clinical studies.

Emotional responses to sensory experience are central to the human condition in health and disease. We hypothesized that principles governing the emergence of emotion from sensation might be discoverable through their conservation across the mammalian lineage. We therefore designed a cross-species neural activity screen, applicable to humans and mice, combining precise affective behavioral measurements, clinical medication administration, and brain-wide intracranial electrophysiology. This screen revealed conserved biphasic dynamics in which emotionally salient sensory signals are swiftly broadcast throughout the brain and followed by a characteristic persistent activity pattern. Medication-based interventions that selectively blocked persistent dynamics while preserving fast broadcast selectively inhibited emotional responses in humans and mice. Mammalian emotion appears to emerge as a specifically distributed neural context, driven by persistent dynamics and shaped by a global intrinsic timescale.