Papers of the Week – Editors’ Picks

Psoriatic arthritis (PsA) is anatomically much more heterogeneous than rheumatoid arthritis, as, beyond synovitis, it often also involves enthesitis, peritendinitis, tenosynovitis, osteitis and periostitis. This heterogeneity currently precludes a gold standard for objectively defining resolution of inflammation following treatment, with enthesitis posing a particular challenge. Despite these difficulties, we apply lessons learned from rheumatoid arthritis to describe how patients with PsA and an inadequate response to therapy can be designated within two patient subgroups, characterized by persistent inflammatory PsA (PIPsA) and non-inflammatory PsA (NIPsA), respectively. The NIPsA phenotype is defined by the lack of ongoing joint inflammation, as confirmed through clinical assessment and imaging, along with normalized inflammatory marker levels. NIPsA might be associated with obesity, biomechanical-related pain, osteoarthritis, fibromyalgia, secondary post-inflammatory damage and central pain mechanisms. In this article, we frame PsA composite outcomes measures in relationship to the PIPsA and NIPsA phenotypes and propose that this approach might help to minimize unnecessary or ineffective cycling of PsA therapy in patients who acquire dominant non-inflammatory mechanisms and might also inform future trial design.

Pain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings and chemogenetic manipulations indicate that pain-facilitated fentanyl use is mediated by enhanced ventral tegmental area dopamine (VTA) neuron responses during self-administration. In females, ovariectomy enhances fentanyl self-administration, but the protective effects of ovarian hormones are not solely mediated by estradiol per se. Instead, pain and high estradiol states-naturally occurring in intact females or artificially produced in males-suppress fentanyl self-administration and associated VTA activity through VTA estrogen receptor beta signaling. These findings highlight the importance of assessing hormonal factors in opioid misuse liability in the context of pain.

The human brain has a remarkable ability to learn and update its beliefs about the world. Here, we investigate how thermosensory learning shapes our subjective experience of temperature and the misperception of pain in response to harmless thermal stimuli. Through computational modeling, we demonstrate that the brain uses a probabilistic predictive coding scheme to update beliefs about temperature changes based on their uncertainty. We find that these expectations directly modulate the perception of pain in the thermal grill illusion. Quantitative microstructural brain imaging further revealed that individual variability in computational parameters related to uncertainty-driven learning and decision-making is reflected in the microstructure of brain regions such as the precuneus, posterior cingulate gyrus, cerebellum, as well as basal ganglia and brainstem. These findings provide a framework to understand how the brain infers pain from innocuous thermal inputs, with important implications for the etiology of thermosensory symptoms under chronic pain conditions.

A subset of peripheral sensory neurons expressing specific Mas-related G-protein-coupled receptors and transient receptor potential channels mediate pruritogen-induced chemical itch. However, the molecular mechanisms that regulate the excitability of these cells, and consequently itch sensation, are poorly understood. TWIK-related spinal cord K+ channel (TRESK) is a background K+ channel that modulates the resting membrane potential, action potential firing, and neuronal excitability, and it has been involved in somatosensation and pain transduction. Here, we demonstrate that this channel contributes to pruritic transduction and it is a potential target for treating chronic itch pathologies. TRESK channel coexpress with Mas-related G-protein-coupled receptor A3, MrgprC11 and MrgprD in mouse sensory neurons, and with MrgprX1 in human ones. Genetic ablation of TRESK enhances firing of MrgprA3-expressing pruriceptors and acute itch in response to intradermal injection of chloroquine, while the response to histamine, BAM8-22, or leukotriene C4 remains unaffected. TRESK deletion also exacerbates chronic itch in mouse models of allergic contact dermatitis, dry skin, and imiquimod-induced psoriasiform dermatitis, resulting in a significantly increased scratching behavior that develops earlier and is more robust. Moreover, pharmacologically enhancing TRESK function diminishes both acute and chronic itch in wild-type mice but not in TRESK knockout (KO) animals. In summary, our data indicate that TRESK plays a role in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators represents a promising antipruritic therapeutic approach that can be combined with other compounds for the treatment of nonhistaminergic itch, which currently lack adequate treatment options.

Pain independent of disease activity is frequently reported by rheumatoid arthritis patients and remains undertreated. Preclinical evidence suggests that imbalance of neuroimmune proresolving interactions within dorsal root ganglia (DRG) rather than at the site of inflammation plays mechanistic roles in persistent arthritis pain. Here, we inhibited production of proresolving lipid mediators by silencing 12/15-lipoxygenase expression in CX3CR1 monocyte/macrophages conditional knockout (cKO) mice. In an arthritis model, hind paw mechanical hypersensitivity is exacerbated in male and female cKO mice in association with DRG infiltration of neutrophils, which migrate in response to leukotriene B released by macrophages through 5-lipoxygenase conversion of arachidonic acid provided by neuron-derived vesicles. Neutrophils apoptosis promotes primary macrophage efferocytosis which is defective in cKO macrophages. In wild-type (WT) and cKO mice, intrathecal injection of MerTK activating antibody, attenuates persistent hypersensitivity and polarizes DRG macrophages toward a proresolving phenotype with production of antinociceptive lipoxin A. Thus, we delineate a neuron-macrophage-neutrophil bidirectional circuit that can be exploited to reduce persistent arthritis pain.

Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (K = 0.7 µM) leads to ‘1350, a 0.95 nM ligand and a full CB1R agonist of G signaling. A cryo-EM structure of ‘1350 in complex with CB1R-G confirms its predicted docked pose. The lead agonist is strongly analgesic in male mice, with a 2-20-fold therapeutic window over hypolocomotion, sedation, and catalepsy and no observable conditioned place preference. These findings suggest that unique cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from analgesia, supporting the further development of cannabinoids as pain therapeutics.

The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations-an extended binding pocket that opens rarely and leads to the conserved signalling residue D (ref. ). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors.

Pain hypersensitivity arises from the induction of plasticity in peripheral and spinal somatosensory neurons, which modifies nociceptive input to the brain, altering pain perception. We applied longitudinal calcium imaging of spinal dorsal projection neurons to determine whether and how the representation of somatosensory stimuli in the anterolateral tract, the principal pathway transmitting nociceptive signals to the brain, changes between distinct pain states. In healthy mice, we identified stable outputs selective for cooling or warming and a neuronal ensemble activated by noxious thermal and mechanical stimuli. Induction of acute peripheral sensitization by topical capsaicin transiently re-tuned nociceptive output neurons to encode low-intensity stimuli. In contrast, peripheral nerve injury resulted in a persistent suppression of innocuous spinal outputs coupled with persistent activation of a normally silent population of high-threshold neurons. These results demonstrate differential modulation of spinal outputs to the brain during nociceptive and neuropathic pain states.

Pain and itch are aversive sensations with distinct qualities, processed in overlapping pathways and brain regions, including the anterior cingulate cortex (ACC), which is critical for their affective dimensions. However, the cellular mechanisms underlying their processing in the ACC remain unclear. Here, we identify modality-specific neuronal populations in layer II/III of the ACC in mice involved in pain and itch processing. Using a synapse labeling tool, we show that pain- and itch-related neurons selectively receive synaptic inputs from mediodorsal thalamic neurons activated by pain and itch stimuli, respectively. Chemogenetic inhibition of these neurons reduced pruriception or nociception without affecting the opposite modality. Conversely, activation of these neurons did not enhance stimulus-specific responses but commonly increased freezing-like behavior. These findings reveal that the processing of itch and pain information in the ACC involves activity-dependent and modality-specific neuronal populations, and that pain and itch are processed by functionally distinct ACC neuronal subsets.

Ronald Dubner (1934-2023) was a “giant” in the field of pain. His more than 5 decades of research programs at the US National Institutes of Health and the University of Maryland resulted in important discoveries that considerably advanced our understanding of the neural and nonneural processes underlying acute and chronic pain and their behavioral and clinical correlates. Through his multidisciplinary and translational research approaches, his novel findings as well as his training as a dentist and neuroscientist, Ron was able to bring to the attention of the pain field the clinical implications of these findings and thereby positively influence the clinical management of pain. Also especially notable were his mentorship of numerous pain scientists and clinicians, many of whom went on to develop their own research programs that significantly benefitted the pain field. Ron also played leadership roles in the International Association for the Study of Pain and other scientific organizations, and his editorial positions for the Pain journal significantly and positively influenced the journal’s stature and its impact on the pain field. This article, which is part of the journal’s series this year that is celebrating its 50th anniversary, highlights Ron’s research and related activities during his years at the National Institutes of Health and University of Maryland and includes comments that Ron himself made about these activities. The article also considers his background and personal attributes that underpinned the many contributions that Ron Dubner made to the pain field, including those to the International Association for the Study of Pain and Pain.