Patrick M. Dougherty

In randomized controlled trials (RCTs), study participants and research personnel are often blinded to minimize biases related to knowing treatment allocation. To determine if blinding was effective, participants may be asked which treatment they believe they received (“treatment guess”). This descriptive review characterized blinding assessment (BA) reporting in pharmacotherapy and neuromodulation neuropathic pain RCTs. Of 288 papers, 36 (12.5%) reported a BA. One paper reported the results of 2 studies, so in total 37 studies with a BA were assessed. Of these, 19 were crossover, 17 parallel, and 1 partial crossover in design. All 37 studies assessed participant blinding, and 10 also assessed investigator blinding. Approximately 27% included an “unsure” answer option for treatment guess, and 38% asked the reason for the guess. There were no clear patterns in BA reporting across time nor based on treatment type. Seventeen trials provided sufficient data to calculate Bang Blinding Index (BI) to determine blinding success. Participants remained blinded (BI = 0 ± 0.2) in 10/17 placebo and 10/17 treatment arms, 6 placebo and 5 treatment arms had a BI > 0.2 suggesting possible unblinding, whereas 1 placebo and 2 treatment arms had a BI < −0.2 suggesting misinformed guessing. Overall, we found that BAs are done in a minority of published neuropathic pain trials and with variable methodology. Given the importance of minimizing risk of bias because of treatment unblinding, future studies should consider including BAs, and further consensus building is necessary to determine if and how BAs should be conducted and interpreted in analgesic clinical trials.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling, often irreversible toxicity that affects millions of patients, limits life-saving cancer therapy, and lacks proven treatment. In this work, we show that as little as two doses of psilocybin before chemotherapy durably prevented the onset of CIPN across platinum- and taxane-based models, including repeated chemotherapy cycles, without impairing antitumor efficacy. Peripherally, psilocybin maintained tactile sensitivity and intraepidermal nerve fiber endings through axonal mitochondrial trafficking and distribution preservation, through the TrkB-Akt-PAK5-MAP2-KIF5B pathway and remobilization of syntaphilin-anchored mitochondria. Centrally, it normalized medial prefrontal cortical synaptic activity and cortical alpha and beta electroencephalography power. This stabilization of peripheral axonal energy balance establishes psilocybin as a first-in-class prophylactic agent for CIPN while also preserving central neural function. Given psilocybin’s established safety, these discoveries support clinical evaluation as a strategy to prevent CIPN.

Cholesterol-rich lipid rafts are organizing platforms for many excitatory ion channels and receptors in neurons and for inflammatory receptors like toll-like receptor 4 (TLR4) in immune cells. Human dorsal root ganglion (hDRG) neurons that express nociceptor markers also express high levels of TLR4. Apolipoprotein A-I binding protein (AIBP) binds to TLR4 and promotes cholesterol depletion and lipid raft disruption in cells where TLR4 is expressed. The current study conducted with male and female hDRG demonstrates that TLR4-lipid rafts are expressed with higher density in pain- versus non-pain-associated tissues and localized to neurons expressing transient receptor potential vanilloid 1 (TRPV1) typically expressed by nociceptors. This increased density of TLR4-lipid rafts results in increased excitability of hDRG TRPV1 receptors. Additionally, whole-cell recordings show that disruption of TLR4-rafts with AIBP inhibited pain-associated ectopic action potential generation and evoked neuronal excitation in hDRG neurons. AIBP treatment impacted several action potential dynamics specifically in cells with ongoing ectopic action potentials rather than nonspontaneously active neurons. Finally, AIBP is shown to be localized with satellite cells in human DRG and its expression increases along with glutamine synthetase in pain-associated hDRG. Given that TLR4-raft expression in DRG neurons is largely confined to nociceptors, a TLR4-raft-specific therapeutic such as AIBP may have potential as a novel pain therapeutic with a low-side effect profile.

Nonselective antagonists of voltage-gated sodium channels (VGSCs) provide effective local analgesia, but systemic administration is fraught with unwanted cardiovascular and central nervous system toxicity. The development of antagonists targeting VGSCs preferentially expressed in peripheral neurons, such as Na _V 1.7, 1.8, and 1.9, could mitigate these risks. One such new small molecule that selectively inhibits Na _V 1.8, is orally bioavailable, and has recent FDA approval for the treatment of acute pain is suzetrigine (VX-548, brand name JOURNAVX). Here we tested the effects of this agent on human dorsal root ganglion neurons obtained from either patients undergoing surgical thoracic vertebrectomy or from organ donors in parallel electrophysiology studies across 2 laboratories. Bath application of 10 nM suzetrigine abolished spontaneous discharges previously shown to be associated with on-going neuropathic pain within minutes. In contrast, suppression of discharges evoked by intracellular current injection was moderate. These results suggest that suzetrigine will likely show efficacy vs spontaneous pain but may have less robust effects on evoked or breakthrough pain.

Oncostatin M (OSM), a member of the interleukin 6 (IL-6) pro-inflammatory cytokine family, is upregulated in the dorsal root ganglia of patients with neuropathic pain and thus may be an important contributor to this condition. Although suggested to contribute to itch in mice, the effects of OSM on nociceptive behavior and nociceptors in rats remain undefined. Here we show that a singular intrathecal dose of OSM (10 ng) induces significant mechanical hypersensitivity in both sexes of rats, yet does not alter thermal withdrawal latencies. When applied to cultured rat dorsal root ganglion (DRG) neurons, OSM (10 ng/mL) elicited robust action potential discharges and exaggerated fluctuations in membrane potential that was not mitigated by an IL-6 receptor antagonist. Neurons reactive to OSM typically did not respond to capsaicin, aligning with the behavioral observations. Immunohistochemical analysis revealed frequent co-localization of OSM and its receptor (OSMR) with isolectin B4–positive and calcitonin gene–related peptide–positive DRG neurons, but only scarce co-localization in transient receptor potential vanilloid 1–positive DRG neurons. In a model of paclitaxel chemotherapy–induced peripheral neuropathy, there is a notable increase in DRG neurons expressing OSM or its receptor (OSMR), alongside an upsurge in several OSM/OSMR downstream signaling molecules. These findings suggest that OSM acts as a signal for mechanical nociception and that heightened OSM expression and OSMR signaling in the DRG may be a key factor in the sensitization of specific nociceptor subsets. Consequently, targeting the OSM/OSMR pathway may offer a promising avenue for treatment in particular neuropathic pain phenotypes.

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families but the functional role of these kinases is underexplored. We find that the presynaptic release of the tyrosine-directed ectokinase, vertebrate lonesome kinase (VLK/ Pkdcc ), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses for phosphorylation of the ectodomain of EphB2 and mediation of injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is enriched at synapses and released from neurons in an activity- and soluble N -ethylmaleimide-sensitive factor activating protein receptor (SNARE)–dependent manner to drive extracellular interactions. Our results show that presynaptic sensory neuron–specific VLK knockout attenuates postsurgical pain in mice without changing sensorimotor performance, suggesting that VLK critically regulates synaptic protein-protein interactions and acute pain in response to injury.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types¹, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1^−/−) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

The spinothalamic tract has long been known as a primary conductor of nociceptive information, with its anatomical and physiological understanding evolving over centuries of research. This comprehensive review traces the history of the spinothalamic tract beginning with Brown-Sequard’s 1860 report of contralateral analgesia following a hemisection of the spinal cord. As clinical and surgical interventions, such as cordotomies have advanced, so did our understanding of the spinothalamic tract’s function and anatomy. The spinothalamic tract’s role as a crossed pathway conducting pain and temperature sensations was solidified by the mid-20th century. However, intricate details of its somatotopic arrangement, anatomical distributions and sensory modalities were further refined by subsequent studies. Additionally, by examining complications of cordotomies, such as Ondine’s Curse (central hypoventilation syndrome), urinary and autonomic dysfunction, motor weakness and late-onset new pain, the intricate relationships between the spinothalamic tract, the ascending and descending reticular tracts, the spinocerebellar tracts and other vital pathways governing micturition and autonomic functions were discovered.

Non-selective antagonists of voltage-gated sodium channels (VGSCs) provide effective local analgesia, but systemic administration is fraught with unwanted cardiovascular and central nervous system toxicity. The development of antagonists targeting VGSCs preferentially expressed in peripheral neurons, such as Na _V 1.7, 1.8, and 1.9, could mitigate these risks. One such new small molecule that selectively inhibits Na _V 1.8, is orally bioavailable, and has recent FDA approval for the treatment of acute pain is suzetrigine (VX-548). Here we tested the effects of this agent on human dorsal root ganglion (hDRG) neurons obtained from either patients undergoing surgical thoracic vertebrectomy or from organ donors in parallel electrophysiology studies across 2 laboratories. Bath application of 10 nM suzetrigine abolished spontaneous discharges previously shown to be associated with on-going neuropathic pain within minutes. In contrast, suppression of discharges evoked by intracellular current injection required more prolonged application times. These results suggest that suzetrigine will likely show efficacy versus spontaneous pain but may have less robust effects on evoked or breakthrough pain.