Developing nociceptor-selective treatments for acute and chronic pain

Jayakar, Selwyn S.; Shim, Jaehoon; Jo, Sooyeon; Bean, Bruce P.; Singeç, Ilyas; Woolf, Clifford J.

doi:10.1126/scitranslmed.abj9837

Cited by 34 publications

(34 citation statements)

References 254 publications

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“…Pluripotent and differentiating cells, harvested at different timepoints, were compared to adult human DRG samples. Since pain is associated with structural and functional plasticity 7 , we also included tissue samples obtained from individuals with a clinical history of chronic pain. PCA plots showed that DRG samples clustered together and were distinct from cultured cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nociceptor-selective sodium channels are promising targets to develop new analgesics 7,39 . To test whether hPSC-derived nociceptors could be used in high-throughput fashion, we performed a functional screen using an automated patch-clamp system (Qube 384, Sophion Bioscience).…”

Section: Resultsmentioning

confidence: 99%

“…Development of new analgesics has largely failed over the last decades and the current opioid crisis in the United States underscores the need for effective and safe pain-relieving drugs without abuse liability, tolerance, and other adverse effects 7 . Generation of well-characterized human nociceptors from iPSCs as an inexhaustible source is urgently needed for basic and translational pain research and drug development.…”

Section: Discussionmentioning

confidence: 99%

“…The structure-function relationship is particularly important for polarized neuronal cells and expression and localization of ion channels have distinctive patterns in cell bodies and different axon segments (e.g., proximal versus distal, peripheral versus central projection). Currently, little information is available on ion channel distribution in the DRG system 7 . Streamlined production of pseudo-unipolar sensory neurons from human iPSCs should help to better understand ion channel biology and neuronal excitability with the goal to develop nociceptor-selective analgesics.…”

Section: Discussionmentioning

confidence: 99%

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Scalable Generation of Pseudo-Unipolar Sensory Neurons from Human Pluripotent Stem Cells

Deng

Tristan

Weber

et al. 2022

Preprint

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Development of new non-addictive analgesics requires advanced strategies to differentiate human pluripotent stem cells (hPSCs) into relevant cell types amenable for translational research. Here, we developed a highly efficient and reproducible method that differentiates hPSCs into peptidergic and non-peptidergic nociceptors. By modulating specific cell signaling pathways, hPSCs were first converted into SOX10+ neural crest cells, followed by differentiation into sensory neurons with an in vivo-like pseudo-unipolar morphology. Detailed characterization confirmed that the hPSC-derived nociceptors displayed molecular and cellular features comparable to native dorsal root ganglion (DRG) neurons, and expressed high-threshold primary sensory neuron markers, transcription factors, neuropeptides, and over 150 ion channels and receptors, including critical pain-relevant drug targets (e.g., TRPV1, TAC1, CALCA, NAV1.7, NAV1.8). Moreover, after confirming robust functional activities and differential response to noxious stimuli and specific drugs, a robotic cell culture system was employed to produce large quantities of human sensory neurons, which can be used to develop nociceptor-selective analgesics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Scalable Generation of Pseudo-Unipolar Sensory Neurons from Human Pluripotent Stem Cells

Deng

Tristan

Weber

et al. 2022

Preprint

Self Cite

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“…Also, the use of induced pluripotent stem cell (iPSC)-derived neurons for compound screening is a promising approach to identify novel analgesics [ 112 ]. For example, disease modeling using iPSC-derived neurons from persistent pain patients could be used to identify common pathophysiological alterations that may be responsible for the pain state of subgroups of patients.…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

Sisignano

Gribbon

Geißlinger

2022

Drugs

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Phenotypic Screening of Prospective Analgesics Among FDA‐Approved Compounds using an iPSC‐Based Model of Acute and Chronic Inflammatory Nociception

Black,

Ghazal,

Lojek

et al. 2024

Advanced Science

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Classical target‐based drug screening is low‐throughput, largely subjective, and costly. Phenotypic screening based on in vitro models is increasingly being used to identify candidate compounds that modulate complex cell/tissue functions. Chronic inflammatory nociception, and subsequent chronic pain conditions, affect peripheral sensory neuron activity (e.g., firing of action potentials) through myriad pathways, and remain unaddressed in regard to effective, non‐addictive management/treatment options. Here, a chronic inflammatory nociception model is demonstrated based on induced pluripotent stem cell (iPSC) sensory neurons and glia, co‐cultured on microelectrode arrays (MEAs). iPSC sensory co‐cultures exhibit coordinated spontaneous extracellular action potential (EAP) firing, reaching a stable baseline after ≈27 days in vitro (DIV). Spontaneous and evoked EAP metrics are significantly modulated by 24‐h incubation with tumor necrosis factor‐alpha (TNF‐α), representing an inflammatory phenotype. Compared with positive controls (lidocaine), this model is identified as an “excellent” stand‐alone assay based on a modified Z’ assay quality metric. This model is then used to screen 15 cherry‐picked, off‐label, Food and Drug Administration (FDA)‐approved compounds; 10 of 15 are identified as “hits”. Both hits and “misses” are discussed in turn. In total, this data suggests that iPSC sensory co‐cultures on MEAs may represent a moderate‐to‐high‐throughput assay for drug discovery targeting inflammatory nociception.

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Developing nociceptor-selective treatments for acute and chronic pain

Abstract: Phenotypic screens using human induced pluripotent stem cell–derived nociceptors hold promise for the development of better analgesics.

Cited by 34 publications

References 254 publications

Scalable Generation of Pseudo-Unipolar Sensory Neurons from Human Pluripotent Stem Cells

Scalable Generation of Pseudo-Unipolar Sensory Neurons from Human Pluripotent Stem Cells

Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

Phenotypic Screening of Prospective Analgesics Among FDA‐Approved Compounds using an iPSC‐Based Model of Acute and Chronic Inflammatory Nociception

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