Human cells and networks of pain: Transforming pain target identification and therapeutic development

Renthal, William; Chamessian, Alexander; Curatolo, Michele; Davidson, Steve; Burton, Michael D.; Dib‐Hajj, Sulayman D.; Dougherty, Patrick M.; Ebert, Allison D.; Gereau, Robert W.; Ghetti, Andre; Gold, Michael S.; Hoben, Gwendolyn M.; Menichella, Daniela; Mercier, Philippe; Ray, Wilson Z.; Salvemini, Daniela; Seal, Rebecca P.; Waxman, Stephen G.; Woolf, Clifford J.; Stucky, Cheryl L.; Price, Theodore J.

doi:10.1016/j.neuron.2021.04.005

Cited by 56 publications

(35 citation statements)

References 11 publications

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“…Finally, this dataset can be a foundation to more thoroughly vet targets that have been discovered in studies of peripheral nerves in animal pain models. Our findings now make it possible for conservation of gene expression in human nociceptors to be a first step in de-risking pain targets for future drug development (4).…”

Section: Discussionmentioning

confidence: 93%

“…Because sex differences in pain mechanisms are increasingly recognized (24, 25), we performed our studies with an equal number of male and female samples. We anticipate that our data will advance our understanding of molecular pain mechanisms in humans and create a new path forward for pain and itch therapeutic development (4).…”

Section: Introductionmentioning

confidence: 97%

“…While some new mechanism-based therapeutics have recently been approved for treatment of pain, these were developed based on biochemical observations in clinical studies, such as the calcitonin gene-related peptide (CGRP) link to migraine headache (2). There has been an unsatisfying failure to translate preclinical work on peripheral pain mechanisms, which has largely been done in rodents, into effective pain therapeutics (3, 4). A potential explanation for this failure to translate is that important species differences in nociceptor molecular phenotypes exist between mice and humans, an idea partially supported by bulk RNA sequencing experiments (5, 6), and other lines of evidence (7, 8).…”

Section: Introductionmentioning

confidence: 99%

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Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

Tavares‐Ferreira

Shiers

Ray

et al. 2021

Preprint

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Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. Equivalent information from human nociceptors is lacking. We used spatial transcriptomics to molecularly characterize transcriptomes of single dorsal root ganglion (DRG) neurons from 8 organ donors. We identified 10 clusters of human sensory neurons, 6 of which are C nociceptors, 1 Aβ nociceptor, 1 Aδ, and 2 Aβ subtypes. These neuron subtypes have distinct expression profiles from rodents and non-human primates and we identify new markers for each of these subtypes that can be applied broadly in human studies. We also identify sex differences, including a marked increase in CALCA expression in female putative itch nociceptors. Our data open the door to new pain targets and unparalleled molecular characterization of clinical sensory disorders.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

Tavares‐Ferreira

Shiers

Ray

et al. 2021

Preprint

Self Cite

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“…The present study suggests that there could be mechanistic heterogeneity yet to be identified to explain this variability in manifestations ( McCarthy et al, 2012 ), as has been suggested for convergent/divergent trajectories in pain development between the sexes ( Mogil, 2012 ). Moving forward, the formation of a translational pain research consortium as proposed by Renthal et al ( Renthal et al, 2021 ) could prove invaluable in providing the samples and tools necessary to understanding mechanisms underlying the variability in pain development.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in patterns of pain development after nerve injury in rats and the influence of sex

Sherman

Woyach

Eisenach

et al. 2021

Neurobiology of Pain

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“…Given the societal need but lagging pace of discovery for safe and efficacious analgesics, concern has arisen over the perceived obstacle of significant species differences between rodent models and humans. This has led to an acceleration of research effort aimed at investigating human tissues directly (27). Unprecedented recent characterization of human dorsal root ganglia through gene analysis (28) and physiological studies with live human sensory neurons in vitro (29)(30)(31)(32) have begun to draw comparisons and some contrasts with the rodent literature.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity

et al. 2021

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Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system. Anatomical characterization of in situ gene expression and immunoreactivity showed that 61 and 53% of human sensory neurons express the CB1 gene and receptor, respectively. Calcium influx evoked by the algogen capsaicin was measured by Fura-2AM in dissociated human sensory neurons pre-exposed to the inflammatory mediator prostaglandin E2 (PGE2) alone or together with CB13 (1 μM), a cannabinoid agonist with limited blood–brain barrier permeability. Both a higher proportion of neurons and a greater magnitude of response to capsaicin were observed after exposure to CB13, indicating cannabinoid-mediated sensitization. In contrast, membrane properties measured by patch-clamp electrophysiology demonstrated that CB13 suppressed excitability and reduced action potential discharge in PGE2-pre-incubated sensory neurons, suggesting the suppression of sensitization. This bidirectional modulation of sensory neuron activity suggests that cannabinoids may suppress overall membrane excitability while simultaneously enhancing responsivity to TRPV1-mediated stimuli. We conclude that peripherally restricted cannabinoids may have both pro- and anti-nociceptive effects in human sensory neurons.

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Human cells and networks of pain: Transforming pain target identification and therapeutic development

Cited by 56 publications

References 11 publications

Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

Heterogeneity in patterns of pain development after nerve injury in rats and the influence of sex

Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity

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