Sensory Neuron cAMP Signaling in Chronic Pain

AbstractDistinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

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The Role of Voltage-Gated Sodium Channels in Pain Signaling

Physiological Reviews ◽

10.1152/physrev.00052.2017 ◽

2019 ◽

Vol 99 (2) ◽

pp. 1079-1151 ◽

Cited By ~ 95

Author(s):

David L. Bennett ◽

Alex J. Clark ◽

Jianying Huang ◽

Stephen G. Waxman ◽

Sulayman D. Dib-Hajj

Keyword(s):

Chronic Pain ◽

Sodium Channels ◽

Sensory Neuron ◽

Sensory Neurons ◽

Expression Patterns ◽

Sensory Transduction ◽

Gene Variants ◽

Sensory Stimuli ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.

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O-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0601819103 ◽

2006 ◽

Vol 103 (45) ◽

pp. 17030-17035 ◽

Cited By ~ 136

Author(s):

J. Ekberg ◽

A. Jayamanne ◽

C. W. Vaughan ◽

S. Aslan ◽

L. Thomas ◽

...

Keyword(s):

Chronic Pain ◽

Sodium Channels ◽

Sensory Neuron ◽

Pain Behavior ◽

Motor Deficits

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Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0708003105 ◽

2008 ◽

Vol 105 (3) ◽

pp. 1055-1060 ◽

Cited By ~ 96

Author(s):

B. Storek ◽

M. Reinhardt ◽

C. Wang ◽

W. G. M. Janssen ◽

N. M. Harder ◽

...

Keyword(s):

Chronic Pain ◽

Lumbar Puncture ◽

Sensory Neuron

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Cyclic nucleotide signaling in sensory neuron hyperexcitability and chronic pain after nerve injury

Neurobiology of Pain ◽

10.1016/j.ynpai.2019.100028 ◽

2019 ◽

Vol 6 ◽

pp. 100028 ◽

Cited By ~ 12

Author(s):

Ze-Hua Li ◽

Dong Cui ◽

Cheng-Jie Qiu ◽

Xue-Jun Song

Keyword(s):

Chronic Pain ◽

Nerve Injury ◽

Sensory Neuron ◽

Cyclic Nucleotide ◽

Nucleotide Signaling

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Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

10.1101/2020.12.07.414193 ◽

2020 ◽

Author(s):

Jussi Kupari ◽

Dmitry Usoskin ◽

Daohua Lou ◽

Marc Parisien ◽

Yizhou Hu ◽

...

Keyword(s):

Chronic Pain ◽

Dorsal Root Ganglion ◽

Sensory Neuron ◽

Sensory Neurons ◽

Dorsal Root ◽

Species Conservation ◽

Cell Types ◽

Individual Gene ◽

Cellular Origin ◽

Neuronal Types

AbstractDistinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of human chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

Download Full-text