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A microfluidic-based model of nociceptor sensitization reveals a direct activation of sensory axons by prostaglandin E2

Georgios Kimourtzis, Natasha Rangwani, Bethan J. Jenkins, Peter A. McNaughton, View ORCID ProfileRamin Raouf
doi: https://doi.org/10.1101/2022.03.18.484883
Georgios Kimourtzis
1Wolfson Centre for Age-Related Diseases, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London UK SE1 1UL
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Natasha Rangwani
1Wolfson Centre for Age-Related Diseases, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London UK SE1 1UL
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Bethan J. Jenkins
1Wolfson Centre for Age-Related Diseases, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London UK SE1 1UL
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Peter A. McNaughton
1Wolfson Centre for Age-Related Diseases, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London UK SE1 1UL
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Ramin Raouf
1Wolfson Centre for Age-Related Diseases, Institute of Psychology, Psychiatry & Neuroscience, King’s College London, London UK SE1 1UL
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  • ORCID record for Ramin Raouf
  • For correspondence: ramin.raouf@kcl.ac.uk
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Abstract

Prostaglandin E2 (PGE2) is one of the major contributors to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of the nociceptive axons is incompletely understood. We used a microfluidic cell culture platform to investigate the changes in responsiveness of sensory axons following treatment with PGE2. We show that the application of PGE2 to fluidically isolated axons leads to sensitization of their responses to depolarising stimuli, and the inclusion of zatebradine, a blocker of HCN channels, blocks this enhancement. However, unexpectedly, we also found that the application of PGE2 to the axons elicited a direct and persistent spiking activity in the sensory neurons. We demonstrate that this persistent activity is due to a direct depolarization of axons by PGE2, which is inhibited by Nav1.8 sodium channel blockers but is mainly refractory to Nav1.7 channel blockade. Both the persistent activity and the membrane depolarization in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Our data indicate that PGE2/EP4/cAMP pathway culminates in a sustained depolarization in the sensory axons, leading to the generation of action potentials propagating to the soma. PGE2 therefore, not only mediates nociceptor sensitization but can directly elicit discharges in nociceptive axons, hence redefining its role as a pain mediator in inflammatory conditions.

One Sentence Summary Prostaglandin E2 can depolarise nociceptive axons in the absence of any noxious stimuli leading to a sustained activation of pain sensing neurons.

Competing Interest Statement

P.A.M. is involved in a drug discovery programme in collaboration with Merck & Co, Inc, to develop HCN2-selective molecules as novel analgesics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 19, 2022.
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A microfluidic-based model of nociceptor sensitization reveals a direct activation of sensory axons by prostaglandin E2
Georgios Kimourtzis, Natasha Rangwani, Bethan J. Jenkins, Peter A. McNaughton, Ramin Raouf
bioRxiv 2022.03.18.484883; doi: https://doi.org/10.1101/2022.03.18.484883
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A microfluidic-based model of nociceptor sensitization reveals a direct activation of sensory axons by prostaglandin E2
Georgios Kimourtzis, Natasha Rangwani, Bethan J. Jenkins, Peter A. McNaughton, Ramin Raouf
bioRxiv 2022.03.18.484883; doi: https://doi.org/10.1101/2022.03.18.484883

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