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Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat.

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Omerbašić, Damir 
Smith, Ewan St John  ORCID logo
Moroni, Mirko 
Homfeld, Johanna 
Eigenbrod, Ole 


The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.



calcium imaging, capsaicin receptor, electrophysiology, hyperalgesia, nerve growth factor, nociceptor development, receptor kinase signaling, sensitization, transcriptome assembly, Animals, Ganglia, Spinal, HEK293 Cells, Humans, Ion Channel Gating, Mole Rats, Nerve Growth Factor, Neurons, Nociceptors, Pain, Protein Domains, Proteomics, Receptor, trkA, TRPV Cation Channels

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Elsevier BV
This work was supported by a European Research Council grant (grant 294678 Extremeophile Mammal) to G.R.L. E.S.J.S. acknowledges support from the Alexander von Humboldt foundation.