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 molerat
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.