Pathological pain results in part from a dysequilibrium between pro- and anti-hyperalgesic
signaling pathways in nociceptive neurons. Many available pain therapies are designed to
inhibit specific pro-hyperalgesic signals or enhance specific anti-hypergesic signals. However,
an alternative approach would be to proportionately redirect endogenous pathological pro-
hyperalgesic signaling towards activation of anti-hyperalgesic pathways. Such an approach
could clamp nociceptive function under evolving pathological conditions, and do so without
compromising protective pain reflexes. In this proposal, we outline a strategy to redirect
signaling from the pro-hyperalgesic TrkA receptor to achieve inhibition of pro-hyperalgesic
cAMP and Ras/Rap driven signaling. We have developed a modular and customizable system,
which we call Inducible Membrane Anchoring (IMA), that operates on the principle that many
effector proteins function most efficiently when recruited to the plasma membrane, where their
targets reside. We will first optimize this system in HEK293 cells, then move to cultured mouse
dorsal root ganglion neurons, to determine if the cAMP and Ras/Rap pathways in those cells
can be controllably modulated in this way. These studies will serve as proof-of-concept for
future application of our hyperalgesic signal-shunting system in animal models in vivo and may
lead to the development of novel therapies for pain. Furthermore, the modularity of our IMA
system makes it adaptable to a wide range of input signals and output effectors. The tools and
concepts that we develop may therefore have utility elsewhere in the nervous system and in
other settings such as cancer and immunology.