Abstract

Nerve Growth Factor (NGF) has been implicated as playing a significant role in the generation and maintenance of the nociceptive pain associated with a variety of human diseases. NGF is thought to signal primarily through binding to tropomyosin receptor kinase A (TrkA) which triggers subsequent downstream upregulation of various cellular processes implicated in neuronal hypersensitization, including upregulation of Brain Derived Neurotrophic Factor (BDNF) and its cognate receptor tropomyosin receptor kinase B (TrkB) in subpopulations of neurons in the DRG and their terminals in the spinal dorsal horn. Despite extensive study, the relative contributions of the NGF/TrkA axis and the BDNF/TrkB axis to various peripheral pain states remains poorly understood. To address this, we have developed potent, highly selective small molecules that inhibit TrkA kinase by allosteric modulation or the entire TrkA / TrkB / TrkC kinase axis in concert by binding to the ATP site. Moreover, these inhibitors demonstrate good oral exposure in rodents and maintain high peripheral distribution relative to CNS making them useful tools for separating peripheral vs CNS contributions of the NGF/TrkA and BDNF/TrkB axis. Herein the effects of these two distinct classes of Trk inhibitors in a rodent model of peripheral pain are discussed. In the model tested, inhibition of the TrkA receptor via allosteric modulation was sufficient to demonstrate significant and sustained relief of nociceptive pain. There was no observed benefit to simultaneously inhibiting the BDNF/TrkB axis. Furthermore these studies suggest that potent, selective small molecule inhibitors of the TrkA receptor may provide a novel therapeutic approach to pain management.