Brain-derived neurotrophic factor (
BDNF), a major focus for regenerative
therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of
tyrosine receptor kinase B (TrkB), a major receptor for
BDNF, indicate that certain effects of the
TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among
TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic
pain. A truncated
isoform of the
receptor, TrkB.T1, lacks the intracellular
kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic
pain, and TrkB.T1 inhibition reduces
neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular
calcium in astrocytes, as well as through interactions with
neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic
pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.