Research ArticlePain

Brain-derived neurotrophic factor stimulation of T-type Ca2+ channels in sensory neurons contributes to increased peripheral pain sensitivity

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Science Signaling  24 Sep 2019:
Vol. 12, Issue 600, eaaw2300
DOI: 10.1126/scisignal.aaw2300

Treating neuralgias

The trigeminal ganglion (TG) is a cluster of neurons near the temporal bone that provides nociceptive sensation in the head and is associated with various pain disorders, including migraine and trigeminal neuralgia. Increased expression of the neurotrophic factor BDNF and its receptor TrkB is implicated in the heightened sensitivity of the TG. Wang et al. uncovered a cross-pathway kinase cascade through which BDNF-TrkB sensitizes the TG to mechanical and inflammatory stimuli. The pathway triggered the opening of a subtype of Ca2+ channels, and the consequent pain-associated behavior in rats was diminished by intra-TG injection with respective channel blockers or kinase inhibitors. These findings may be relevant to patients that suffer from TG-associated neuralgias and may lead to the development of effective therapies.


Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Cav3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.

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