Calcitonin gene‐related peptide enhances release of native brain‐derived neurotrophic factor from trigeminal ganglion neurons

Abstract

Activity-dependent plasticity in nociceptive pathways has been implicated in pathomechanisms of chronic pain syndromes. Calcitonin gene-related peptide (CGRP), which is expressed by trigeminal nociceptors, has recently been identified as a key player in the mechanism of migraine headaches. Here we show that CGRP is coexpressed with brain-derived neurotrophic factor (BDNF) in a large subset of adult rat trigeminal ganglion neurons in vivo. Using ELISA in situ, we show that CGRP (1-1000 nM) potently enhances BDNF release from cultured trigeminal neurons. The effect of CGRP is dose-dependent and abolished by pretreatment with CGRP receptor antagonist, CGRP(8-37). Intriguingly, CGRPmediated BDNF release, unlike BDNF release evoked by physiological patterns of electrical stimulation, is independent of extracellular calcium. Depletion of intracellular calcium stores with thapsigargin blocks the CGRP-mediated BDNF release. Using transmission electron microscopy, our study also shows that BDNF-immunoreactivity is present in dense core vesicles of unmyelinated axons and axon terminals in the subnucleus caudalis of the spinal trigeminal nucleus, the primary central target of trigeminal nociceptors. Together, these results reveal a previously unknown role for CGRP in regulating BDNF availability, and point to BDNF as a candidate mediator of trigeminal nociceptive plasticity.

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

“…Ca 2ϩ -dependent release of BDNF has been most well characterized in neurons where this neurotrophin is stored in large dense-core vesicles (Altar and DiStefano, 1998) and released from both presynaptic terminals and postsynaptic dendrites (Balkowiec and Katz, 2002;Kolarow et al, 2007). In nerve terminals, BDNF release triggered by depolarization depends on Ca 2ϩ influx through voltage-gated Ca 2ϩ channels and, as well, on release of Ca 2ϩ from intracellular stores (Lever et al, 2001;Buldyrev et al, 2006). Release of BDNF from postsynaptic dendrites is also mediated by influx of Ca 2ϩ , initiated by opening NMDA receptors or voltage-gated Ca 2ϩ channels (Kolarow et al, 2007).…”

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

“…The increased CGRP plasma levels in migraineurs (Goadsby et al, 1990), which return to baseline after administration of migraine abortive drugs (such as sumatriptan; Durham and Russo, 2002), the fact that injection of CGRP triggers migraine pain in sensitive subjects (Lassen et al, 2002), as well as the efficacy of CGRP antagonists in treating migraine patients (Olesen et al, 2004), demonstrate the important role of CGRP in migraine pathophysiology. More recently, an additional peripheral role for CGRP in sensitizing TG neurons and modulating crosstalk with SGCs has emerged: CGRP releases BDNF from TG neurons (Buldyrev et al, 2006;Simonetti et al, 2008), and stimulates NO and cytokine release form SGCs (Durham, 2008). It is worth mentioning that CGRP acting on TG neurons promotes its own synthesis and release through MAP kinase activation, so that selective MAP kinase inhibitors have been proposed as novel approaches for dampening CGRP levels in migraine (Durham and Russo, 2002;Tajti et al, 2011).…”

“…The primary transduction mechanism activated by CGRP receptors is via adenylyl cyclase, though coupling to phospholipase C with consequent rise in intracellular calcium has also been shown (Buldyrev et al, 2006). To determine whether CGRP could directly activate SGCs, and whether intracellular calcium was involved, we acutely applied 1 M CGRP to primary mixed TG cultures, and observed a calcium increase in 24.3 Ϯ 4.3% of SGCs (n ϭ 24 cells from 2 independent experiments).…”

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

“…In nerve terminals, the release of BDNF is triggered by depolarization that depends upon Ca 2+ influx through voltage-gated Ca 2+ channels, and upon release of Ca 2+ from intracellular stores (Buldyrev et al, 2006;Lever et al, 2003). Release of BDNF from postsynaptic dendrites is also mediated by influx of Ca 2+ , initiated by opening NMDA receptors or voltage-gated Ca 2+ channels (Kolarow et al, 2007).…”