Abstract
Nerve growth factor (NGF) is known to intensify pain in various ways, so perturbing pertinent effects without negating its essential influences on neuronal functions could help the search for much-needed analgesics. Towards this goal, cultured neurons from neonatal rat trigeminal ganglia—a locus for craniofacial sensory nerves—were used to examine how NGF affects the Ca2+-dependent release of a pain mediator, calcitonin gene-related peptide (CGRP), that is triggered by activating a key signal transducer, transient receptor potential vanilloid 1 (TRPV1) with capsaicin (CAP). Measurements utilised neurons fed with or deprived of NGF for 2 days. Acute re-introduction of NGF induced Ca2+-dependent CGRP exocytosis that was inhibited by botulinum neurotoxin type A (BoNT/A) or a chimera of/E and/A (/EA), which truncated SNAP-25 (synaptosomal-associated protein with Mr = 25 k) at distinct sites. NGF additionally caused a Ca2+-independent enhancement of the neuropeptide release evoked by low concentrations (<100 nM) of CAP, but only marginally increased the peak response to ≥100 nM. Notably, BoNT/A inhibited CGRP exocytosis evoked by low but not high CAP concentrations, whereas/EA effectively reduced responses up to 1 µM CAP and inhibited to a greater extent its enhancement by NGF. In addition to establishing that sensitisation of sensory neurons to CAP by NGF is dependent on SNARE-mediated membrane fusion, insights were gleaned into the differential ability of two regions in the C-terminus of SNAP-25 (181–197 and 198–206) to support CAP-evoked Ca2+-dependent exocytosis at different intensities of stimulation.
Highlights
The neurotrophin, nerve growth factor (NGF), influences many functional aspects of neurons [1,2] with its intriguing roles in pain signalling being of particular interest [3,4]
Binding of CAP causes the opening of a channel in transient receptor potential vanilloid receptor 1 (TRPV1) that conducts Ca2+ into neurons, and microscopic imaging of dorsal root ganglia (DRG) neurons (DRGNs) or trigeminal ganglion neurons (TGNs) loaded with Ca2+-sensitive fluorescent dyes is a convenient method to study this nociceptive process [8,32]
Amongst the factors released during chronic inflammation that contribute to persistent intransigent pain, NGF signalling has emerged as a prime candidate for therapeutic interventions [3,4]
Summary
The neurotrophin, nerve growth factor (NGF), influences many functional aspects of neurons [1,2] with its intriguing roles in pain signalling being of particular interest [3,4]. One of the most intensively studied sensors expressed in nociceptors is the transient receptor potential vanilloid receptor 1 (TRPV1), a non-selective cation channel that is activated by noxious heat (>43 ◦C), protons and various chemicals including capsaicin (CAP), the component of chilli peppers responsible for causing heat sensation [7]. These activators open a channel pore in TRPV1 to permit an influx of Na+ and Ca2+. The resultant hypersensitivity of nociceptors can contribute to persistent chronic pain
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