Abstract
Nociceptors sense hazards via plasmalemmal cation channels, including transient receptor potential vanilloid 1 (TRPV1). Nerve growth factor (NGF) sensitises TRPV1 to capsaicin (CAPS), modulates nociceptor excitability and induces thermal hyperalgesia, but cellular mechanisms remain unclear. Confocal microscopy was used to image changes in intracellular Ca2+ concentration ([Ca2+]i) across neuronal populations in dorsal root ganglia (DRG) explants from pirt-GCaMP3 adult mice, which express a fluorescent reporter in their sensory neurons. Raised [Ca2+]i was detected in 84 neurons of three DRG explants exposed to NGF (100 ng/mL) and most (96%) of these were also excited by 1 μM CAPS. NGF elevated [Ca2+]i in about one-third of the neurons stimulated by 1 μM CAPS, whether applied before or after the latter. In neurons excitable by NGF, CAPS-evoked [Ca2+]i signals appeared significantly sooner (e.g., respective lags of 1.0 ± 0.1 and 1.9 ± 0.1 min), were much (>30%) brighter and lasted longer (6.6 ± 0.4 vs. 3.9 ± 0.2 min) relative to those non-responsive to the neurotrophin. CAPS tachyphylaxis lowered signal intensity by ~60% but was largely prevented by NGF. Increasing CAPS from 1 to 10 μM nearly doubled the number of cells activated but only modestly increased the amount co-activated by NGF. In conclusion, a sub-population of the CAPS-sensitive neurons in adult mouse DRG that can be excited by NGF is more sensitive to CAPS, responds with stronger signals and is further sensitised by transient exposure to the neurotrophin.
Highlights
The intricacies of how peripheral sensory nerve fibres elaborated from neurons clustered in dorsal root ganglia (DRG) and trigeminal ganglia (TG) efficiently sense an array of noxious stimuli are intriguing and pose research challenges for developing much-needed pain therapeutics that are effective and safe
Cloning of the CAPS receptor established its identity as transient receptor potential (TRP) vanilloid family member 1 (TRPV1), a non-selective cation channel with preference for Ca2+ that is activated by temperature, extracellular protons plus numerous chemical deterrents [1,3]
Two experimental protocols were devised to test how sensitivity to Nerve growth factor (NGF) might be related to the robustness of responses to CAPS (Figure 1A), employing repeated stimulation of DRG so that signals elicited by various treatments could be compared within the same populations of neurons
Summary
The intricacies of how peripheral sensory nerve fibres elaborated from neurons clustered in dorsal root ganglia (DRG) and trigeminal ganglia (TG) efficiently sense an array of noxious stimuli are intriguing and pose research challenges for developing much-needed pain therapeutics that are effective and safe. Cloning of the CAPS receptor established its identity as TRP vanilloid family member 1 (TRPV1), a non-selective cation channel with preference for Ca2+ that is activated by temperature (threshold 43 ◦ C), extracellular protons plus numerous chemical deterrents [1,3] In rat, it is expressed in just below half of the primary sensory neurons in both DRG and TG, where it functions in the hyper-sensitisation that underlies pain processing. It is concluded that NGF-sensitive nociceptors in ganglia of healthy adult mouse represent a primed population acutely tuned to sense noxious environmental cues They are rapidly sensitised even further by acute exposure to NGF, a likely mechanism for the hyperalgesia associated with its heightened expression during inflammatory pain
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