Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor

JK Bonnington, PA McNaughton - The Journal of physiology, 2003 - Wiley Online Library
JK Bonnington, PA McNaughton
The Journal of physiology, 2003Wiley Online Library
Nerve growth factor (NGF) causes a rapid sensitisation of nociceptive sensory neurones to
painful thermal stimuli owing to an action on the heat and capsaicin receptor TRPV1
(formerly known as VR1). We have developed a new technique to study this rapid
sensitisation of TRPV1 by monitoring the effects of NGF on the increase in intracellular
calcium concentration ([Ca2+] i) following exposure to capsaicin. Brief applications of
capsaicin caused a rise in [Ca2+] i, and NGF was found to enhance this rise in 37% of …
Nerve growth factor (NGF) causes a rapid sensitisation of nociceptive sensory neurones to painful thermal stimuli owing to an action on the heat and capsaicin receptor TRPV1 (formerly known as VR1). We have developed a new technique to study this rapid sensitisation of TRPV1 by monitoring the effects of NGF on the increase in intracellular calcium concentration ([Ca2+]i) following exposure to capsaicin. Brief applications of capsaicin caused a rise in [Ca2+]i, and NGF was found to enhance this rise in 37 % of capsaicin‐responsive neurones within 2 min. Pathways responsible for transducing the sensitisation of TRPV1 by TrkA, the NGF receptor, were characterised by observing the effects of inhibitors of key members of NGF‐activated second messenger signalling cascades. Specific inhibitors of the ras/MEK (mitogen‐activated protein and extracellular signal‐regulated kinases) pathway and of phospholipase C did not abolish the NGF‐induced sensitisation, but wortmannin, a specific inhibitor of phosphatidylinositol‐3‐kinase (PI3K), totally abolished the effect of NGF. Pharmacological blockade of protein kinase C (PKC) or calcium‐calmodulin‐dependent protein kinase II (CaMK II) activation also prevented NGF‐induced sensitisation, while blockade of protein kinase A (PKA) was without effect. These data indicate that the crucial early pathway activated by NGF involves PI3K, while PKC and CaMK II are also involved, probably at subsequent stages of the NGF‐activated signalling pathway.
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