Nerve growth factor (
NGF) is elevated in certain
chronic pain conditions and is a sufficient stimulus to cause lasting
pain in humans, but the actual mechanisms underlying the persistent effects of
NGF remain incompletely understood. We developed a rat model of
NGF-induced persistent
thermal hyperalgesia and
mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of
NGF. Persistent thermal
hypersensitivity and
mechanical allodynia require de novo protein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar)
injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal
hypersensitivity via peripheral and spinal sites of action and
mechanical allodynia via only a spinal site of action. Therefore,
NGF-evoked thermal and
mechanical allodynia are mediated by spatially distinct mechanisms.
NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased
capsaicin-evoked nocifensive responses, increased
calcitonin gene-related peptide release from hindpaw skin biopsies, and increased
capsaicin-evoked inward current and membrane expression of TRPV1
protein in dorsal root ganglia neurons. Finally, we showed that
NGF treatment increased concentrations of linoleic and
arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active
lipids were reduced by peripheral and
spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that
NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized
lipid TRPV1 agonists.