| Insulin and insulin-like growth factors (IGFs) maintain vital neuronal functions such as survival, outgrowth, and synaptic integrity. Consequently, their deficiency or resistance in diabetes mellitus leads to changes in peripheral sensation. Vanilloid receptor 1 (also called VR1) is an ion channel, present on sensory neurons, that responds to various noxious stimuli (capsaicin, heat, protons, endocannabinoids and inflammatory mediators). Here we demonstrate that insulin and IGF-I enhance VR1 mediated membrane current by increasing single channel activity and receptor translocation to plasma membrane through a signaling cascade that activates protein kinase C (PKC). Furthermore, we show dysregulation of VR1 in diabetic neuropathy. Diabetic mice exhibiting decreased thermal sensitivity had reduced VR1 expression and receptor-mediated release of the vasodilator, calcitonin gene-related peptide (CGRP), with heat sensation partially restored by IGF-I injection. In contrast, VR1 levels are increased in a subset of mice with hyperalgesia. These studies establish for the first time a link between the insulin family of trophic factors and vanilloid receptors as well as confirm the involvement of VR1 in the pathogenesis of diabetic neuropathy. |
