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Over the past few decades, several studies have demonstrated that insulin, apart from being a pivotal regulator of carbohydrate metabolism, is significantly involved in various neuronal processes such as neural survival, initiation of neurite outgrowth and regulation of neuronal activity. It has also been revealed that neural effects of insulin are mediated by the InsR, which has been demonstrated in the nerve tissue, too. In addition, experiments on cultured rat PSNs demonstrated that insulin may sensitize the nociceptive ion channel, the TRPV1 by increasing the activation of this channel by capsaicin. TRPV1-expressing PSNs comprise over 90% of Cfibre ganglion cells and are involved in pain sensation and implicated in neurogenic inflammatory responses through the release of sensory neuropeptides such as CGRP and SP. Further, it has been suggested that interaction among insulin, the InsR and the TRPV1 expressed in PSNs may contribute to physiological and pathophysiological processes in various organs. Immunohistochemical studies provided further support to this notion by showing a substantial co-localization of the TRPV1 and the InsR in rat and mouse PSNs of unidentified target innervation territories. The expression of the InsR in nociceptive sensory nerves of different organs and tissues may bear of particular interest as regards the modulatory influence of insulin on a variety of tissue processes. Hence, exploring the localization of the InsR in PSNs serving different organs is of critical importance for the further understanding of the role of these particular afferent nerves in physiological and pathological processes. Therefore, the aim of the present experiments summarized in this Thesis was to reveal, by using hodological and immunohistochemical methods, the expression of the InsR in rat cutaneous, muscle, pancreatic and urinary bladder spinal and vagal afferent neurons and its co-localization with the TRPV1. Further, considering the importance of nociceptive PSNs in the pathologies of both the exocrine and endocrine pancreas, we evaluated morphometric and neurochemical properties of identified rat spinal and vagal pancreatic afferent neurons with particular emphasis on the co-localization of the InsR with SP and CGRP. Our results indicate that almost one-half of the visceral and less than one-quarter of somatic PSNs express the InsR. A great majority of these neurons exhibits TRPV1 immunoreactivity. Our quantitative data also show that ~15% of somatic and ~30% of visceral spinal PSNs displayed InsR and TRPV1 co-localization. Additionally, co-localization of the InsR with SP or CGRP was demonstrated in pancreatic spinal and vagal neurons. These findings provide evidence for the co-localization of the InsR and the TRPV1 in somatic and visceral PSNs and demonstrate that a higher proportion of visceral PSNs express the InsR and display InsR-TRPV1 co-localization. Furthermore, our findings also show that a relatively high proportion of pancreatic spinal and vagal PSNs display co-localization of the TRPV1, the InsR and sensory neuropeptides. The findings suggest that insulin may modulate TRPV1 activation and subsequent peptide release from visceral afferents and contribute to nociceptive and inflammatory mechanisms of the viscera.

Morphometric and neurochemical characterization of primary sensory neurons expressing the insulin receptor in the rat