Holger Sann

Regulation of Efferent Functions of C-Fiber Nociceptors

C-fiber nociceptors serve not only afferent but also local efferent functions. These local efferent functions are mediated by the local release of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide (CGRP) from the peripheral endings of C-fiber nociceptors. These peptides induce different reactions of small peripheral vessels such as vasodilatation, flare reaction, and plasma extravasation, which characterize neurogenic inflammation, but the induction, maintenance, and duration of this reaction vary among animal species. CGRP is the main mediator of the flare reaction in mammalian skin. In pig skin, vasodilatation results from the activation of specific heat nociceptors. Plasma extravasation in pig skin determined by means of blister base perfusion or by microdialysis can be evoked by histamine but not by electrical stimulation or capsaicin. The neurogenic component of the histamine response appears to be mediated via NK2 receptors and can be modulated by CORP. Further inhibitory modulation of plasma extravasation by exogenous galanin was observed in pig skin. In pigeons, antidromic vasodilatation was unmasked and plasma extravasation was enhanced by the galanin receptor antagonist M35, indicating an inhibitory action of endogenous galanin. The efferent function of C-fiber afferents appears also to be dependent on trophic factors. Binding of endogenous nerve growth factor (NGF) by the fusion molecule trkA-IgG resulted in a marked decrease of neurogenic plasma extravasation in pig skin. There is evidence that sensory neuropeptides can also sensitize or stimulate nociceptors. Certain aspects of hyperalgesia appear to be caused by altered functions of C-fiber nociceptors. In essence, the efferent functions of C-fiber nociceptors appear to be precisely regulated, and interactions of coreleased sensory neuropeptides as well as trophic factors appear to play a key role for this regulation.