The enigma of potassium ion in the management of dentine hypersensitivity: is nitric oxide the elusive second messenger?

摘要

We report the development of a 'second-messenger' model in an attempt to re-evaluate the role of K+ as a desensitising agent. Despite unequivocal validation of the effectiveness of potassium-based dentifrices in the management of dentine hypersensitivity, the mechanism(s) of action of K+ remains unclear. Although experimental paradigms of the Nernst equation demonstrate a direct inhibitory effect of K+ ion upon nerve conduction, in vivo considerable constraints can be argued to preclude this mechanism of action. Indeed, measurements of solution velocity within individual dentinal tubules obtained by scanning electrochemical microscopy indicate that outward movement of tubular fluid may represent a far greater barrier to the inward diffusion of K+ ions than previously estimated from measurements of hydraulic conductance across bulk dentine. Despite such probable limited penetration of dentine tubules, K+ ions may desensitise deeply-located nerve terminals through activation of a second-messenger transduction pathway that is capable of controlling the gain of K+-evoked effects which remain physically restricted to the more superficial aspects of the tubule. In addition to a direct effect upon transmembrane potential K+ can also indirectly attenuate neural activity through effects upon levels of the endogenously-synthesised free radical, nitric oxide (NO). Stimulation of the release of NO by K+ has been observed using a variety of cell preparations, which include endothelium, smooth muscle, adrenal medulla, hypothalamus and cerebellum. Importantly, a growing number of studies now report that an increase in the production of NO is associated with analgesia through a modulation of nociceptive input and a downregulation of sensitised nociceptors, most likely achieved through an increase in intraneural content of cGMP. The clinical role of a K+-evoked liberation of NO as a principal mechanism in the management of dentine hypersensitivity is supported by recent findings which include: (1) the localisation of NADPH-diaphorase activity and inducible nitric oxide synthase (iNOS) immunoreactivity within odontoblasts, their processes in dentine, and the subodontoblast layer of the pulp; (2) iNOS causes a sustained release of large (nanomolar) amounts of NO; (3) NO is freely diffusible and capable of displaying remarkably potent effector actions at distant target cells; (4) the actions of NO may be enhanced by endogenous carrier molecules such as S-nitrosothiols; (5) the synthesis of NO can be evoked by concentrations of K+ ion far less (i.e. <1 mM) than those required for direct inhibitory effects upon neural activity.