Mechanisms regulating excitability of primary afferent nociceptors

The perception of pain - burning, aching and soreness - acts as a physiological warning that protects us from real or potential injury by employing both behavioural and reflex avoidance responses. Unfortunately, this sensory modality can outlive its usefulness and become chronic and debilitating. Indeed, inflammatory mediators released following tissue trauma can sensitise pain fibres (primary afferent nociceptors) to a diverse range of mechanical, chemical and thermal stimuli. The aim of the present study was to investigate the molecular mechanisms regulating the excitability of primary afferent nociceptors.;The present study has demonstrated that cyclooxygenase-1 (COX-1) was constitutively expressed in a subpopulation of putatively defined nociceptors in the rat dorsal root ganglion (DRG), using immunocytochemical techniques. Consistent with these immunocytochemical findings, sharp-electrode recordings revealed that depolarisations evoked by the inflammatory mediator, bradykinin on cultured rat DRG neurons, were significantly attenuated by selective COX-1 inhibition. These findings suggest that activation of bradykinin receptors in nociceptors, may in addition to activating phospholipase C, also release arachidonic acid, which is then specifically metabolised by COX-1 to synthesise pro-inflammatory prostaglandins.;There is increasing evidence to suggest that inflammatory mediators can regulate neuronal excitability by phosphorylating ion channels expressed on primary afferent nociceptors. However, the identities of the ion channels underlying these effects have not been fully elucidated. The present studies demonstrated the expression and distribution of the inwardly rectifying potassium channel, Kir2.3 and tetrodotoxin-resistant (TTX-R) sodium channel NaV1.8, in a sub-population of putatively defined nociceptors. Using the whole-cell patch clamp technique, it was demonstrated that the inflammatory mediator, bradykinin could modulate the functions of the Kir and TTX-R sodium currents in cultured rat DRG neurons.;Taken together, the results from the present studies have increased our understanding of the molecular mechanisms regulating nociceptor excitability, and as such, may also contribute to the development of more efficacious analgesic therapies