Transient receptor potential cation channels in visceral sensory pathways

Abstract

The extensive literature on this subject is in direct contrast to the limited range of clinical uses for ligands of the transient receptor potential cation channels (TRPs) in diseases of the viscera. TRPV1 is the most spectacular example of this imbalance, as it is in other systems, but it is nonetheless the only TRP target that is currently targeted clinically in bladder sensory dysfunction. It is not clear why this discrepancy exists, but a likely answer is in the promiscuity of TRPs as sensors and transducers for environmental mechanical and chemical stimuli. This review first describes the different sensory pathways from the viscera, and on which nociceptive and non-nociceptive neurones within these pathways TRPs are expressed. They not only fulfil roles as both mechano- and chemo-sensors on visceral afferents, but also form an effector mechanism for cell activation after activation of GPCR and cytokine receptors. Their role may be markedly changed in diseased states, including chronic pain and inflammation. Pain presents the most obvious potential for further development of therapeutic interventions targeted at TRPs, but forms of inflammation are emerging as likely to benefit also. However, despite much basic research, we are still at the beginning of exploring such potential in visceral sensory pathways.

Keywords: TRP channels; inflammation; mechanosensitivity; pain.

Figure 1

Diagram of ways in which TRPs on visceral afferents may become activated. Environmental mechanical and chemical stimuli may act directly on the channel to increase its probability of opening, allowing cation influx. Alternatively, extracellular mediators such as cytokines and inflammatory mediators may activate them via specific receptors, which recruit a range of intracellular cascades (these are discussed in other articles in this theme). We have evidence that some receptors may preferentially act via opening of sodium channels and some via TRPs. There is also the possibility of closure of potassium channels as a means of increasing excitability.