Some new insights into the molecular mechanisms of pain perception

Abstract

Bradykinin is the most potent endogenous inducer of acute pain. However, the way in which it excites nociceptive sensory nerve endings is still unclear. In an article recently published in the JCI, Liu et al. suggest a new mechanism via which bradykinin induces acute spontaneous pain. The authors report that the stimulation of B2 bradykinin receptors by bradykinin triggers the release of intracellular calcium ions from nociceptive sensory neurons of rat dorsal root ganglia. This depolarizes the sensory nerve endings by simultaneously closing M-type potassium channels and opening TMEM16A chloride channels, resulting in the production of nociceptive signals. Here, we discuss the relationship between this effect and a previously described mechanism for pain sensitization and evaluate its potential significance for therapeutic pain control. A separate study by Patwardhan et al. in this issue of the JCI identifies oxidized linoleic acid metabolites as novel mediators of thermally induced pain.

Figure 1. Pathway of bradykinin formation.

Bradykinin is formed by the interaction of factor XII, prekallikrein, and high-molecular-weight kininogen. The 9–amino acid sequence of bradykinin is shown in red. See ref. for further details.

Figure 2. Pain generation and sensitization.

The schematic illustrates the bifurcating pathways to acute pain generation (left), as recently reported in the JCI by Liu et al. (5), and pain sensitization (right; ref. 4), following stimulation of B₂ receptors by bradykinin. The two responses result from the generation of different second messengers following Gq/phospholipase-activated phosphoinositide hydrolysis. IP₃R, IP₃ receptor; PLCβ, phospholipase Cβ.