Add time:08/22/2019         Source:sciencedirect.com

Bradykinin is a potent mediator formed upon tissue damage and inflammation. It can both excite and sensitize nociceptors to heat, mechanical, and chemical stimuli. Two types of bradykinin receptors (B1 and B2) have been identified of which the constitutive B2 receptors mediate most of the acute effects of bradykinin in uninflamed tissues while the B1 receptors are induced and become activated during inflammation. Both receptor subtypes utilize similar signaling pathways including activation of protein kinase C (PKC), elevation of intracellular Ca2+ concentration, and release of arachidonic acid. PKC activation is the major mechanism underlying the neuronal excitatory and heat-sensitizing actions of bradykinin while Ca2+ accumulation induces formation of nitric oxide within sensory neurons which is involved – together with receptor downregulation – in the development of tachyphylaxis of B2 receptor-mediated effects of bradykinin. Nitric oxide, however, may also contribute to the excitatory and sensitizing actions of bradykinin. Cyclooxygenase metabolites of arachidonic acid (prostanoids) may also be involved in both the excitatory and the sensitizing effects of bradykinin. Recently, a new signaling mechanism has been revealed for bradykinin which involves activation of the capsaicin TRPV1 receptor through PKC activation and formation of 12-lipoxygenase products of arachidonic acid. According to a novel hypothesis, the neuronal excitatory action of bradykinin is not a separate effect but in fact a heat response as a result of a massive heat sensitization with a threshold drop below the ambient temperature. Prostanoids can also sensitize nociceptors to heat, mechanical, and chemical stimuli predominantly via the cyclic adenosine 3′,5′-monophosphate–protein kinase A pathway that modulates various membrane channels including Ca2+-dependent or voltage-gated K+ channels, tetrodotoxin-resistant Na+ channels as well as ligand-gated or noxious heat-gated ion channels.

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