The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels
Boyi Liu, … , Hailin Zhang, Nikita Gamper
Boyi Liu, … , Hailin Zhang, Nikita Gamper
Published March 24, 2010
Citation Information: J Clin Invest. 2010;120(4):1240-1252. https://doi.org/10.1172/JCI41084.
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The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels

Abstract

Bradykinin (BK) is an inflammatory mediator and one of the most potent endogenous pain-inducing substances. When released at sites of tissue damage or inflammation, or applied exogenously, BK produces acute spontaneous pain and causes hyperalgesia (increased sensitivity to potentially painful stimuli). The mechanisms underlying spontaneous pain induced by BK are poorly understood. Here we report that in small nociceptive neurons from rat dorsal root ganglia, BK, acting through its B2 receptors, PLC, and release of calcium from intracellular stores, robustly inhibits M-type K+ channels and opens Ca2+-activated Cl– channels (CaCCs) encoded by Tmem16a (also known as Ano1). Summation of these two effects accounted for the depolarization and increase in AP firing induced by BK in DRG neurons. Local injection of inhibitors of CaCC and specific M-channel openers both strongly attenuated the nociceptive effect of local injections of BK in rats. These results provide a framework for understanding spontaneous inflammatory pain and may suggest new drug targets for treatment of such pain.

Authors

Boyi Liu, John E. Linley, Xiaona Du, Xuan Zhang, Lezanne Ooi, Hailin Zhang, Nikita Gamper

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Figure 3

BK induces Ca2+ activated CaCC in DRG neurons.

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BK induces Ca2+ activated CaCC in DRG neurons. (A–F) Representative ...
(A–F) Representative current traces showing inward currents induced by BK (200 nM) and CAP (1 μM). Traces were obtained by continuous recording at a holding potential of –60 mV. Dotted lines indicate zero current level. Timing of the BK and CAP application is indicated by black bars; white bars indicate pretreatment with 10 μM Ca2+ channel blocker RR (B and D), 10 μM HCN blocker ZD7288 (E), and 100 μM Cl– channel blocker DIDS (F). (G) Summary for the pharmacology of the BK-induced inward current in DRG. Bars show the peak inward current amplitude induced by the following substances: 1 μM CAP; CAP + 10 μM RR; 200 nM BK; BK + 10 μM RR; BK + 10 μM ZD7288; BK + 100 nM Hoe-140; BK + 10 μM edelfosine; BK + 1 μM Xe-C; BK + 2 μM thapsigargin; BK + high BAPTA pipette solution; BK + low [Cl–]i pipette solution; BK + 100 μM DIDS. The number of experiments is given above each bar in parentheses; **P ≤ 0.01.