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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Research Article

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 8

M channel openers and CaCC blockers attenuate BK-induced nocifensive behavior.

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M channel openers and CaCC blockers attenuate BK-induced nocifensive beh...
(A) Cl– channel blockers NPPB (10 nmol/site), NFA (50 nmol/site), DIDS (50 nmol/site), or M channel opener retigabine (RTG, 5 nmol/site) or vehicles (DMSO, Veh1; NaHCO3, Veh2) were dissolved in saline and injected into the rat hind paw 5 minutes before the injection of BK (10 nmol/site) or saline in 50 μl (second injection was done into the same site). Nocifensive behavior was quantified as the time spent licking, biting, and flinching during 30 minutes. n = 7 for each group. (B) RR attenuated CAP- but not BK-induced nocifensive behavior. RR (50 nmol/site) or vehicle were preinjected 5 minutes prior to CAP or BK injection; n = 8 for each group. (C) Injection of M channel blocker XE991 (30 nmol/site) induced nocifensive behavior and attenuated BK-induced nociception. XE991 or vehicle control were injected into the plantar surface of the right hind paw either on their own or as pretreatment prior to BK injection; n = 7 for each group. *P ≤ 0.05; **P ≤ 0.01.