A Role for TRPV1 in Bradykinin-Induced Excitation of Vagal Airway Afferent Nerve Terminals

Abstract

Using single-unit extracellular recording techniques, we have examined the role of the vanilloid receptor-1 (VR1 aka TRPV1) in bradykinin-induced activation of vagal afferent C-fiber receptive fields in guinea pig isolated airways. Of 17 airway C-fibers tested, 14 responded to bradykinin and capsaicin, 2 fibers responded to neither capsaicin nor bradykinin, and 1 fiber responded to capsaicin but not bradykinin. Thus, every bradykinin-responsive C-fiber was also responsive to capsaicin. Bradykinin (200 l of 0.3 M solution) evoked a burst of approximately 130 action potentials in C-fibers. In the presence of the TRPV1 antagonist capsazepine (10 M), bradykinin evoked 83 Ϯ 9% (n ϭ 6; P Ͻ 0.01) fewer action potentials. Similarly, the TRPV1 blocker, ruthenium red (10 M), inhibited the number of bradykinin-evoked action potentials by 75 Ϯ 10% (n ϭ 4; P Ͻ 0.05). In the presence of 5,8,11,14-eicosatetraynoic acid (10 M), an inhibitor of lipoxygenase and cyclooxygenase enzymes, the number of bradykinin-induced action potentials was reduced by 76 Ϯ 10% (n ϭ 6; P Ͻ 0.05). Similarly, a combination of the 12-lipoxygenase inhibitor, baicalein (10 M) and the 5-lipoxygenase inhibitor ZD2138 [6-[3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone] (10 M) caused significant inhibition of bradykinin-induced responses. Our data suggest a role for lipoxygenase products in bradykinin B 2 receptor-induced activation of TRPV1 in the peripheral terminals of afferent C-fibers within guinea pig trachea.The pharmacological activation of primary afferent neurons often involves the opening of ligand-gated ion channels such as 5-hydroxytryptamine 3 receptors, P2X purinoceptors, nicotinic acetylcholine receptors, and vanilloid receptor 1 (TRPV1), the first cloned capsaicin receptor (Wood and Docherty, 1997). Upon agonist binding to these channels, their ion pore opens, allowing the influx of cations, resulting in a membrane depolarization of sufficient magnitude to initiate action potentials. Bradykinin, an endogenous metabolite of the kallikrein-kinin system often associated with inflammation, also directly activates nociceptive-like afferent neurons, but does so via metabotropic G protein-coupled bradykinin B 2

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

“…Several signaling pathways converge on TRPV1 to modulate its activity and, as shown in this and previous studies, alter neuron excitability (Bhave et al, 2003;Carr et al, 2003;Moriyama et al, 2003;Dai et al, 2004;Ferreira et al, 2004;Liu et al, 2004;Premkumar et al, 2004;Puntambekar et al, 2004). The potential role of TRPV1 in integrating different physical, chemical, and inflammatory signals and the comparatively high number of capsaicin-responsive colon sensory neurons support the relevance of this channel in sensation and visceral nociception.…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Furthermore, 12-LOX is exclusively expressed in platelets, and activated platelets excite nociceptors and induce hyperalgesia (606,641). Further support for the involvement TRPV1 and LOX products was provided by a study on guinea pig vagal afferents in which the action potential-generating effect of bradykinin was diminished by capsazepine or ruthenium red as well as by inhibition of 12-LOX or 5-LOX (88). The effect of bradykinin, however, was not altered by PLA 2 inhibition, similarly to a previous work (162), pointing to a PLA 2 -independent liberation of arachidonic acid in vagal nociceptive nerve endings, perhaps involving DAG lipase.…”

“…Several studies suggest a major involvement of 12-LOX products in bradykinin signaling (88,653,781; see more details in sect. IIC3A).…”

Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses

“…That TRPV1 is important in pathological states is further suggested by its ability to respond, and be potentiated by, multiple stimuli including those that are physical (heat and mechanical) and chemical (e.g., vanilloid compounds and acid). In addition, TRPV1 currents can be potentiated by interactions with G-coupled proteins like the bradykinin receptors (Shin et al, 2002;Sugiura et al, 2002;Carr et al, 2003;Ferreira et al, 2004) and the P2Y2 ATP receptor (Moriyama et al, 2003). It is also important to note that behavioral heat hyperalgesia induced by either complete Freund's adjuvant, carrageenan, or ATP is absent in TRPV1 Ϫ/Ϫ mice (although pretreatment responses are normal) (Caterina et al, 2000;Davis et al, 2000;Moriyama et al, 2003).…”