Sensitizing effects of bradykinin on the heat responses of the visceral nociceptor

Abstract

1. Whether bradykinin (BK), which is known as an endogenous pain-producing substance, induces augmentation of the discharges of polymodal receptors evoked by heat stimulation was investigated in in vitro canine testis-superior spermatic nerve preparations. 2. The heat response was significantly augmented by pretreatments with BK at concentrations greater than 0.094 nM, whereas BK induced significant increases in the mean discharge rates at concentrations above 9.4 nM. Both effects increased in a concentration-dependent manner. The augmenting effect of BK on the heat response diminished within 10 min after application of BK, regardless of concentration. 3. When 9.4 nM BK was applied in a mixture with 940 nM NPC349, a B2 receptor antagonist, the averaged mean discharge rate evoked by BK and the averaged augmenting effect were both significantly suppressed compared with those induced by BK given alone. 4. The augmenting effect of BK on the heat response of polymodal receptors could be observed even in the absence of BK-evoked discharges per se in several cases in which low concentrations of BK or BK plus B2 antagonists were given. 5. These findings suggest that the augmenting effects of BK on the heat response depend on B2 receptor-mediated intracellular processes acting in parallel to, but not directly on, the impulse-generation mechanism of the heat response of the polymodal receptor.

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia

“…BK both activates (17) and sensitizes (20) sensory neurons. In the present study, it appears that capsaicin receptors are activated by BK, which would be consistent with the suggestion that 12-HPETE acts as an agonist of VR1 (5).…”

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

“…Lower concentrations of bradykinin are required for the heat-sensitizing effect than for the excitatory one (392). The heat-sensitizing effect of bradykinin was shown to be more sustained than the excitatory one (465) and could occur in the absence of bradykinin-induced discharge activity (46,350,392). A strong correlation was found between the degrees of heat sensitization and excitation by bradykinin both in the canine testis and rat skin preparations (392,431).…”

“…The high-threshold mechanosensitive C-fibers were not excited by bradykinin, but 50% of them gained transient heat sensitivity following bradykinin treatment, indicating a de novo recruitment of heat responsiveness by the agent. Low pH-induced current in DRG neurons In the isolated canine testis-spermatic nerve preparation, bradykinin enhanced the number of spikes evoked by heat stimulation of the A␦ polymodal nociceptors (392). This augmenting effect could be induced by 100 times lower concentration than required for inducing spike discharge of nociceptors, and it was short-lived, outlasting the bradykinin superfusion for no more than 10 min; it was suppressed by a B 2 receptor antagonist.…”

“…This hypothesis would explain why a major contribution of PKC activation was revealed in studies employing short bradykinin exposures, whereas a predominant role of COX products became evident after a prolonged bradykinin superfusion. It is worth mentioning that COX inhibition failed to diminish bradykinin-induced heat sensitization in rat testicular and tail nociceptors in vitro (392,616). It should be kept in mind, however, that a cross-talk between the PKC and cAMP-PKA pathways has been revealed as phorbol ester-induced activation of PKC led to activation of adenylyl cyclase (AC) in various cell types including rat DRG neurons (662).…”

“…IID1A). Lower concentrations of bradykinin are required for the heat-sensitizing effect than for the excitatory one (392). The heat-sensitizing effect of bradykinin was shown to be more sustained than the excitatory one (465) and could occur in the absence of bradykinin-induced discharge activity (46,350,392).…”