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Abstract
Bradykinin (Bk) is a potent inflammatory mediator that causes hyperalgesia. The action of Bk on the sensory system is well documented but its effects on motoneurons, the final pathway of the motor system, are unknown. By a combination of patch-clamp recordings and two-photon calcium imaging, we found that Bk strongly sensitizes spinal motoneurons. Sensitization was characterized by an increased ability to generate self-sustained spiking in response to excitatory inputs. Our pharmacological study described a dual ionic mechanism to sensitize motoneurons, including inhibition of a barium-sensitive resting K(+) conductance and activation of a nonselective cationic conductance primarily mediated by Na(+). Examination of the upstream signaling pathways provided evidence for postsynaptic activation of B2 receptors, G protein activation of phospholipase C, InsP3 synthesis, and calmodulin activation. This study questions the influence of motoneurons in the assessment of hyperalgesia since the withdrawal motor reflex is commonly used as a surrogate pain model.
Highlights
The nanopeptide bradykinin (Bk) is an important mediator of pain and inflammation (Dray and Perkins, 1993; Calixto et al, 2000)
Bk had no effect on the transient short latency reflexes but recruited a longlasting reflex such that the distribution of peristimulus time histograms (PSTHs) shifted from unimodal to bimodal (Figure 1E,F)
We showed that Bk signaling is independent of Gi or Gs protein by showing that after 7 hr of preincubation with either the Gi inhibitor pertussis toxin (PTX, 2 μg.ml−1) or the Gs inhibitor cholera toxin (CTX, 2 μg.ml−1) the magnitude of Bk responses was not disturbed (CTX: 14.7 ± 2.7 mV, n = 5 cells, p = 0.6; PTX: 16.7 ± 1.8 mV, n = 4 cells p = 0.3; control: 12.9 ± 0.6 mV, n = 54 cells, Mann–Whitney test; data not shown)
Summary
The nanopeptide bradykinin (Bk) is an important mediator of pain and inflammation (Dray and Perkins, 1993; Calixto et al, 2000). It causes hyperalgesia (Manning et al, 1991; Dalmolin et al, 2007) by exciting and/or sensitizing components of the pain pathway, including primary afferent terminals, sensory ganglia, and dorsal horn neurons (Dray and Perkins, 1988; Dray et al, 1988; Thayer et al, 1988; McGuirk and Dolphin, 1992; Rueff and Dray, 1993; Jeftinija, 1994; Cesare et al, 1999; Wang et al, 2005).
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