Bradykinin Potentiates the Chemoresponsiveness of Rat Cutaneous C-Fibre Polymodal Nociceptors to Interleukin-2

Abstract

We have recently reported that IL-2 activates a third of cutaneous C-fibre polymodal nociceptors. Responses were dose-dependent and concentration threshold was below 1.2 U/3 µl. Potent tachyphylaxis characterized the response to subsequent injections of the same dose. These nociceptors were also activated by histamine and bradykinin. However, the cross-reactivity between inflammatory mediators was not assessed due to experimental limitations. Nevertheless, we found in preliminary studies that BK enhanced the responsiveness of polymodal nociceptors to IL-2 by reversing IL-2-induced tachyphylaxis and increasing response magnitude. The fact that BK potentiated the responsiveness of nociceptors to a chemical stimulus was unexpected and needed further investigation. In the present study, 40 cutaneous C-fibre polymodal nociceptors were isolated in 26 rat saphenous nerve preparations. Nociceptors were identified by their conduction velocity and response thresholds to electrical, mechanical and thermal stimuli. Two series of experiments were conducted: in the first series of experiments, IL-2 (1.2 U/3 µl) was injected twice prior to BK (150 ng/3 µl) and injected again twice after BK. In the second series of experiments, BK preceded the two injections of IL-2. In the first series of experiments, responses to IL-2 were increased by 55% after BK and this difference was statistically significant in a paired-sample t-test (P<0.02). In the second series of experiments, units responded to IL-2 with a vigorous and irregular (bursting) sustained discharge (255 ± 35 action potentials/300 s) and no tachyphylaxis appeared to the second IL-2 injection. In addition, potent thermal sensitization occurred after BK. Possible cellular and sub-cellular mechanisms of BK-induced potentiation to IL-2 are discussed. We conclude that BK enhances the responsiveness of cutaneous C-fibre polymodal nociceptors to IL-2, which may explain the occurrence of pruritus in the healing process of inflamed skin. ABBREVIATIONS: Interleukin-2 (IL-2); bradykinin (BK); histamine (HIS); acetic acid (AA), action potentials (AP).