Interactions of histamine and bradykinin on polymodal C-fibres in isolated rat skin

Patients suffering from pruritus due to atopic dermatitis show, in asymptomatic skin, reduced itch and flare responses to histamine, the major pruritogenic mediator. We hypothesized that this apparent loss in histamine sensitivity may be overcompensated in inflamed skin and investigated the interactions between histamine and bradykinin, the major inflammatory mediator. The studies were performed using the isolated rat skin-nerve preparation. Forty-two fibres were tested following four different experimental protocols. After characterization of the sensory properties, six fibres were treated repetitively with histamine (HIS1, HIS2) to exclude the possibility that the responses (spikes/min) increase simply by repetition. In 12 other units, histamine (HIS1) was followed by a wash-out period prior to bradykinin (BK) stimulation; in another 12 units, BK followed immediately after HIS1. A further 12 fibres were examined without preceding heat stimulation in order to avoid possible sensitization. If BK was administered after a wash-out period following HIS1, the BK responses were significantly higher than the HIS1 response. The BK response showed a peak discharge which was absent if BK followed directly upon HIS1. If HIS2 was applied directly following BK, the induced discharge was significantly larger than the first histamine response and not different from the BK response, whereas a washout period before HIS2 abolished the sensitizing effect of previous BK.A unidirectional sensitization by previous bradykinin or heat stimulation on the histamine responsiveness of polymodal nociceptors has been demonstrated. If 'itch fibres' in humans were subject to similar interactions of histamine with inflammatory mediators, this may compensate for a down-regulation of histamine receptors in eczematic skin and possibly account for the pruritus.