Altered thermal hyperaemia in human skin by prior desensitization of neurokinin-1 receptors.

Abstract

The neuropeptides substance P (SP) and calcitonin gene-related peptide are believed to be involved in the axon reflex-mediated component of cutaneous thermal hyperaemia, but no studies have specifically addressed this issue. The purpose of this study was to determine whether neurokinin-1 receptors, which preferentially bind SP, contribute to the axon reflex component of cutaneous thermal hyperaemia. Nine subjects were equipped with four microdialysis fibres, and each fibre received one of the following four treatments: (1) lactated Ringer's solution (control); (2) 10 mml-NAME to inhibit nitric oxide synthase; (3) 10 μm SP; or (4) 10 μm SP + 10 mml-NAME. Skin blood flow was monitored via laser-Doppler flowmetry, and local skin temperature was controlled using local heating devices. Sites 3 and 4 were perfused with 10 μm SP for 15 min at a rate of 4 μl min(-1), and the ensuing vasodilatation was allowed to return to baseline. Following SP-induced vasodilatation, all skin sites were locally heated from a baseline temperature of 33°C to 42°C at a rate of 0.5°C every 5 s. Cutaneous vascular conductance (CVC) was calculated as skin blood flow/mean arterial pressure and normalized to the maximal value (%CVC(max)) via 28 mm nitroprusside and local heating to 43°C. The initial peak did not differ between control (79 ± 3%CVC(max)) and SP-only sites (79 ± 2%CVC(max)). The initial peaks at the l-NAME (43 ± 3%CVC(max)) and SP + l-NAME sites (53 ± 3%CVC(max)) were significantly reduced compared with both the control and the SP-only sites (P < 0.001 for both), and l-NAME sites were attenuated compared with SP + l-NAME sites (P < 0.01). There was no observable nadir response at sites pretreated with SP. Compared with control sites (57 ± 4%CVC(max)), the nadirs at the l-NAME (14 ± 2%CVC(max)) and the SP + l-NAME sites (31 ± 5%CVC(max)) were significantly reduced (P < 0.01 for all conditions). l-NAME significantly reduced the nadir compared with SP + l-NAME (P < 0.01). Plateau CVC values did not differ between control (86 ± 3%CVC(max)) and SP sites (91 ± 1%CVC(max)). At l-NAME (36 ± 4%CVC(max)) and SP +l-NAME sites (56 ± 6%CVC(max)), plateau CVC was significantly reduced compared with control and SP-only sites (P < 0.01 for all conditions). The plateau at l-NAME sites was significantly reduced compared with SP + l-NAME sites (P < 0.01). These data suggest that neurokinin-1 receptors contribute to both the axon reflex component and the secondary plateau phase of cutaneous thermal hyperaemia.