Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin

Abstract

The initial skin blood flow response to rapid local heating is an axon reflex, which may be mediated by calcitonin gene-related peptide and substance P released from C-fibres. We investigated the role of nitric oxide (NO) and noradrenaline on the temperature threshold for the axon reflex during gradual local heating. 36 subjects participated in two studies. Using microdialysis, we examined the following interventions: NO synthase inhibition (10 mM N(G)-nitro-L-arginine methyl ester, L-NAME); low-dose NO infusion (1.0 microM sodium nitroprusside, SNP); adrenergic blockade (10 mM bretylium tosylate); and low-dose (0.1 microM) noradrenaline infusion. Laser-Doppler flowmetry was used to measure red blood cell flux. Skin was heated at a rate of 0.1 degrees C min(-1) from 33 degrees C to 40 degrees C. Compared to control skin sites, the axon reflex response was shifted to a higher temperature in 4 subjects in the L-NAME sites (control, 37.0 +/- 0.3 degrees C, n = 16; L-NAME, 39.8 +/- 0.1 degrees C, n = 4; P < 0.001) and absent in 12 subjects. The response was also absent in L-NAME plus low-dose SNP sites and not altered by low-dose SNP infusion alone. Adrenergic blockade, with and without low-dose noradrenaline infusion, also abolished the axon reflex response in all subjects. Low-dose noradrenaline infusion alone shifted the axon reflex to a significantly lower temperature threshold compared to control sites (control, 38.2 +/- 0.5 degrees C; noradrenaline, 37.7 +/- 0.4 degrees C, P < 0.05, n = 5). These results suggest that endogenous NO and noradrenaline contribute to the temperature threshold of the axon reflex response during gradual local heating of the skin.

Figures

Figure 1. Representative tracing of the skin blood flow response as a function of local heater temperature between the control (♦) and l-NAME (⋄) sites

The axon reflex response was absent in 12 out of 16 subjects at the l-NAME site.

Figure 2. Representative tracing of the skin blood flow response as a function of local heater temperature between the control (♦) and l-NAME plus low-dose SNP sites

Figure 3. Temperature threshold (mean ± s.e.m.) for the onset of the axon reflex between the control and l-NAME sites

The threshold for the axon reflex was shifted to a higher temperature at the l-NAME site compared to the control site in 4 subjects (P < 0.05).

Figure 4. Representative tracing of the skin blood flow response as a function of local heater temperature between the control (•) and bretylium tosylate (○) sites

The axon reflex response was absent in all subjects at sites infused with bretylium tosylate alone or with low-dose noradrenaline.

Figure 5. Representative tracing of the skin blood flow response as a function of local heater temperature between the control (•) and low-dose noradrenaline (○) sites

Exogenous noradrenaline without adrenergic blockade shifted the axon reflex response to a lower temperature in comparison to control conditions (P < 0.05).

Figure 6. Temperature threshold (mean ± s.e.m.) for the onset of the axon reflex between the control and low-dose noradrenaline sites

Noradrenaline infusion alone significantly shifted the threshold for the axon reflex to a lower temperature compared to control conditions (P < 0.05).