Bring on the heat: transient receptor potential vanilloid type‐1 (TRPV‐1) channels as a sensory link for local thermal hyperaemia

Beyond the integumentary system role of human skin, the vascular control of the largest continuous organ in the human body contributes to the defence from temperature extremes. During exercise and/or exposure to high environmental heat, the skin blood flow defence to elevated whole body temperature includes a sympathetic active vasodilator (non-acral skin) pathway which involves the complex integration of neural and local mechanisms. In addition to reflex control of the cutaneous circulation during whole body thermal stress, non-painful locally applied heat evokes a substantial elevation in skin blood flow to near maximal values (Kellogg et al. 1999; Minson et al. 2001). The pattern of this robust vasodilatation can be predictable and is characterized by a distinct initial peak to a nadir before stabilizing at a prolonged plateau. The predictable nature of this response has led to an increased clinical application for describing generalized microvascular function. An altered skin blood flow pattern, or altered contribution of the substances involved, is observed with natural ageing and numerous diseases directly or indirectly linked to microvascular pathologies (Holowatz et al. 2008). The popularization of local skin heating protocols as a clinical tool necessitates a better understanding of the pathways involved. Collectively, research over the last 10 years has identified mechanisms related to efferent responses in human skin with local thermal stimuli. Many experiments dissecting these mechanisms have taken advantage of intradermal microdialysis techniques in combination with laser Doppler flowmetry. These methods allow pharmacological manipulation in a small area of skin (microdialysis), where the subsequent blood flow parameters can be non-invasively monitored (laser Doppler flowmetry). Using these techniques, the mechanisms contributing to this predictable blood flow pattern during local skin heating have been identified to some degree. The initial peak and nadir are dependent upon local axon reflexes, as application of EMLA cream on the skin surface (for non-specific cutaneous nerve block) substantially reduces this steep initial rise and peak in skin blood flow and uncouples the initial peak and nadir from the sustained plateau (Minson et al. 2001). The sustained plateau is dependent upon a robust NO-dependent vasodilatation (Kellogg et al. 1999; Minson et al. 2001). However, a NO-independent elevation in skin blood flow remains during NO synthase inhibition. The integration and interaction of signals from local axon reflexes and signals from vascular sources (i.e. NO) is complex. For example, NO modestly contributes to the intitial peak and nadir but only in the absence of cutaneous nerve blockade with EMLA cream (Minson et al. 2001). With these previously described mechanisms in mind, the investigation of Wong & Fieger (2010) in this issue of The Journal of Physiology has taken up the challenge to identify a link between afferent sensory nerves, responding to local heat application, and the resultant hyperaemia in human skin. To that end, they have demonstrated the activation of a transient receptor potential vanilliod (TRPV-1) channel to be compulsory for the full expression of the thermal hyperaemia to local heating. The TRPV-1 channels are located primarily on afferent sensory nerves in human skin and can be activated by a host of stimuli, including direct heat (Caterina, 2007). The authors’ clever, yet simple approach to the question incorporated pharmacological inhibition of TRPV-1 channels with capsazepine (specific TRPV-1 inhibition) via intradermal microdialysis. In contrast to previous work with EMLA cream, which would render all cutaneous nerves unresponsive, capsazepine appears to specifically inhibit TRVP-1 channels on cutaneous afferent sensory nerves. Using this approach, the authors meticulously investigated the direct effect of TRPV-1 channel inhibition on the resultant local cutaneous hypereamia and the interaction between TRPV-1 channels and NO production. The results clearly suggest a role for TRPV-1 channels, linking the thermal stimulus on the skin surface to the ensuing skin blood flow response. More specifically, TRPV-1 channel inhibition substantially reduced the axon reflex mediated portion of this blood flow pattern, i.e. the initial peak and nadir, while the plateau phase of the response was only modestly affected by TRPV-1 channel inhibition. These data extend what is currently known about the cutaneous blood flow response to local heating. The TRPV-1 channels may be directly activated by heat, thereby depolarizing afferent sensory nerves to initiate the axon reflex portion of the local thermal hyperaemia (Wong & Fieger, 2010). There was also an interesting interaction found between the TRPV-1 channel activation and the role for NO in this response. Worth noting, both the investigation of Wong & Fieger (2010) and the work of Minson et al. (2001) failed to completely block axon reflex mediated skin blood flow responses with capsazepine and EMLA cream, respectively. The question therefore remains, was there an incomplete pharmacological blockade or are there additional mechanisms which contribute to the axon reflex portion of the skin blood flow response? Taken in a wider context, the study by Wong and Fieger went beyond a continued reductionist approach to further dissect the mechanisms for the vascular responses to thermal stimulus in human skin. Their data begin to integrate the afferent sensory mechanisms with the efferent vascular control mechanisms for a more complete description of the skin's defence against external heat application. For this, the authors are to be commended.