How important are NK1 receptors for influencing microvascular inflammation and itch in the skin? Studies using Phoneutria nigriventer venom
Introduction
The skin is equipped with a dense network of specialised afferent SP-containing sensory neurons that can be found in all layers (Stander et al., 2003). According to SP-like immunoreactivity studies, tachykinins are widely distributed throughout the mammalian body, being localised primarily within Aδ and C fibres neurons, and also in non-neuronal cells including inflammatory cells (Metwali et al., 1994). Cutaneous sensory neurons possess a range of unique characteristics that include their dual function in terms of ability to respond to a range of nociceptive and noxious stimuli and also to release biologically active agents, primarily neuropeptides such as SP. The NK1 receptor has been located in healthy human skin (Bianchi et al., 1999) and is by far the most studied of the tachykinin receptors here. There is good evidence for its presence on endothelial cells, keratinocytes, mast cells and fibroblasts (Brain, 1997, Parenti et al., 1996). Moreover, it has been demonstrated that immuno-inflammatory cells, such as macrophages (Killingsworth et al., 1997), lymphocytes and leukocytes (Lambrecht, 2001) express the SP gene and protein.
The role of tachykinins in skin biology and their importance in pathophysiology is unclear (Ansel et al., 1996, Brain, 1997, Maggi and Schwartz, 1997, Holzer, 1998, Scholzen et al., 1998, Rawlingson et al., 2003). Tachykinins and their receptors represent novel targets for the treatment of human skin disease. Indeed, research into cutaneous mechanisms involving NK1 receptors has been boosted in recent years following the development of selective, non-peptide tachykinin antagonists and tachykinin receptor knockout mice. Substance P has been suggested to play an important role in the pathogensis of psoriasis, dermatitis and pruritus. For instance, NK1 receptors are expressed on blood vessels and on epidermal keratinocytes in the skin of patients with atopic dermatitis (Staniek et al., 1998) and NK1 antagonists have shown to be effective in inhibiting cutaneous inflammation and skin injury produced by thermal burn (Lofgren et al., 1999) and UV exposure (Benrath et al., 1995).
Neurogenic inflammation observed in skin as erythema, local reddening or flare and oedema is caused by the release of neuropeptides from sensory nerves (Richardson and Vasko, 2002). This was first demonstrated by Bayliss (1901) when antidromic stimulation of sensory nerves resulted in increased blood flow in the skin. In 1913, Bruce demonstrated that mustard oil stimulates an acute inflammatory response, which is not seen when the sensory nerve to the skin is ligated. Capsaicin, the vanilloid found in hot chilli peppers, is also able to selectively stimulate sensory nerves (Jancso et al., 1967). Intradermal injection of capsaicin rapidly produces hypersensitivity and flare as a result of the peripheral actions of SP and other neuropeptides. These symptoms can be prevented by denervation or by pre-exposure to high doses of capsaicin, which desensitises the sensory nerve (Text 1). Furthermore, action potentials transmit information to the spinal cord resulting in initial burning pain or pruritus (Stander et al., 2003). Interestingly, these symptoms are common human features observed after bites from poisonous snakes and spiders. Intense and irradiating pain is a frequent complaint upon hospital admission from patients bitten by spiders of the genus Phoneutria in Brazil (Bucaretchi et al., 2000). Phoneutria nigriventer venom (PNV) causes oedema formation in laboratory species following stimulation of sensory neurons and release of tachykinins (Palframan et al., 1996, Costa et al., 1997, Costa et al., 2003a). PNV, like capsacin, depolarises the rat vagus nerve, which is rich in sensory fibres (Costa et al., 2003b). Recent findings suggest that both peripheral and central tachykinin receptors are responsible for PNV-induced pain in rats (Zanchet and Cury, 2003, Zanchet et al., 2004).
A separate body of experimental and clinical evidence links the tachykinins to pruritus (Stander et al., 2001, Stander et al., 2004, Ohmura et al., 2004, Andoh et al., 1998, Andoh et al., 2004). Pruritus or itch is defined as an unpleasant cutaneous sensation leading to the desire to scratch and is the most common symptom of skin diseases. A subset of primary afferent C-fibres that are mechano-insensitive and heat sensitive mediates itch via a pathway distinct from that which mediates pain (Schmelz et al., 1997, Andrew and Craig, 2001). These neurons are histamine sensitive in the periphery (Hagermark et al., 1978) and the involvement of other mediators that include SP itself has been suggested. Perhaps surprisingly, SP is localised within specific granules of human skin mast cells (Toyoda et al., 2000) and is capable of inducing its degranulation (Church et al., 1989), and in turn increase histamine release as skin mast cells have receptors for neuropeptides on their surface (Lowman et al., 1988). Experiments utilizing mice have demonstrated that tachykinin NK1 receptors play a crucial role in mediating SP-induced itch, albeit at high doses. Andoh and co-workers have shown that leukotriene B4 (LTB4) and nitric oxide (NO) are involved in mediating SP-induced itch (Andoh et al., 2001, Andoh and Kuraishi, 2003).
The separation of itch and painful phenomenon is considered complicated (Ikoma et al., 2003). For example capsaicin, which can induce extreme pain upon intradermal injection (Simone et al., 1989) also activates itch fibres (Schmelz et al., 2003). Therefore, it seems reasonable to speculate that low concentrations of PNV, known to produce pain and oedema formation, can also activate sensory nerves and stimulate sensations in the conscious mouse that, in a similar manner to human itch, lead to increased scratching. The ability of PNV to induce scratching was investigated and the potential role of NK1 receptors examined through the study of genetically modified mice with the NK1 receptor deleted, and use of a selective NK1 receptor antagonist.
Section snippets
Animals and experimental protocol
All experiments were carried out in accordance with the Animals (Scientific Procedures) Act 1986. Male and female mice (Sv129+C57BL/6; 25–30 g), either wildtype (NK1+/+) or NK1 receptor knockout (NK1−/−) were anaesthetized with a mixture of isoflurane and oxygen (2.5:2.5% by inhalation). 125I-bovine serum albumin (BSA, 0.03 MBq/0.1 ml) was injected i.v. and a single intradermal injection (i.d.; 0.05 ml) of test agent or vehicle was made into the shaved dorsal skin. Over a period of 60 min after
Results
The ability of SP and PNV to induce scratching behaviour is shown in Fig. 1A. The i.d. injection of SP (100 nmol/site) had little effect on scratching. By comparison, PNV-induced scratching behaviour at doses up to 10 μg/site was observed in NK1+/+ mice. It was also noted that the scratching induced by higher doses became less and this was replaced by licking behaviour (Fig. 1B). As expected, the intradermal injection of SP is associated with plasma extravasation in NK1+/+, but not in the NK1−/−
Discussion
Experimental evidence from clinical studies, together with the knowledge that skin is innervated by SP-containing sensory nerves, has led to the suggestion that tachykinins and their receptors are involved in the development and maintenance of human skin disease. There is substantial evidence to suggest that SP and its main receptor (NK1) play a role in skin diseases related with a component of itchiness in their pathology, such as dermatitis, urticaria and psoriasis (Pincelli et al., 1990,
Acknowledgements
This study was supported by a grant from British Heart Foundation (BHF, U.K.). We also thank Fapesp (Brazil).
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