Mechanisms of the sensory effects of tacrolimus on the skin
U. Pereira
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorN. Boulais
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorN. Lebonvallet
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorJ.P. Pennec
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorG. Dorange
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorL. Misery
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Department of Dermatology, University Hospital, 5 Avenue Foch, F-29200 Brest, France
Search for more papers by this authorU. Pereira
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorN. Boulais
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorN. Lebonvallet
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorJ.P. Pennec
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorG. Dorange
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Search for more papers by this authorL. Misery
University of Western Brittany, Laboratory of Neuronal Factors and Tissue Structure (EA 4326), Brest, France
Department of Dermatology, University Hospital, 5 Avenue Foch, F-29200 Brest, France
Search for more papers by this authorConflicts of interest L.M. has been a consultant for Astellas.
Summary
Background Tacrolimus is an immunosuppressant drug currently used for the treatment of atopic dermatitis and pruritus. This topical therapy is effective and safe, but transient burning, stinging and itch are frequently reported.
Objectives To understand the mechanisms underlying these burning sensations.
Methods We examined the impact of tacrolimus on substance P (SP) release in an in vitro model of cutaneous neurogenic inflammation. Because phosphorylation of TRPV1 (transient receptor potential subtype vanilloid 1) plays a role in the induction of pain, we investigated whether tacrolimus regulates the phosphorylation state of TRPV1. Finally, we used a macropatch to evaluate the impact of tacrolimus on voltage-gated calcium currents of sensory neurons.
Results Tacrolimus was able to induce initial SP release by extracellular calcium influx and inhibited SP release induced by capsaicin after 1, 24 and 72 h of pretreatment. Analysis of TRPV1 phosphorylation by Western blot confirmed the capacity of tacrolimus to favour phosphorylation. An electrophysiological study showed inhibitory effects on calcium currents.
Conclusions The efficacy of tacrolimus in pruritus, as well as the sensory side-effects, could be explained by a direct effect on neurons through an effect on calcineurin, possibly by a desensitization of TRPV1 and calcium currents through the PIP2 regulation pathway.
References
- 1 Kang S, Lucky AW, Pariser D et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001; 44: S58–64.
- 2 Reitamo S, Rustin M, Harper J et al. A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients. Br J Dermatol 2008; 159: 942–51.
- 3 Stander S, Schurmeyer-Horst F, Luger TA et al. Treatment of pruritic diseases with topical calcineurin inhibitors. Ther Clin Risk Manag 2006; 2: 213–18.
- 4 Senba E, Katanosaka K, Yajima H et al. The immunosuppressant FK506 activates capsaicin- and bradykinin-sensitive DRG neurons and cutaneous C-fibers. Neurosci Res 2004; 50: 257–62.
- 5 Stander S, Stander H, Seeliger S et al. Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin. Br J Dermatol 2007; 156: 1020–6.
- 6 Roosterman D, Goerge T, Schneider SW et al. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev 2006; 86: 1309–79.
- 7 Zegarska B, Lelinska A, Tyrakowski T. Clinical and experimental aspects of cutaneous neurogenic inflammation. Pharmacol Rep 2006; 58: 13–21.
- 8 Lin Q, Li D, Xu X et al. Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin. Mol Pain 2007; 3: 30.
- 9 Sann H, Pierau FK. Efferent functions of C-fiber nociceptors. Z Rheumatol 1998; 57 (Suppl. 2): 8–13.
- 10 Thomsen JS, Simonsen L, Benfeldt E et al. The effect of topically applied salicylic compounds on serotonin-induced scratching behaviour in hairless rats. Exp Dermatol 2002; 11: 370–5.
- 11 Simone DA, Ngeow JY, Whitehouse J et al. The magnitude and duration of itch produced by intracutaneous injections of histamine. Somatosens Res 1987; 5: 81–92.
- 12 Jinks SL, Carstens E. Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior. J Neurophysiol 2002; 87: 1280–9.
- 13 Thomsen JS, Petersen MB, Benfeldt E et al. Scratch induction in the rat by intradermal serotonin: a model for pruritus. Acta Derm Venereol 2001; 81: 250–4.
- 14 Schmelz M, Schmid R, Handwerker HO et al. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 2000; 123: 560–71.
- 15 Lynn B, Schutterle S, Pierau FK. The vasodilator component of neurogenic inflammation is caused by a special subclass of heat-sensitive nociceptors in the skin of the pig. J Physiol 1996; 494: 587–93.
- 16 Gee MD, Lynn B, Cotsell B. The relationship between cutaneous C fibre type and antidromic vasodilatation in the rabbit and the rat. J Physiol 1997; 503: 31–44.
- 17 Ulmann L, Rodeau JL, Danoux L et al. Trophic effects of keratinocytes on the axonal development of sensory neurons in a coculture model. Eur J Neurosci 2007; 26: 113–25.
- 18 Petersen M, Lamotte RH, Klusch A et al. Multiple capsaicin-evoked currents in isolated rat sensory neurons. Neuroscience 1996; 75: 495–505.
- 19 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.
- 20 Malecot CO, Duval A. A macro cell-attached patch-clamp study of the properties of the Na current in the vicinity of the motor endplate region of frog single interosseal skeletal muscle fibres. Pflugers Arch 1992; 420: 231–8.
- 21 Almers W, Stanfield PR, Stuhmer W. Lateral distribution of sodium and potassium channels in frog skeletal muscle: measurements with a patch-clamp technique. J Physiol 1983; 336: 261–84.
- 22 Docherty RJ, Yeats JC, Bevan S et al. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflugers Arch 1996; 431: 828–37.
- 23 Mohapatra DP, Nau C. Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. J Biol Chem 2005; 280: 13424–32.
- 24 Menage HD, Norris PG, Hawk JL et al. The efficacy of psoralen photochemotherapy in the treatment of aquagenic pruritus. Br J Dermatol 1993; 129: 163–5.
- 25 Onuma H, Lu YF, Tomizawa K et al. A calcineurin inhibitor, FK506, blocks voltage-gated calcium channel-dependent LTP in the hippocampus. Neurosci Res 1998; 30: 313–19.
- 26 Nilius B, Mahieu F, Karashima Y et al. Regulation of TRP channels: a voltage-lipid connection. Biochem Soc Trans 2007; 35: 105–8.
- 27 Novakova-Tousova K, Vyklicky L, Susankova K et al. Functional changes in the vanilloid receptor subtype 1 channel during and after acute desensitization. Neuroscience 2007; 149: 144–54.
- 28 Wu L, Bauer CS, Zhen XG et al. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2. Nature 2002; 419: 947–52.
- 29 Gamper N, Reznikov V, Yamada Y et al. Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J Neurosci 2004; 24: 10980–92.
- 30 Lukacs V, Thyagarajan B, Varnai P et al. Dual regulation of TRPV1 by phosphoinositides. J Neurosci 2007; 27: 7070–80.
- 31 Michailidis IE, Zhang Y, Yang J. The lipid connection-regulation of voltage-gated Ca(2+) channels by phosphoinositides. Pflugers Arch 2007; 455: 147–55.
- 32 Liu B, Zhang C, Qin F. Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate. J Neurosci 2005; 25: 4835–43.
