Microinjection of pruritogens in NGF-sensitized human skin

Hans Jürgen Solinski,Roman Rukwied,Martin Schmelz

doi:10.1038/s41598-021-00935-x

Hans Jürgen Solinski, Roman Rukwied + Show 1 more

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https://doi.org/10.1038/s41598-021-00935-x

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Abstract

Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. Focal administration of the non-histaminergic pruritogen cowhage but not histamine resulted in elevated itch at day 21 after NGF administration. Here, we injected bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. β-ALA was the weakest pruritogen, while BAM8–22 and ET-1 were equally potent as histamine. NGF did not sensitize itch or flare reactions induced by any compound, but injection and evoked pain were increased at day 21 and 49. The involvement of histamine H1 receptors in itch was explored in eight subjects after oral cetirizine. ET-1-induced itch and flare were significantly reduced. BAM8–22 and β-ALA itch were not affected, but flare responses after BAM8–22 reduced by 50%. The results indicate that a single NGF injection does not sensitize for experimentally induced itch but increases pain upon pruritogen injection. In healthy humans, pruritic and algetic processing appear differentially regulated by NGF. However, in patients suffering chronic itch, prolonged elevation of NGF-levels under inflammatory conditions may contribute to elevated itch.

Highlights

Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli
NGF via its high- and low-affinity receptors neurotrophic receptor tyrosine kinase 1 (NTRK1) and NGFR is a well-established factor in nociceptive priming[32] and a single recombinant human NGF (rhNGF) injection into the skin of healthy subjects induces hyperalgesia lasting several weeks[17,18,33]
A phase 2B clinical trial revealed that itch in psoriasis patients could be successfully alleviated by NTRK1 inhibition[28], furthering a causal link between upregulated NGF-NTRK1 interaction in the skin and chronic itch

Summary

Introduction

Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. We injected bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. Bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) have been shown to induce itch in healthy volunteers upon intradermal microinjections[4,5,6] Their cognate receptor proteins—MRGPRX1, MRGPRD and ENDRA—are expressed in human dorsal root ganglion (DRG) neurons in a largely overlapping fashion[7,8,9], suggesting a direct stimulatory effect of these pruritogens on pruritic primary afferents. High NGF levels in chronic pain patients have been associated with facilitated nociception under inflammatory conditions and intriguingly, monoclonal antibodies targeting NGF substantially ameliorated their p ain[24,25]. Chronic itch in psoriasis patients could be reduced significantly by topical treatment with a NTRK1-inhibitor[28] and it will be of interest to pursue anti-NGF therapies targeting itch in AD patients

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