Creative Touch Permanent Makeup and Aesthetics

Neuropeptides are small signalling peptides released from sensory and autonomic nerve terminals in the skin, acting as chemical messengers between the nervous system and cutaneous immune, vascular, and epithelial cells. They are the molecular basis of cutaneous neurogenic inflammation – the process by which nerve activation directly triggers vascular, immune, and barrier changes in skin tissue without requiring a systemic inflammatory signal. The four neuropeptides with most direct relevance to skin biology and aesthetics practice are substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP), each with distinct receptor targets and biological actions that are nonetheless deeply interconnected through mast cell activation and mutual cross-stimulation.

Cutaneous nerve endings are not passive pain sensors – they actively secrete signalling molecules that regulate vascular tone, immune cell behaviour, keratinocyte proliferation, mast cell activity, and hair follicle cycling. This makes the skin’s innervation a functional regulatory layer for virtually every biological process relevant to aesthetics practice. When sensory nerves are activated – by heat, capsaicin, mechanical stress, UV, or psychological stress – they release neuropeptides at their terminals in the dermis and epidermis, producing a local inflammatory and vascular response that is neurally initiated rather than immunologically initiated. This is the defining characteristic of neurogenic inflammation, and it explains why skin conditions driven primarily by neural dysregulation – neurogenic rosacea being the clearest clinical example – respond poorly to conventional anti-inflammatory treatments targeting the downstream immune response rather than the upstream neural signal. ^[4]

The shared mechanistic hub of cutaneous neurogenic inflammation is the mast cell. Substance P, CGRP, VIP, and NPY all activate mast cells – through NK1, CGRP-R, VPAC, and NPY-receptor subtypes respectively – triggering degranulation and release of histamine, tryptase, and pro-inflammatory cytokines ( TNF-α, IL-4, IL-6) that amplify the local vascular and immune response. Mast cell tryptase in turn sensitises TRPV1 ion channels on sensory nerve endings, increasing neuropeptide release – a positive feedback loop that sustains neurogenic inflammation beyond the original triggering event. ^[2]

Substance P

Substance P (SP) is an 11- amino acid neuropeptide produced by primary sensory C-fibre neurons and released both centrally (modulating pain transmission) and peripherally at skin nerve terminals. Its skin-relevant actions are mediated primarily through NK1 (neurokinin 1) receptors expressed on mast cells, keratinocytes, fibroblasts, endothelial cells, and dermal papilla cells of the hair follicle.

SP is the principal neuropeptide mediator of stress-related hair follicle disruption – NK1 receptor activation on dermal papilla cells and perifollicular mast cells drives premature catagen entry, mast cell degranulation, and perifollicular neurogenic inflammation, constituting the biologically confirmed mechanism of stress-triggered telogen effluvium. ^[1] It promotes oedema and neovascularisation at the dermis, contributes to itch amplification in atopic dermatitis by stimulating IFN-γ, IL-4, and TNF-α release from peripheral mononuclear cells, and drives mast cell degranulation in rosacea. In psoriasis, SP contributes to keratinocyte hyperproliferation and dermal T-cell recruitment. Its full mechanistic profile is covered in the dedicated Substance P entity.

Calcitonin Gene-Related Peptide

Calcitonin Gene-Related Peptide (CGRP) is a 37-amino acid neuropeptide co-released with substance P from sensory C-fibres and Aδ-fibres, functioning as the most potent endogenous vasodilator in the peripheral microcirculation. In skin, CGRP acts on CGRP receptors (CLR/RAMP1 heterodimers) on vascular smooth muscle, endothelial cells, mast cells, and dendritic cells, producing vasodilation, increased vascular permeability, oedema, and immune cell recruitment to the site of neural activation. ^[3]

CGRP’s clinical significance in aesthetics is primarily in rosacea. Serum CGRP levels are significantly elevated in neurogenic rosacea patients compared to healthy controls and correlate positively with clinical severity, flushing frequency, and treatment outcomes – establishing CGRP as both a pathogenic mediator and a potential disease biomarker in this population. ^[7] The neurogenic vasodilation and oedema driven by CGRP at the facial microvasculature explains the flushing, persistent erythema, and burning characteristic of neurogenic rosacea, and provides the mechanistic rationale for why anti-CGRP approaches – including erenumab, a CGRP receptor antagonist developed for migraine – have shown benefit in neurogenic rosacea refractory to conventional treatment. ^[6] CGRP is additionally a potent immunosuppressant of Langerhans cell antigen presentation – reducing the skin’s capacity to mount contact sensitisation responses – which may contribute to the immune dysregulation in chronically inflamed skin conditions.

Neuropeptide Y

Neuropeptide Y (NPY) is a 36-amino acid peptide co-released with noradrenaline from sympathetic nerve terminals – making it an adrenergic co-transmitter rather than a purely sensory neuropeptide – that acts through Y1, Y2, and Y5 receptor subtypes on cutaneous cells. Its biological profile in skin is distinctly more pro-regenerative than SP or CGRP, positioning it as a wound healing and angiogenic modulator rather than primarily an inflammatory mediator.

NPY promotes endothelial cell proliferation, migration, and angiogenesis through Y2 and Y5 receptors, making it relevant to the vascular phase of wound healing and tissue repair. In the proliferative phase of wound healing, NPY modulates macrophage TNF-α secretion through β-arrestin 2 signalling, contributing to the transition from a pro-inflammatory to an anti-inflammatory macrophage phenotype. ^[8] NPY has additionally been shown to promote hair follicle growth alongside wound repair in animal models – a finding that, while not yet translated to clinical practice, establishes it as a pro-regenerative signal in the follicular environment in contrast to the catagen-inducing effects of substance P.

Vasoactive Intestinal Peptide

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide released from both sensory and autonomic nerve terminals in skin, acting through VPAC1 and VPAC2 receptors on mast cells, T-lymphocytes, dendritic cells, and keratinocytes. Like CGRP, VIP is vasodilatory and increases vascular permeability; like NPY, it has immunomodulatory properties that can be either pro- or anti-inflammatory depending on receptor subtype and cell type context.

VIP is primarily an anti-inflammatory and immunosuppressive neuropeptide at physiological concentrations – inhibiting Th1 cytokine production, promoting T-regulatory cell induction, and reducing dendritic cell activation. This anti-inflammatory profile makes VIP a natural brake on the inflammatory consequences of cutaneous neural activation, counterbalancing the mast cell-activating effects of SP and CGRP. Under pathological conditions of sustained neural activation – as in chronic neurogenic inflammation – the VIP anti-inflammatory balance may be overwhelmed by the pro-inflammatory SP/CGRP signal. VIP also stimulates mast cell degranulation at higher concentrations, adding to the complexity of its net effect in inflamed skin. ^[5]

TRPV1 as the Upstream Activating Channel

The trigger for neuropeptide release from cutaneous sensory nerve endings is largely mediated by TRPV1 (transient receptor potential vanilloid 1) – a non-selective cation channel expressed on C-fibres, keratinocytes, and mast cells that is activated by heat (>43°C), capsaicin, acid pH, UV, and endogenous lipid mediators. TRPV1 activation drives calcium influx into the nerve terminal, triggering vesicular release of SP and CGRP. The mast cell tryptase released in response then further sensitises TRPV1, creating the positive feedback loop that sustains cutaneous neurogenic inflammation. ^[4] TRPV1’s activation profile explains why heat, spicy food, alcohol, and UV exposure are consistent rosacea triggers – each independently activates TRPV1, initiating the neuropeptide-mast cell cascade that produces flushing and erythema.