Creative Touch Permanent Makeup and Aesthetics

Substance P (SP) is an 11- amino acid neuropeptide belonging to the tachykinin family, produced by primary sensory C-fibre neurons and released peripherally at skin nerve terminals and centrally at spinal cord synapses. In skin, it functions as a pro-inflammatory, pro-nociceptive, and hair cycle-disrupting mediator, acting primarily through NK1 (neurokinin 1) receptors on mast cells, keratinocytes, fibroblasts, endothelial cells, and dermal papilla cells. It is the most clinically relevant neuropeptide in aesthetics practice – the mechanistic link between psychological stress and telogen effluvium, a key amplifier in atopic dermatitis itch, a contributor to psoriatic inflammation, and a driver of neurogenic mast cell activation in rosacea.

Substance P is synthesised from the preprotachykinin A (PPT-A) gene and co-released with calcitonin gene-related peptide (CGRP) from unmyelinated C-fibres and thinly myelinated Aδ-fibres at peripheral nerve terminals in the dermis and perifollicular tissue. Its release is triggered primarily by TRPV1 channel activation – heat, capsaicin, acid pH, UV, and endogenous lipid inflammatory mediators all activate TRPV1, driving calcium influx and SP vesicular exocytosis. The mast cell tryptase released in response to SP further sensitises TRPV1 on adjacent nerve terminals, creating a positive feedback loop that sustains SP release beyond the initial triggering stimulus. ^[3]

Mast Cell Activation and Neurogenic Inflammation

The primary downstream effector cell of SP in skin is the mast cell. NK1 receptor activation on mast cells triggers degranulation – release of histamine, tryptase, TNF-α, IL-4, and IL-6 – producing the vascular and immune changes of neurogenic inflammation: vasodilation, increased vascular permeability, oedema, erythema, and immune cell recruitment to the dermal tissue. This SP→mast cell→histamine/cytokine cascade is neurally initiated rather than immunologically triggered, explaining why neurogenic inflammation can occur in the absence of allergen exposure or tissue injury. ^[2]

SP also directly activates peripheral blood mononuclear cells – T-lymphocytes, monocytes, and natural killer cells – via NK1 receptors, stimulating their secretion of IFN-γ, IL-4, and TNF-α. This direct immune cell activation provides an SP-driven inflammatory signal that operates independently of mast cell degranulation, giving SP dual access to both innate and adaptive immune responses in skin. ^[4]

Hair Follicle Disruption and Stress-Triggered Telogen Effluvium

SP’s most directly aesthetics-relevant action is its inhibitory effect on the hair follicle – the mechanistic basis of stress-triggered telogen effluvium. NK1 receptors are expressed on dermal papilla cells, outer root sheath keratinocytes, and perifollicular mast cells, giving SP multiple access points to the follicular growth cycle. Psychological stress drives sympathetic activation and SP release at perifollicular nerve terminals, producing four converging hair growth-inhibitory effects:

• Premature induction of catagen (growth phase termination) in anagen follicles through NK1-mediated inhibition of pro-proliferative IGF-1 and SCF signalling in dermal papilla cells
• Perifollicular mast cell degranulation, generating a hostile inflammatory microenvironment that further suppresses follicular cycling
• Downregulation of the immune privilege of the hair follicle epithelium – the mechanism by which the follicle normally protects itself from immune attack – potentially exposing it to T-cell-mediated damage
• Direct inhibition of hair follicle keratinocyte proliferation through NK1 signalling ^[1]

In murine stress models, substance P receptor antagonism fully blocks the stress-induced premature catagen effect – confirming SP as the necessary mediator rather than an associated correlate, and establishing the NK1 receptor as a potential therapeutic target for stress-triggered hair loss. ^[5] The clinical implication is that diffuse hair shedding presenting 2–3 months after a period of significant psychological stress has a coherent SP-mediated pathophysiological explanation – and that the shedding resolves spontaneously as the stressor resolves and SP-driven catagen recruitment ceases, consistent with the typical self-limiting course of stress-triggered telogen effluvium.

Role in Atopic Dermatitis and Pruritus

SP is a primary amplifier of itch in atopic dermatitis. NK1 receptor activation on keratinocytes drives release of TSLP – the epithelial alarmin that activates ILC2s and Th2 cells and drives the IL-4/ IL-13 inflammatory loop – while SP-activated mast cell degranulation releases histamine and serotonin that directly stimulate itch-mediating sensory fibres. The itch-scratch cycle in AD has a neurogenic component mediated substantially by SP: scratching activates C-fibres, which release SP, which activates mast cells, which release histamine, which activates itch fibres, which drive further scratching. SP levels in lesional AD skin correlate with itch severity, and NK1 receptor antagonism reduces pruritus in clinical AD models. ^[4]

Psoriasis and Rosacea Contributions

In psoriasis, SP drives keratinocyte hyperproliferation through NK1-mediated activation of NF-κB, contributes to the dermal T-cell infiltrate characteristic of psoriatic plaques, and synergises with TNF-α to amplify the inflammatory cascade. Psoriatic skin shows elevated SP content and increased NK1 receptor expression compared to healthy skin, and clinical psoriatic flares are consistently associated with periods of elevated psychological stress – the stress→sympathetic activation→SP release pathway providing the mechanistic link. ^[4]

In rosacea, SP-driven mast cell degranulation contributes to the perivascular inflammatory infiltrate and vascular hyperreactivity of the erythematotelangiectatic subtype. SP acts in concert with CGRP at the facial microvasculature – CGRP producing vasodilation, SP producing mast cell degranulation and oedema – to create the flushing, erythema, and burning characteristic of neurogenic rosacea. The TRPV1 triggers that are most commonly reported by rosacea patients (heat, spicy food, alcohol, UV) are precisely the stimuli that most reliably activate SP and CGRP co-release, consistent with a TRPV1-initiated neuropeptide cascade as the primary mechanism of rosacea triggering.