Table 1: Major non-neuronal neuroactive mediators involved in the modulation of NAU afferent fiber excitability.

MediatorsNon-neuronal cells releasing neuroactive mediatorsReceptors and actions on NAU afferent fiber terminalsEffects on NAU afferent fiber excitabilityReference

Serotonin (5-HT)Platelets, mast cells5-HT3 receptor+[17]
5-HT1 receptor 𝛼 2 [203]
Noradrenaline (NA)Mainly released from sympathetic nerve varicosities. Epidermal cells may be NA-storing cells. 𝛼 2 Receptors 𝛼 2 [51]
AcetylcholineKeratinocytes and injured efferent fiber terminalsMuscarinic M2 receptor[204]
HistamineMast cellsH3 receptor[17]
H1 receptor+
Glutamate/aspartateAll skin epithelial cells and macrophageAutoreceptors (?) (?)[35, 36, 205]
γ-aminobutyric acid (GABA)Macrophages and lymphocytesGABAA receptors[206, 207]
β-endorphinKeratinocytes, melanocytes, dermal fibroblasts, and leukocytesμ-opiate receptors[47, 48, 208]
Substance P (SP)Mast cells, fibroblasts, platelets, keratinocytes, and macrophages.Autoreceptor (?) (?)[14, 37, 38, 46]
Calcitonin gene-related peptide (CGRP)Epithelial cells, T cells, macrophagesAutoreceptor (?) (?)[39, 209, 210]
Somatostatin (SS)Merkel cells, keratinocytesSS receptors[21, 211213]
Nitric Oxide (NO)Local tissuesInhibits SP release from primary afferent terminals and enhances acetylcholine and β-endorphin.[50, 214, 215]
ATP/cGMPEpidermal cellsP2X and P2Y receptor[31, 214, 216]
AdenosineDegraded from ATP released in response to mechanical, electrical, or heat stimulation.A1 receptor[31]
BradykininLocal tissues and cellsB1/2 receptors+[217219]
Cytokines (IL-1β, IL-6, IL-8, and TNF-α)Local tissues and cellsStimulate afferent fibers and augment their excitability+[217221]
Cytokines (IL-4 and IL-10)Local tissues and cellsInhibits the production of inflammatory pain signals in afferent terminals[220, 222]
ProstaglandinsLocal tissues and cellsEP receptors+[221, 223]

aQuestion marks (?) indicate to be determined.