Table 1.
Major non-neuronal neuroactive mediators involved in the modulation of NAU afferent fiber excitability.
| Mediators | Non-neuronal cells releasing neuroactive mediators | Receptors and actions on NAU afferent fiber terminals | Effects on NAU afferent fiber excitability | Reference |
|---|---|---|---|---|
| Serotonin (5-HT) | Platelets, mast cells | 5-HT3 receptor | + | [17] |
| 5-HT1 receptor | −− | [203] | ||
| Noradrenaline (NA) | Mainly released from sympathetic nerve varicosities. Epidermal cells may be NA-storing cells. | α 2 Receptors | −− | [51] |
| Acetylcholine | Keratinocytes and injured efferent fiber terminals | Muscarinic M2 receptor | −− | [204] |
| Histamine | Mast cells | H3 receptor | −− | [17] |
| H1 receptor | + | |||
| Glutamate/aspartate | All skin epithelial cells and macrophage | Autoreceptors (?) | −− (?) | [35, 36, 205] |
| γ-aminobutyric acid (GABA) | Macrophages and lymphocytes | GABAA receptors | −− | [206, 207] |
| β-endorphin | Keratinocytes, melanocytes, dermal fibroblasts, and leukocytes | μ-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, macrophages | Autoreceptor (?) | −− (?) | [39, 209, 210] |
| Somatostatin (SS) | Merkel cells, keratinocytes | SS receptors | −− | [21, 211–213] |
| Nitric Oxide (NO) | Local tissues | Inhibits SP release from primary afferent terminals and enhances acetylcholine and β-endorphin. | −− | [50, 214, 215] |
| ATP/cGMP | Epidermal cells | P2X and P2Y receptor | −− | [31, 214, 216] |
| Adenosine | Degraded from ATP released in response to mechanical, electrical, or heat stimulation. | A1 receptor | −− | [31] |
| Bradykinin | Local tissues and cells | B1/2 receptors | + | [217–219] |
| Cytokines (IL-1β, IL-6, IL-8, and TNF-α) | Local tissues and cells | Stimulate afferent fibers and augment their excitability | + | [217–221] |
| Cytokines (IL-4 and IL-10) | Local tissues and cells | Inhibits the production of inflammatory pain signals in afferent terminals | −− | [220, 222] |
| Prostaglandins | Local tissues and cells | EP receptors | + | [221, 223] |
aQuestion marks (?) indicate to be determined.