Table 1 An overview of the most important characteristics of the individual signal molecules (i.e. the site of origin and synthesis, the main receptors they bind to in humans, their half-lives and whether they can cross the BBB), except for the ions potassium and calcium. We have focused on evidence in human tissue/studies as much as possible and we refer the reader to the Guide to Pharmacology (www.guidetopharmacology.org) for a more detailed overview of the receptor pharmacology. Characteristics of CGRP are added for comparison reasons

CGRP

Multiple sources of CGRP are present (including lymphocytes, monocytes and endothelial cells), but the neuronal sources (perivascular nerve endings) are considered to be the most important source [22]

Human CGRP receptor –

with a between 10 and 100-fold higher affinity than for the AMY₁ receptor (as well as for the AMY₂ and AMY₃ receptors) [23]

6.9 ± 0.9 min for the fast decay; 26.4 ± 4.7 min for the slow decay [24]

Possibly, supported by preclinical data showing its contribution to central sensitization [23]

PACAP

Central nervous system neurons, but also the peripheral nervous system and several nonneural tissues (such as the adrenal gland, gonads, and immune system), reviewed by [25]

PAC₁ receptor – with a > 1000-times higher affinity than for the VPAC₁ receptor or VPAC₂ receptor [26]

PACAP38: < 5–10 min, reviewed by [27]

PACAP27: > 45 min [28]

Yes [29]

VIP

Produced by neurons, endocrine and immune cells [30]

VPAC₁, VPAC₂ and PAC₁ receptors, with an approximately

1000-times higher affinity for VPAC₁ and VPAC₂ compared to PAC₁, reviewed by [31]

Less than 1 min [32]

Yes, probably unidirectionally from blood to brain [33]

Amylin

In β-cells of the islets of Langerhans in the pancreas, reviewed by [34]

CTR, AMY₁ receptor (CTR + RAMP1), AMY₂ receptor (CTR + RAMP2), AMY₃ receptor (CTR + RAMP3) [34] with roughly overlapping potencies according to the Guide to Pharmacology

Compartment 1: 2.1 ± 0.2 min; Compartment 2: 12.2 ± 1.0 min; Compartment 3: 46.9 ± 6.0 min; Mean residence time: 27.7 ± 2.1 min [35]

Compartments 1 and 2 display rapid distribution between vascular and extravascular spaces. Compartment 3 displays a slowly exchanging pool

Yes [36]

Adrenomedullin

Mainly expressed by the vascular endothelium and by vascular smooth muscle cells; also been described in neurons of the dorsal root ganglia and trigeminal ganglia [37, 38, 39]

AM1 receptor (CLR + RAMP2), AM2 receptor (CLR + RAMP3), CGRP receptor (CLR + RAMP1) (tenfold less potent than αCGRP) [34], for an extensive overview please refer to [40]

22 ± 1.6 min [41]

Yes, it has also shown to play a role in the regulation of BBB characteristics [42]

NO

Synthesized by different isoforms of NOS from L-arginine in various tissues [43]

Soluble guanylyl cyclase [44]

0.09 to > 2 s (extravascular half-life), depending on the oxygen concentration [45]

Yes, as well as NO derived from glyceryl trinitrate, nitroglycerine [46]

PDE-3

The expression of PDE-3 depends on its subtype (PDE-3A and PDE-3B), but is generally located in vascular smooth muscle cells, the kidney, and trigeminal ganglia (of rats). PDE-3A is mainly expressed in cardiovascular tissue and platelets, while PDE-3B is expressed in adipocytes, immune cells, and hepatocytes [47, 48]

PDE-3 hydrolyses both cAMP and cGMP [48]

Not applicable

Unclear, already distributed within the central nervous system [49]

PDE-5

PDE-5 is located in vascular and trabecular smooth muscle cells of various organs (aorta, heart, renal vessels, pulmonary vessels, genital apparatus vessels and brain vasculature). It is localized also in myometral cells, blood cells (megakariocytes and platelets), and trigeminal ganglia (of rats) [47, 50]

PDE-5 specifically hydrolyses intracellular cGMP [48]

Not applicable

Unclear, already distributed within the central nervous system [49]

TRPV agonist capsaicin

Active component of chilli peppers

TRPV1 channel

24 h upon 3% capsaicin topical administration [51]; 24.9 ± 5.0 min after oral administration [52]; 7.1 ± 3.3 min after intraperitoneal administration in rats [53]. Its bioavailability and implications for drug delivery are reviewed by [54]

Likely [55, 56]