Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Nervous connections between the trigeminal ganglia and cerebral blood vessels have recently been identified in experimental animals and have been termed the trigeminovascular system. Existence of this system in humans is inferential. Trigeminovascular neurons and their peripheral unmyelinated nerve fibers contain the neurotransmitter peptide substance P. Most newly synthesized substance P is transported from ganglion cell bodies to afferent nerve fibers, where depolarization-induced release of neurotransmitter into the wall of the cerebral blood vessel occurs. Substance P dilates pial arteries, increases vascular permeability, and activates cells that participate in the inflammatory response. The relationship of trigeminovascular fibers to the pathogenesis of vascular head pain sheds light on possible mechanisms of migraine and other central nervous system conditions associated with headache and inflammation.

The neurobiology of vascular head pain.

The tachykinin peptide family

Asthma as an axon reflex

1. Substance P (SP) induces histamine release from isolated rat peritoneal mast cells at concentrations of 0.1-10 muM.2. Inhibitors of glycolysis and oxidative phosphorylation prevent the release of histamine induced by SP.3. Cells heated to 47 degrees C for 20 min release histamine when treated with an agent causing cell lysis but fail to release in response to SP.4. SP does not release histamine by interacting with cell-bound IgE.5. Histamine release by SP is rapid, with more than 90% of the response occurring within 1 min of the addition of the peptide to mast cells at 37 degrees C.6. Substance P, unlike antigen-antibody or compound 48/80, does not show enhanced release of histamine when calcium (0.1-1 mM) is present in the extracellular medium but calcium increases the response to SP when the ion is added after the peptide. Extracellular calcium (0.1-1 mM), magnesium (1-10 mM) and cobalt (0.01-0.1 mM) all inhibit SP-induced histamine release when added before the peptide. Pre-treatment of the cells with EDTA (10 mM) and washing in calcium-free medium inhibits the histamine release induced by SP.7. Histamine release induced by SP was optimum at an extracellular pH of 7.2.8. A number of peptides structurally related to SP were examined for histamine-releasing activity. At the concentrations tested, the N-terminal dipeptides Lys-Pro and Arg-Pro, tuftsin, physalaemin, eledoisin, SP(3-11), SP(4-11) and [p-Glu(6), p-amino Phe(7)]-SP(6-11) were all found to be inactive. The relative activities of the other peptides were: [Formula: see text]9. Rat basophilic leukaemia cells (RBL-2H3) fail to respond to SP at concentrations which activate rat mast cells. Release of 5-hydroxytryptamine by immunological activation of RBL cells is not changed by the presence of SP.10. The mechanism of action of SP on mast cells and the nature of the SP receptor on mast cells is discussed in relation to SP receptors in other cell types.

The effects of substance P on histamine and 5-hydroxytryptamine release in the rat

Substance P (6.25-25 p-mole) produced dose-dependent flare and wheal responses when injected intradermally into the volar surface of the human forearm. The maximum flare response was obtained within the first 3 min of injection and declined thereafter. The wheal response reached a maximum after 12 min following the injection. Only those peptides having one or more basic residues in the N-terminal region were effective in producing a flare reaction. Eledoisin-related peptide and SP1-9 were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1-11 was twice as active. The N-terminal tetrapeptide, SP1-4 and eledoisin were inactive in the dose range tested. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin (2.0): [D-pro2, D-phe7, D-trp9]SP1-11 (1.1): SP1-11 (1.0): SP4-11 (0.4): SP1-9 (0.15): eledoisin-related peptide (0.08): eledoisin (0.06). The N-terminal tetrapeptide failed to produce a wheal response in the dose range tested. Substance P was approximately equi-active with poly-L-arginine in the production of wheal and flare and both of these agents were about 10 times more potent than histamine. Adenosine triphosphate (25-400 n-mole) produced dose-dependent wheal and flare responses and was 10,000 times less potent than substance P. Pre-treatment of the subjects with the H1 histamine antagonist, chlorpheniramine, (20 mg I.V.) reduced the wheal and flare responses to substance P. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine. The results are discussed in relation to the mechanism of the ‘axon reflex’ vasodilatation in skin. This is thought to involve mast cells in addition to substance P-containing primary afferent neurones.

J. C. Foreman

Papers

The effects of substance P on histamine and 5-hydroxytryptamine release in the rat

Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin.

Histamine release from mast cells by substance P and substance P sequences.