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

PHARMACOLOGICALLY evoked selective degeneration of neurones with a specific function or functioning with known transmitter substances, has been reported only in the monoaminergic neurone systems1,2. We report here that selective degeneration of neurones with a highly specific function can be produced by chemical agents in the somatosensory system as well. Capsaicin given to newborn rats induces selective degeneration of a distinct population of primary sensory neurones involved in mediation of chemogenic pain.

Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones

1.

Antidromic vasodilation and neurogenic plasma extravasation were induced by antidromic stimulation of the saphenous nerve in guanethidine-treated rats. Vasodilation was measured by the change of outflow from the femoral vein and plasma extravasation was determined by Evans blue exudation.




2.

Antidromic vasodilation was reduced by 85% in adult rats which were pretreated with capsaicin on the second day of life.




3.

Antidromic vasodilation was inhibited by 46% after pretreatment with cimetidine plus mepyramine and by 64% after pretreatment with compound 48/80, but was not affected by pretreatment with cimetidine, atropine, methysergide, or indomethacin. Similarly, neurogenic plasma extravasation was reduced by 50% after pretreatment with cimetidine plus mepyramine, and by 88% after pretreatment with compound 48/80, but was not altered after pretreatment with indomethacin.




4.

Infusion of substance P into the femoral artery dose-dependently produced vasodilation (threshold: 0.1 pmol min−1) and plasma extravasation (threshold: 0.5 pmol·min−1). Vasodilation induced by substance P was inhibited by 47% after pretreatment with cimetidine plus mepyramine and by 58% after pretreatment with compound 48/80. Plasma extravasation induced by substance P was reduced by 61% after pretreatment with cimetidine plus mepyramine and by 81% after pretreatment with compound 48/80. Pretreatment with indomethacin had no influence on substance P-induced vasodilation and plasma extravasation.




5.

It is concluded that vasodilation and plasma extravasation following antidromic stimulation of sensory nerves are initiated by peripheral release of substance P from chemosensitive pain fibres. The actions of substance P include, besides direct effects, release of histamine from mast cells.

Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation

,8-IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the

The physiological action of β-iminazolylethylamine

The role of dopamine in drug abuse viewed from the perspective of its role in motivation

1. Local injection of carrageenin in the rat's paw produced oedema and leakage of dye which had been administered previously by the intravenous route. A net dissociation between both parameters was observed: while oedema developed slowly, maximal intensity being attained after 4-5 h, dye-leakage was maximum after 1 hour.2. Anti-inflammatory drugs such as acetylsalicylic acid and indomethacin were effective in reducing oedema and dye-leakage when given before the injection of carrageenin, but much less effective when given 30 or 60 min after carrageenin. Hexadimethrine bromide was effective in reducing dye-leakage also when given 1 h after the injection of carrageenin.3. Combined administration of benadryl and methysergide, before the injection of carrageenin caused only a slight reduction in oedema and dye-leakage.4. When the paws were heated (55 degrees C for 30 s) as a noxious stimulus the dissociation between maximal oedema and maximal dye-leakage was not observed, both phenomena running parallel. Pre-treatment of the animals with indomethacin did not afford any protection.5. These results suggest that the inflammatory reaction to mild stimuli (carrageenin in our experiments) develops through different phases: initially the increased vascular permeability involves extravasation of plasma proteins and that phase is followed by an increased permeability mainly to water. Stronger stimuli (heating in our experiments) produce an overlapping of both phases, probably by inflicting severe damage to the vascular bed of the affected area.6. The anti-inflammatory drugs employed affected chiefly the initial phase of the response.

Pharmacological analysis of the acute inflammatory process induced in the rat's paw by local injection of carrageenin and by heating.

1
The response to vasoactive agents of microvessels of the rat was tested in vivo by direct microscopic observation of the exteriorized mesentery and assessment of cutaneous vascular permeability changes with Evans blue.

2
The constrictor response to a standard amount of noradrenaline in mesenteric microvessels was fully antagonized by acetylcholine in normal, diabetic, adrenalectomized and diabetic-adrenalectomized rats. In contrast, the minimum doses of histamine or bradykinin, effective in normal or adrenalectomized animals, had to be increased about 20 fold to be active in diabetic or diabetic-adrenalectomized animals.

3
Topical application of insulin to mesenteric microvessels of diabetic animals, in amounts not causing any increase in serum insulin levels, improved or restored the capacity of the animals to respond to histamine or bradykinin, acting as antagonists of the vasoconstrictor response to noradrenaline. Topical insulin, however, was ineffective in normal animals given 2-deoxyglucose, the acute effects of which result from cellular glucopaenia unrelated to insulin deficiency.

4
Vascular permeability responses to intracutaneous histamine or bradykinin were decreased in animals pretreated with 2-deoxyglucose as much as in diabetic animals.

5
Pretreatment of normal animals with indomethacin produced no effect on the responses of these animals to histamine or bradykinin, tested as antagonists of noradrenaline on mesenteric microvessels, or as vascular permeability-increasing factors in the skin.

6
Pretreatment of normal animals with chloroquine, mepacrine or dexamethasone had no effect on the reactivity of mesenteric microvessels to histamine and bradykinin, acting as antagonists to noradrenaline.

7
It is suggested that vasoactive substances, endowed with permeability-increasing properties, evoke relaxation of microvessels through an insulin-dependent action on endothelial cells, unrelated to the release of arachidonic acid metabolites. This action would lead to increased vascular permeability, with opening of interendothelial junctions, and temporary changes in composition of extravascular fluid, which in turn, would provide the basis for vasodilatation. Diabetes mellitus apparently impairs such responses as a result of the accompanying cellular glucopaenia. Adrenal corticosteroids are not involved in the impaired responses.

/pdf/vascular-reactivity-in-diabetes-mellitus-possible-role-of-xk0pv036hd.pdf

Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell.

1 Noradrenaline (NA) evoked a vasoconstrictor response in rat mesenteric microvessels in situ, the latency and nature of which was analogous in normal and alloxan-diabetic animals.

2 Histamine and bradykinin (Bk) were capable of antagonizing the response to NA in normal but not in diabetic animals. In contrast, acetylcholine (ACh) was equally effective as an antagonist to NA in both groups of animals.

3 The altered responses to histamine and Bk were not associated with hyperglycaemia since fasting rendered the diabetic animals normoglycaemic and yet did not restore the reactivity of microvessels. Previous administration of insulin to diabetic animals corrected the impaired responses to histamine and Bk.

4 A similar condition of impaired responses to histamine and Bk was produced in normal animals by the intravenous injection of 2-deoxyglucose although ACh remained fully active.

5 Apparently, the functional changes observed in the response to histamine or Bk, as antagonists of the vasoconstrictor reaction to NA, were not associated with a defective response of all smooth muscle. First, because ACh remained active in diabetic animals, and, second, because extravascular smooth muscles obtained from either normal or diabetic rats were equally relaxed by histamine or Bk in vitro.

6 It is suggested that histamine and Bk antagonized the vasoconstrictor response of microvessels to NA through an action on lining endothelial cells resulting in increased vascular permeability and hyperosmolarity of extracellular fluids.

7 The process depended on the availability of insulin, and, therefore, might be affected by intracellular glucopaenia as occurring in diabetes.

8 Intracellular glucopaenia markedly affected other structures. Reduced atria rates were observed in diabetes, despite the fact that the isolated preparation responded normally to NA, ACh or tyramine. Partial substitution of glucose in the bathing fluid by 2-deoxyglucose or addition of NaF to the organ bath evoked similar changes in atria from normal animals.

9 ACh which has little effect on vascular permeability must exert its vasodilator effects through mechanisms which are different from those influenced by the biochemical changes occurring in diabetes.

Influence of diabetes on the reactivity of mesenteric microvessels to histamine, bradykinin and acetylcholine

1 Increased vascular permeability following electric antidromic stimulation of the rat saphenous nerve was observed in the skin area supplied by the nerve, confirming previous results by other authors.

2 The phenomenon was not affected by pretreatment of the rats with diphenhydramine, burimamide or their combination; atropine, methysergide, methysergide plus diphenhydramine, carboxypeptidase B, acetylsalicylic acid, indomethacin or methiazinic acid. It was partially reduced by previous injection of cellulose-sulphate, a kininogen-depleting agent.

3 Perfusates from the subcutaneous tissue of the paw area supplied by the saphenous nerve contained permeability increasing activity as shown by intradermal tests in other rats. This activity was present in perfusates collected during nerve stimulation but not in those collected before stimulation. It was not destroyed by heating to 100° C, or by α-chymotrypsin or trypsin.

4 Bradykinin-like activity may appear later in the perfusates, depending on the intensity of the stimuli.

5 It is concluded that following electrical antidromic stimulation of the saphenous nerve a permeability increasing factor is released, possibly from nerves. It is dialysable and can be distinguished from acetylcholine, histamine, 5-hydroxytryptamine, plasma kinins, substance P, prostaglandins and high molecular weight proteins. The increased vascular permeability induced by this factor leads to plasma exudation and activation of the kinin system.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1974.tb10673.x

J. Garcia Leme

Papers

Pharmacological analysis of the acute inflammatory process induced in the rat's paw by local injection of carrageenin and by heating.

Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell.

Influence of diabetes on the reactivity of mesenteric microvessels to histamine, bradykinin and acetylcholine

Formation of a factor increasing vascular permeability during electrical stimulation of the saphenous nerve in rats.

Antagonists of Bradykinin