P. L. Del Bianco

SEROTONIN--BRADYKININ POTENTIATION ON THE PAIN RECEPTORS IN MAN.

Abstract Bradykinin produces no pain if injected in small doses into a vein of the back of the hand, but becomes strongly algogenic if serotonin has been previously infused into the vein. The 5-HT pretreated vein is a suitable substrate to the test pain-producing properties of bradykinin and kallidin. By using this substrate, an inverted relationship is noted between the latent period preceding the onset of pain and the dose of bradykinin.

5-Hydroxytryptamine supersensitivity as a new theory of headache and central pain: A clinical pharmacological approach with p-chlorophenylalanine

Vascular supersensitivity to 5-hydroxytryptamine, but not to noradrenaline is observed in volunteers suffering from untreatable migraine, following treatment with parachlorophenylalanine, a specific serotonin depletor. A similar supersensitivity at brain level is claimed to explain an unusual systemic pain syndrome developed in 4 patients affected by migraine and treated with this serotonin depleting agent; hyperalgesia, hyperpathia, spontaneous pain, according to the picture of central pain, are demonstrable. The pain syndrome is reversible with the drug discontinuation; it reappears promptly when the treatment is started again.The pain from serotonin depletion may represent a chemical approach to the mechanism of central pain, such as thalamic syndrome, and may give a new suggestive light to the serotonin interpretation of migraine and some daily headaches.The increased vascular and nervous responsitivity in patients suffering from migraine, to monoamines and correlated drugs (5-HT, noradrenaline, metaraminol, LSD-25 and psylocibine), may be interpreted in terms of central and peripheral monoamine supersensitivity.

Morphine abstinence and serotonin supersensitivity in man: analogies with the mechanism of migraine?

Supersensitivity to serotonin during migraine attack has been previously observed. Since the attack has been attributed to a critical lowering of morphine-like factors, we can expect serotonin supersensitivity during morphine abstinence. Slight signs of morphine abstinence have also been induced in volunteers after mild (10–24 mg/day) and limited (3 days) treatment. To evaluate the sensitivity to serotonin, dopamine, noradrenaline, and tyramine in the smooth muscle of the hand dorsal vein, in vivo, the computerized venotest was applied before, during, and 24 h after withdrawal of morphine. Venous sensitivity to serotonin and dopamine (but not to noradrenaline and tyramine) increased 10- to 20-fold after morphine withdrawal.Venous monoamine supersensitivity in morphine abstinence, similar to that observed during migraine attacks, could be indirect evidence of an analogous mechanism in both conditions.

Kinins and intracranial hemorrhages.

* Department of Medicine, Division of Clinical Pharmacology, University of Florence, Florence, Italy. Presented at The Tenth Annual Meeting of the International College of Angiology, Geneva, Switzerland, July 23 to 28, 1968. This research was financed partly by the National Research Council, Rome, Italy. The pathogenesis of some of the phenomena which follow apoplexy and subarachnoid hemorrhage, even today, has not been convincingly interpreted. It is logical that under these conditions one should not look for the mechanism of these phenomena only in large, asphyctic processes, either edematous or destructive, but also in the action of the biologic substances which may be activated and concentrated in nervous tissue and in the cerebrospinal fluid (CSF) after intracranial bleeding. Recent advances in biochemistry and pharmacology give evidence that vari-

Kinins in the Pathogenesis of Cardiogenic Shock and Pain

One usually speaks of cardiogenic shock when, as result of myocardial infarction, a severe arterial hypotension with symptoms of nervous hypoxia occurs. In some cases it actually is shock; in others the term is used incorrectly, as it is merely a failure in arterial pressure, with consequent brain hypoxia. The distinction is subtle but important both from a practical and theoretical point of view.

Prekallikrein and Kallikrein Inhibitor in Plasma of Patients Affected by Recent Myocardial Infarction

Different causes may carry to the shock. The shock credibly has a pathological substrate, that is a damage of the microvessels, particularly capillaries and venules, vasa vasorum included; the sufference of the microvessels concerns mainly the endothelial and basal membrane. Pathogenetically the basic mechanism of the shock is the capillary damage by hypoxia. Hypoxia, in order to establish a capillary damage, must be calibrated in intensity and duration; differently hypoxia, if too important and acute, provokes death following an acute brain damage; if instead too slight, hypoxia does not damage sufficiently the microvessels.

Kallikreinogen and kallikrein inhibitor in liver cirrhosis and hepatitis

In animals, it has been proved that the kininogen synthesis occurs in the liver (1). In man, the liver origin of kininogen has not been directly demonstrated; however, in liver cirrhosis, the plasma kininogen resulted lowered, while it was normal in viral hepatitis (2). In the present study, plasma kallikreinogen (prekallikrein) and kallikrein inhibitor, assayed with the kaolin activable esterase method (3), have been evaluated in 20 patients with hepatic cirrhosis, in 12 cases with jaundice from acute viral hepatitis, and in 9 normal subjects. A significant reduction of the plasma kallikreinogen and kallikrein inhibitor in cirrhosis patients has been found. A reduction of plasma kallikreinogen and kallikrein inhibitor has also been observed in viral hepatitis; in this condition however, the modification were less important than those observed in cirrhosis. The modifications in jaundice from viral hepatitis were not reported in cases with obstructive jaundice, where normal kallikreinogen levels were found. (4). In a few case of hepatitis, the state of the plasma kallikreinogenand kallikrein inhibitor have been controlled during the period of the disease and compared with the state of some conventional parameters, such as transaminase and bilirubin. A normalization of kallikreinogen and kallikrein inhibitor levels has been observed when the hepatitis is resolved. These data confirm the implication of the kallikreinogen-kinin system in severe liver diseases, and indirectly points out the role of the liver in maintaining the physiological balance of the kallikreinogen-kinin system.

Human 5-hydroxytryptamine venomotor receptors

Abstract The venoconstriction test (VCT) is a method for exploring the monoamine venomotor receptors in man: it is a painless, innocuous technique, able to give the maximum information with the minimum trouble, according to the requirements of the clinical pharmacological tests. The VCT records the local venospasm when very small amounts of 5-HT, noradrenaline or epinephrine are administered through a needle inserted orthodromically into the vein. The VCT is a suitable technique for an acceptable pharmacological evaluation of the vascular reactivity to 5-HT in man. The threshold effect, even if different from subject to subject, is quite constant in the same subject; the threshold doses of 5-HT in the majority of adult men and women, range between 100 and 500 ng. The inhibiting activity of anti-serotonin drugs such as LSD-25, BOL-148, methysergide, nicergoline, BC-105, cyproheptadine, and MY-25 is evaluated in man in quite a satisfying way. An unexpected result was the enhancement of 5-HT and noradrenaline reactivity by treatment with monoamine oxidase inhibitors. Supersensitivity to 5-HT but not to noradrenaline has been observed following administration of parachlorophenylalanine, a specific 5-HT depletor. Skin reaction, capillary permeability, blood pressure and blood flow are used to test the vascular activity of 5-hydroxytryptamine ( Fontanini et al. 1958 ; Scherbel and Harrison, 1958 ; Halpern et al. 1960 ): however, these parameters, when applied in human pharmacology, are quite unsuitable because of technical difficulties, scarce sensitivity and reproductivity. Human veins are very sensitive to the spasmogenic action of 5-HT ( Magalini et al. 1956 ). However the venous tone is quite difficult to measure because of the influence of the autonomous nervous system and of the humoral agents ( Duggan et al. 1953 ; Sharpey-Schafer and Ginsburg, 1962 ; Sharpey-Schafer, 1963 ). few years ago a technique was arranged to test the sensitivity of the 5-HT venomotor receptors in man ( Sicuteri et al. 1964 ). This technique (venoconstriction test: VCT) is based upon the high responsiveness to 5-HT of the vein. The method is highly sensitive, being able to detect the activity of fractions of micrograms of 5-HT; it is practically painless and innocuous, in view of the exiguity of the doses; and the results are quite constant and reproductive. VCT has been used successfully to test agonists, antagonists and correlated drugs on the monoamine (5-HT and catecholamines) venomotor receptors: in the present paper we have collected the most significant information on the human pharmacology of the 5-HT venomotor reactivity, reported fragmentarily in short communications ( Sicuteri et al., 1964a , Sicuteri et al., 1965 , Sicuteri et al., 1966 ).

Some Physiological and Pathological Roles of Kininogen and Kinins

Some biological substances may be called “vasoneuroactive” since their target organs are the blood vessels and the nervous system (Sicuteri, 1965b). This is an arbitrary way to group these substances but useful for handling the pathogenetic problems of some important syndromes characterized by local circulatory disorders and nervous reactions, such as neuropsychic troubles and pain.

Impaired 5-Hydroxytryptamine Tachyphylaxis in Migraine

Tachyphylaxis (TPX) to the spasmogenic activity of 5HT can be demonstrated in vivo in the superficial hand dorsal veins in man by the computerized venotest. The 5HT-TPX is reverted by previous local naloxone administration. Tachyphylaxis to 5HT is usually absent in the migraineur. The restored 5HT spasmogenic effect by naloxone suggests the possibility of local opioid apparatus participation in TPX to 5HT.