B. Anselmi

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.

Intermittent hypoendorphinaemia in migraine attack

Beta-endorphin (RIA method, previous chromatographic extraction) was evaluated in plasma of migraine sufferers in free periods and during attacks. Decreased levels of the endogenous opicid peptide were found in plasma sampled during the attacks but not in free periods. Even chronic headache sufferers exhibited significantly lowered levels of beta-endorphin, when compared with control subjects with a negative personal and family history of head pains. The mechanism of the hypoendorphinaemia is unknown: lowered levels of the neuropeptide, which controls nociception, vegetative functions and hedonia, could be important in a syndrome such as migraine, characterized by pain, dysautonomia and anhedonia. The impairment of monoaminergic synapses (“empty neuron” condition) constantly present in sufferers from serious headaches, could be due to the fact that opioid neuropeptides, because of a receptoral or metabolic impairment, poorly modulate the respective monoaminergic neurons, resulting in inbalance of synaptic neurotransmission.

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.

TERMINATION OF MIGRAINE HEADACHE BY A NEW ANTI-INFLAMMATORY VASOCONSTRICTOR AGENT.

Indomethacin, a new nonsteroid anti‐inflammatory agent causes headache, a marked decrease in cerebrospinal fluid pressure, and an increase in retinal arterial pressure, while it produces little and inconstant change in the pressure of the carotid and brachial arteries. Despite the headache, indomethacin was investigated in sub;ects with vascular headache because of its vasoconstrictor action. Clinical improvement similar or slightly inferior to that with ergotamine was observed.

Somatostatin: peripheral venoconstrictive activity and interaction with monoamines in man

The mechanism of somatostatin venoconstriction and tachyphylaxis in the human hand vein in vivo has been investigated. No cross-tachyphylaxis was observed between somatostatin and 5-hydroxytryptamine, noradrenaline, adrenaline, dopamine or tyramine-induced venoconstriction. Somatostatin potentiates the venoconstrictive activity of noradrenaline, adrenaline and dopamine, but not that of 5-hydroxytryptamine and tyramine. Phentolamine antagonizes the somatostatin-induced venoconstriction, whereas methysergide, haloperidol and morphine do not. It is suggested that somatostatin could act on specific receptors in the hand vein, but the mechanism of somatostatin venoconstriction and interaction with vasoactive monoamines remains to be defined.

Systemic non-organic central pain: a new syndrome with decentralization supersensitivity.

SYNOPSIS

Comparison Between Venoconstrictor Effects of Sumatriptan and Ergotamine in Migraine Patients

SYNOPSIS

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.

Clinical and Animal Pharmacology of Migraine: New Perspectives

Animal and clinical pharmacological studies show in certain vascular beds a biphasic action [potentiation and inhibition of serotonin (5-HT) responses] of some anti-migraine drugs, such as ergotamine, methysergide and more recently Org GC 94. Potentiation occurs at therapeutic drug concentrations. The present investigations seem to support the 5-HT theory of migraine and other essential headaches. In this theory, anti-migraine drugs, such as ergotamine, methysergide, pizotifen, and Org GC 94 could reduce the occurrence of pain in migraine and other esscutial headaches by acting as partial agonists tending to correct a deficiency of central 5-HT concentrations or turnover.

Painful vein overdistension in migraine patients: no relationship with serotoninergic parameters

Overdistension of the hand-forearm veins after a period of ischaemia-induced stasis causes local pain in a high percentage of migraineurs, but never in healthy subjects. To investigate the mechanism of such pain, we compared 5-hydroxytryptamine (5HT) whole blood levels and hand vein 5HT reactivity of migraine subjects who did experience pain during venous overdistension to those who did not. No differences were found in whole blood 5HT levels or in the venoconstrictor activity of 5HT between subjects experiencing pain and those who did not. No correlation was found between whole blood 5HT levels and the degree of 5HT-induced venoconstriction. Our results suggest that, if platelets are considered as a model of central antinociceptive 5HT neurons, pain appearance is not due to reduced 5HT at a central level and, therefore, to increased perception of peripheral nociceptive stimuli. Moreover, the similar 5HT venoconstrictive effect (indirect marker of venous tone and, therefore, of venous distensibility) seems to indicate that a mechanical factor is not involved in pain appearance during the HAVD test.