Clinical Studies | Pain Disorders


CLINICAL STUDY 1 — Attenuation of Tourniquet-Induced Pain in Man by D-Phenylalanine, a Putative Inhibitor of Enkephalin Degradation

—Nurmikko T, Pertovaara A, Pontinen PJ., Department of Neurology, University Central Hospital, University of Tampere, Finland

The effect d-phenylalanine (DPA), a putative inhibitor of enkephalin degradation, on the two separate pain components produced by the submaximal effort tourniquet test was evaluated in healthy human volunteers (N = 8). DPA attenuated the increase of the intensity of the ischemic and pressure pain components with increasing ischemia duration, but only the effect on the pressure pain component was significant. The results support some earlier reports suggesting that DPA has analgesic properties. PMID: 2895566

CLINICAL STUDY 2 — Comparative Characteristics of the Functioning of Brain Structures Exposed to Morphine and D-Phenylalanine

—Iarosh AK, Goruk PS, Luk’ianov EA.

In experiments on rats it was shown that morphine and d-phenylalanine in doses of 5 and 100 mg/kg, respectively, produce a similar by the degree increase of pain reaction thresholds at stimulation of paws through the electrified floor of the chamber. Experiments on rabbits demonstrated that the main factor in morphine action is a decrease of excitability and blood filling of the reticular formation of the midbrain and the central gray matter and an increase of excitability of the dorsal hippocamp without significant changes in the frontal cortex excitability. D-phenylalanine also caused a decrease of excitability of the reticular formation but in contrast to morphine failed to change excitability of the dorsal hippocamp and enhanced excitability of the central gray matter. PMID: 3582628

CLINICAL STUDY 3 — Serotonergic Markers and Lowered Plasma Branched-Chain-Amino Acid Concentrations in Fibromyalgia

—Maes M, Verkerk R, Delmeire L, Van Gastel A, van Hunsel F, Scharpé S. – Department of Psychiatry & Neuropsychology, University Hospital of Maastricht, Postbus 5800, 6202 AZ, Maastricht, The Netherlands

The aims of the present study were to examine serotonergic markers, i.e. [3H] paroxetine binding characteristics and the availability of plasma tryptophan, the precursor of serotonin (5-HT), and the plasma concentrations of the branched chain amino acids (BCAAs), valine, leucine and isoleucine, in fibromyalgia. The [3H] paroxetine binding characteristics, B(max) and K(d) values, and tryptophan and the competing amino acids (CAA), known to compete for the same cerebral uptake mechanism (i.e. valine, leucine, isoleucine, phenylalanine and tyrosine), were determined in fibromyalgia patients and normal controls. There were no significant differences in the [3H] paroxetine binding characteristics (B (max) and K (d)) between fibromyalgia and control subjects. There were no significant differences in plasma tryptophan or the tryptophan/CAA ratio between fibromyalgia patients and normal controls. In the fibromyalgia patients, there were no significant correlations between [3H] paroxetine binding characteristics or the availability of tryptophan and myalgic or depressive symptoms. Patients with fibromyalgia had significantly lower plasma concentrations of the three BCAAs (valine, leucine and isoleucine) and phenylalanine than normal controls. It is hypothesized that the relative deficiency in the BCAAs may play a role in the pathophysiology of fibromyalgia, since the BCAAs supply energy to the muscle and regulate protein synthesis in the muscles. A supplemental trial with BCAAs in fibromyalgia appears to be justified. PMID: 11104853

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 4 — D-Phenylalanine and Other Enkephalinase Inhibitors as Pharmacological Agents: Implications for Some Important Therapeutic Application

—Ehrenpreis S.

A number of compounds have been shown to inhibit the degradation of enkephalins. As expected, these compounds produce naloxone reversible analgesia and potentiate the analgesia produced by enkephalins and by acupuncture. One of these, d-phenylalanine, is also anti-inflammatory. D-phenylalanine has proven to be beneficial in many human patients with chronic, intractable pain. It is proposed the enkephalinase inhibitors may be effective in a number of human “endorphin deficiency diseases” such as depression, schizophrenia, convulsive disorders and arthritis. Such compounds may alleviate other conditions associated with decreased endorphin levels such as opiate withdrawal symptoms. PMID: 6128972

CLINICAL STUDY 5 — Elusive Amines and Primary Headaches: Historical Background and Prospectives

—D’Andrea G, Terrazzino S, Fortin D, Cocco P, Balbi T, Leon A. – Headache and Comorbidity Center, Department of Clinical Pathology, Este and Monselice Hospital. Via San Fermo 10, I-35042 Este (PD), Italy

Although the role of trace amines such as tyramine, octopamine and synephrine in the pathogenesis of migraine has been debated for decades, this issue remains still unresolved. In spite of a relevant body of work, the inability to demonstrate specific receptors for these compounds and the lack of sensitive non-radioactive methods for the detection of trace amines in biological samples have limited their investigation in humans. However, the recent identification of a new, large family of G protein-coupled receptors, some of which bind and are activated by trace amines, has focused renewed attention on these compounds. This discovery, together with the possibility of providing novel insights for evaluation of the pathophysiological role of trace amines in primary headaches, may offer new opportunities for pharmacological strategies acting on these receptors. In light of the new scientific background, this review outlines a historical perspective and summarizes evidence supporting a role of trace amines in the pathogenesis of migraine and cluster headache. PMID: 12811595

(Trace amines include p-tyramine, β-phenylethylamine, tryptamine, octopamine, and 3-iodothyronamine)

CLINICAL STUDY 6 — L-Dopa Effect on Prolactin Plasma Levels in Complicated and Common Migraines Patients

—J. Vardi , M.D. S. Flechter, M.D. D. Ayalon, M.D. T. Cordova, M.Sc. Z. Oberman, M.Sc. – From the Department of Neurology The Municipal-Governmental Medical Center – lchilov Hospital, Tel Aviv, Israel

Dopamine is known as an inhibitor of Prolactin (PRL) secretion; Prostaglandin F 2a is known as a stimulator of its production. These effects probably occur at the hypothesis. Prostaglandins are thought to be involved in the mechanism of migraine attacks. Prolactin response (as plasma levels) to l-dopa inhibitory test was measured in migraine patients. Two different Prolactin curves were obtained during the migraine attacks, according to the type of the migraine, common and complicated. It was found that during an attack of a common migraine, Prolactin plasma levels were reduced in response to l-dopa loading test, while during an attack of complicated migraine a hyperprolactinemic curve was obtained. The significant difference elaborated statistically, cannot be explained by one single factor, like serotonin, which is supposed to be involved in the mechanism of both types of migraine; therefore we have to assume that another factor associated with Prolactin secretion is specifically connected to complicated type of migraine. It is suggested that the hyperprolactinemic responses may indicate an interaction between l-dopa and Prostaglandin F 2a , and should be considered as an indirect evidence that Prostaglandin F 2a is involved in the mechanism of the complicated migraine attacks, but not in common migraine. PMID: 7461966

(phenylalanine is the precursor to tyrosine, which in turn is the precursor to l-dopa)

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