MINI-REVIEW
Endorphins, Opiate Receptors and Migraine Headache Federigo Sicuteri, M.D. Department of Clinical Pharmacology, Headache Centre, University of Florence, Florence, Italy Reprint requests to: Department of Clinical Pharmacology, Headache Centre, University of Florence, Clinica Medica Generale, 85, Viale Morgagni, 50134 Florence, Italy (Prof. Sicuteri) Accepted for publication: 10/10/77 (Headache 17:253-256, 1978) NON-ORGANIC central pain (NOCP) refers to a number of painful conditions, the most common being migraine and other idiopathic headache (IH). For these two conditions there is clinical and pharmacologic evidence suggesting a central nature of the pain.1 The term "non-organic" is used to distinguish these conditions from organic pain (thalamic syndrome)2 sustained from vascular, neoplastic and inflammatory lesions of the central nociceptive system. The shifting of pain from side to side to various regions, the fluctuation in time and physiologic or environmental influences strongly suggest a chemical basis for NOCP which involves neurotransmitters.3,4 Thus, pain in IH does not arise from mechanical stimulation of peripheral nociceptors, but from a functional disorder of neurotransmitters in the nociceptive system. Nociception includes antinociception which modulates pain. Antinociception is activated in emergencies in anxiety, terror, rage, sexual excitement and violent pain itself. The activation of this system provokes a physiologic analgesia. The antinociceptive system is also minimally active under normal non-painful conditions, modulating the slight inflow of pain from different regions of the body.5 Impairment of the antinociceptive system renders painful stimuli which are normally painless. More profound disorders of the antinociceptive system allow spontaneous pains to appear. This can be considered akin to sensory hallucinations and similar to organic central pain of the thalamic syndrome.2 The pain in IH has the characteristics of central pain. It is poorly localized, has affective coloration, anesthesia or paresthesia are present and it outlasts the stimulus. Though the patient thinks it is localized to the head, frequent reference to pain in the neck, shoulders, trunk and arms is made. When pain thresholds are studied by ischemic muscular work, post-ischemic congestion of the superior arm and calf compression, a significant depression of the deep pain threshold is found.6 A lowering of the deep pain threshold cannot be explained by a peripheral origin of the pain because pain arising peripherally enhances rather than decreases pain threshold.7 Serotonin has been considered of importance in IH. It is thought that it provokes pain peripherally by stimulating or sensitizing vascular and perivascular nociceptors.8 Antiserotonin drugs improve migraine and IH9 and animal10,11 and clinical12 evidence has shown the role of serotonin as a transmitter of the antinociceptive system. This supports the non-organic central origin theory of the pain in IH. The study of the pathyphysiology and pharmacology of pain has been aided by the discovery of naturally occurring morphine-like factors (MLF: enkephalins and endophins) which act on opiate receptors in the human and animal brain and produce opiate-like analgesia and behavioral modifications.13-15 Because the pain in IH is thought to arise centrally, MLF's could be involved in its genesis.16 I wish to emphasize some clinical and pharmacologic aspects of NOCP and IH, and consider the fundamental role of morphine-like peptidergic neurons in central pain mechanisms. PAIN Pain is the most important phenomenon of IH; it is considered peripheral in origin, caused by vascular-mechanical17 or biochemical (5-HT and kinin) peripheral stimulation of head nociceptors.18 Recently, however, it has been proposed that this pain arises centrally and that it is due to a failure of the antinociceptive system attributed to a deficiency of modulating neurotransmitters.4 MLF's seem to be the main transmitters of the antinociceptive system because they provoke a morphine-like analgesia reversible by naloxone, an opiate antagonist, when inoculated in discrete areas of the
brain.19-21 The highest concentrations of opiate receptors have been found in the amygdala and periacqueductalgray of the brain, and in the medial thalamus and hypothalamus,22 which corresponds to the anatomic extent of the antinociceptive system. The substantia gelatinosa, including laminae 2a and 3a, are rich in opiate receptors. They are also abundant in the spinal trigeminal nucleus which receives painful stimuli from the hand and face through trigeminal, facial, glossopharyngeal and vagus nerves.23 This suggests that pain modulation by MLF's occurs also at spinal and brain stem levels. Morphine loses its analgesic effect in rats depleted of serotonin.10,11 MLF's could exert their analgesic properties through serotoninergic neurons by a deficiency in peptidergic neurons, or an opiate receptor hypersensitivity; a failure of serotoninergic neurons or a defect in both systems. Because morphine is a poor analgesic in IH, the possibility of a serotonin deficiency and/or hyposensitivity of opiate receptors can be postulated. There are no evidences that deficiency of MLF's produces supersensitivity which occurs with deficiency of neurotransmitters. Apparently, chronic administration of morphine does not change the binding capacity of opiate receptors,23 but doubles the neuronal content of MLF's. This suggests a presynaptic mechanism for tolerance and physical dependence.24 Ergotamine is a potent analgesic in migraine, more so than morphine. If the origin of pain in IH is central, one can postulate that ergotamine acts by facilitating the antinociceptive action of serotonin at a central leve.25,26 Hypothetically, ergotamine may facilitate internal opiate binding to specific receptors in the antinociceptive system. The phenomenon of physical dependence on ergotamine and methysergide, which develops in the majority of IH sufferers with dramatic and repeated crises on withdrawal of these drugs, suggests the possibility of a central (MFL and/or serotonin) mechanism of ergotamine analgesia. DEPRESSION IH sufferers are not usually depressed. However, when the pain is severe and frequent they may become depressed. During migraine attacks, temporary acute depression is frequently present. This depression is in part due to pain and also to stress and frustration. Actually it is common for depression to start in the pre-headache phase (depressive aura). It is not surprising, therefore, that impairment in turnover of the same neurotransmitters, mainly serotonin and dopamine, involved in central nociception is also thought to be concerned with mood. MLF's seem to have some importance in behavior. In the cerebrospinal fluid of patients with chronic psychosis, an abnormal concentration of endorphin has been found;27 Naloxone, a morphine antagonist, can reverse auditory hallucinations in schizophrenics.28 This drug, however, has been reported by others to have little or no effect on hallucinations.29 Intracisternal endorphin provokes long-lasting rigidity and immobility, rather like a catatonic state.30 This suggests that impairment of peptidergic neurons could be a mechanism of psychopathology. An abnormal increase in CSF endorphin content was observed also in patients with schizophrenic and manic-depressive psychosis.27 I do not find that pain is the only symptom of depression.31 During a migraine attack concomitant transitory depression occurs and acute depression usually develops together with the pain. In manic-depressives, pain is a frequent symptom.32 Undoubtedly, depression is largely due to pain and it is provocative that serotonin and MLF's are both implicated in depression and IH. VOMITING Vomiting is common during migraine attacks; it might not depend on stress (pain) because it can arise before the start of the pain (emetic aura). IH patients have an enhanced susceptibility of the vomiting centers (CTZ) to normally subemetic doses of apomorphine, I-dopa and 5-hydroxytryptophan.33 This might be due to a super-sensitivity of CTZ dopamine receptors. Opiate receptors are also concentrated in the area postrema of the brain stem which includes the CTZ.34 Vomiting in IH might result from a psychogenic mechanism (repulsion of the imminent attack) or be due to direct stimulation of dopamine receptors of the CTZ (hypersensitivity to I-dopa and apomorphine) or indirectly (tryptophan or serotonin) by a release of dopamine. A direct hypersensitivity of the specific opiate receptors of CTZ is suggested by the facility of provoking nausea and vomiting after administering morphine to IH sufferers. To interpret the sensitivity of CTZ both to dopamine and related drugs (apomorphine and I-dopa) the interactions between these substances on analgesia and locomotor activity in rats have to be considered. Morphine seems to exert some of its central actions by interfering with dopaminergic transmission and initiating a mechanism which resembles denervation supersensitivity. Administration of this drug increases sensitivity to dopamine precursors.35 SEXUAL FUNCTION Ovulation, menstruation, pregnancy, erotic stimulation or intercourse, influence IH. Conversely, severe
NOCP such as daily IH or migraine with frequent severe attacks can provoke sexual deficits and impotence. Pharmacologic manipulation of serotonin and dopamine with fenclonine or serotonin and dopamine precursors can correct sexual deficits in IH sufferers,36,37 but not in other patients.37,38 This shows the precariousness of brain monoamine metabolism in NOCP. Beta-endorphin when inoculated into the lateral ventricles, in rats exposed to estrous females, enhanced the number of mountings; this excitatory effect can be inhibited by naloxone, suggesting that the effect was provoked via opiate receptors.39 CONSTIPATION IH sufferers complain frequently of constipation during a migraine attack or during chronic daily headache. MLF has been found in the intestinal tract. Exogenous and endogenous opiates can reduce or abolish peristaltic activity of the isolated intestine induced by electrical stimulation or through increased intraluminal pressure.40 Guinea-pig ileum spontaneously releases an opiate-like material which inhibits peristaltic activity.41 The possibility suggests itself, therefore, that MLF may participate in the APUD (Amine Precursor Uptake and Decarboxylation) cellular system in the same way as gastrin, somatostatin, vasoactive and intestinal peptides do.23,42 The intestinal symptoms in IH patients (constipation, more rarely diarrhea) could be related to release and depletion of MLF from the intestinal tract. OLIGURIA Oliguria frequently occurs before a migraine attack an terminates with compensatory polyuria after the attack is over. An opiate substance of unknown structure of low molecular-weight, has been extracted from human plasma. This substance induces prolonged analgesia, reversible with naloxone, when injected into rat periaqueductal-gray matter. It differs from enkephalin by its thin layer chromatographic mobility, behavioral effects, induction of long-lasting analgesia and ability to pass the blood-brain barrier. This substance, named anodynin, is probably derived from the pituitary gland because it disappears from the circulation after hypophysectomy.43 The posterior, and to a lesser extent, the anterior pituitary gland, possesses opiate receptors.44 Because opiates stimulate the release of antidiuretic hormones from the posterior pituitary gland, MLF could participate in the modulation of hormonal antidiuresis23 and the fluid retention in migraine attacks could be due to a release of antidiuretic hormones. HALLUCINATIONS Visual scotomata and olfactory or gustatory sensations during the aura or during migraine attacks can be thought of as elementary hallucinations. Sometimes hallucinations in migraine are elaborate and refer to changes in the dimension of some parts of the body. IH sufferers have hypersensitivity to hallucinogenic drugs related to serotonin, such as LSD-25 and psilocybin. Frank hallucinations can be provoked in migraineurs by doses which are not hallucinogenic in controls.45 The antinociceptive system is therefore also implicated in the production of spontaneous and pharmacologic hallucinations. It has been proposed that narcotics act on multiple opiate receptors.46,47 They could have affinity to a morphine receptor (micron) producing analgesia and euphoria by affinity to another receptor (kappa) they could produce sedation and sleep, different types of analgesia and dependence and, finally, through affinity to a sigma receptor, could produce dysphoria and hallucinations.46 I have observed clinically that IH sufferers do not tolerate, or tolerate very poorly, pentazocine. They complain ot disagreeable dysphoria, depersonalization and frank hallucinations more often than non-IH sufferers. Pentazocine acts mainly on sigma receptors, producing dysphoria and hallucinations.48 Idiopathic headache could be the most common expression of central pain, caused by functional disorders of neurotransmitters of antinociception. Thus, IH could be a genetic disorder of the central peptidergic (enkephalins and endorphins) neurons and of serotonin-dopaminergic neurons which seem to be involved in the internal opiate system. This results in painful sensations and functional disorders (nausea, vomiting, oliguria, dysphoria and hallucinations) of discrete areas of the brain which are largely influenced through opiate receptors. Further studies should focus on the turnover of MLF by evaluating neurotransmitters in cerebrospinal fluid in IH. In a pilot study, the level of MLF was lower in IH sufferers than in controls.16 We are also studying the capacity of inactivating labelled enkephalin from CSF of IH sufferers. Pharmacologic investigations of specific receptor binding by using opiate agonists and antagonists could also provide information on the possible role of the opioid peptidergic system in IH and other NOCP which can also be thought of as the pain disease for antonamasia. REFERENCES 1.
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Sicuteri F: Prophylactic and therapeutic properties of 1-methly-lysergic acid butanolamide in migraine. Int Arch Allergy 15:300-307, 1959.
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Pasternak GM, Goodman R, Synder SH: An endogenous morphine-like factor in mammalian brain. Life Sci 16:1765-1769, 1975.
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Terenius L. Wahlström A: Morphine-like ligand for opiate receptors in human CSF. Life Sci 16:1759-1764, 1975.
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Sicuteri F: Morphine-like factors in CSF of headache patients. Satellite Symposium to the Internat Meeting of Neurochemistry: Endorphins. (Brescia) Aug. 28-30, 1977. Raven Press, in press.
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Wolff HG: Headache Mechanism. Intern Arch of AIlergy and Appl Immun 7:210-278, 1955.
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Sicuteri F: Vasoneuroactive substances and their implication in vascular pain. Res Clin Stud Headache, 6-45, (Karger, Basle) 1967.
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Bellussi JD, Grant N, Garsky V, Sarantakis D, Wise CD, Stein L: Analgesia induced in vivo by central administration of enkephalin in rat. Nature 266:625-626, 1976.
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Chang JK, Fang BTW, Pert A, Pert CB: Opiate receptors affinities and behavioural effects of enkephalin: structure-activity relationship of ten synthetic peptide analogues. Life Sci 18:1473-1482, 1976.
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Büscher HH, Hill RC, Römer D et al: Evidence for analgesic activity of enkephalin in the mouse. Nature 261:423-425, 1976.
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Kuhar MJ, Pert CB, Snyder SH: Regional distribution of opiate receptor binding in monkey and human brain. Nature 245:447-450, 1973.
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Snyder SH, Simantöv R: The opiate receptors and opioid peptides. J of Neurochem 28:13-20, 1977.
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Klee WA, Streaty RA: Narcotic receptor sites in morphine-dependent rats. Nature 248:61-63, 1974.
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Sicuteri F, Franchi G, Fanciullacci M: New perspectives on analgesia from ergotamine and methysergide in migraine. 2nd Hungr Congress Pharmacological Society, Abstract 1/28 (Budapest), 1974.
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Franchi G, Fanciullacci M, Galli P, Sicuteri F: Possible monoamine mediation of the analgesic activity of ergotamine and other lysergic derivatives in migraine. In: Adv in Pain Res and Ther. Edited by JJ Bonica and D Albe-Fessard, 1:881-885, 1976.
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Terenius L, Wahlström A, Linström L, Widerlöv E: Increased CSF levels of endorphines in chronic psychosis. Neurosci Letters 3:157-162, 1976.
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Gunne LM, Lindström L, Terenius L: Naloxone-induced reversal of schizophrenic hallucinations. J Neurol Transmission 40:13-19, 1977.
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Davis GC, Bunny WE, Defraites EG, Kleinman JE, van Kammen DP, Past RM, Wyatt RJ: Intravenous naloxone administration is schizophrenia and affective illness. Science 197:74-77, 1977.
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Bloom F, Segal D, Ling N, Guillemin R: Endorphines profound behavioural effects in rats suggest new etiological factors in mental illness. Science 194:630-631, 1976.
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Ibor JJL: Masked depression. Brit J Psychiat 120:245-258, 1977.
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Cassidy WL, Flanagan NB, Spellman M, Cohen ME: Clinical observations in manic-depressive diseases: a quantitative study of one hundred manic-depressive paitnes and fifty medically sick controls. J Amer Med Ass 164:1535, 1957.
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Sicuteri F, Fanciullacci M, Del Bene E: Dopamine system and Idiopathic Headache. Joint Meeting Italo/Scandinavian Headache and Migraine Societies, June 2/3 (Florence), 1976. (Biomedical Press: Headache New Vistas).
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Atweh SF, Kuhar MJ: Autoradiographic localization of opiate receptors in rat brain spinal cord and lower medulla. Brain Res 124:53-67, 1977.
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Eidelberg E, Erspamer R: Dopaminergic mechanisms of opiate actions in brain. J Pharm and Exper Ther 192:50-57, 1975.
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Sicuteri F, Del Bene E, Fonda C: Sex, Migraine and Serotonin Interrelationships. Mongr Neurol Sci 3:94-101, 1976.
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Hyyppa MT, Falck S, Gavert J, Kytomaki O, Rautakorpi I, Syvalahti E: L-tryptophan administration in man: Effects on gonadotropin, growth hormone and cortisol secretion and on sexual motivation. Mongr Neurol Sci 3:102-108, 1976.
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Benkert O: Effect of parachlorophenylkalanine and 5-hydroxytryptophan in human sexual behaviour. Mongr Neurol Sci 3:81-87, 1976.
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Meyerson BJ, Terenius L: Endorphine and male sexual behaviour. Europ J Pharmaco 42:191-192, 1977.
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Waterfield AA, Smokcum RWJ, Hughes J, Kosterlitz HW, Henderson G: In vitro pharmacology of the opioid peptides, enkephalins and endorphines. Eur J Pharmaco 43:107-116, 1977.
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Schulz R, Wuster M, Simantov R, Snyder S, Herz A: electrically stimulated release of opiate-like material from the myenteric plexus of the guinea-pig ileum. Eur J Pharmaco 41:347-348, 1977.
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Pearse ACE: Peptides in brain and intestine. Nature 262:92-94, 1976.
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Pert CP, Pert A, Tallman JF: Isolation of a novel endogenous opiate analgesic from human blood. Proc Natl Acad Sci USA 73:2226-2230, 1976.
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Cox BM, Opheim KE, Leschemacher H, Goldstein A: A peptide-like substance from pituitary that acts like morphine. 2. Purification and properties. Life Sci 16:25-30, 1975.
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Fanciullacci M, Franchi G, Sicuteri F: Hypersensitivity to lysergic acid diethylamide (LSD-25) and psilocybin in essential headache. Experientia 30:1441, 1974.
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Martin WR: Naloxone. Anns Int Med 85:765-768, 1976.
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Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW: Multiple opiate receptors. In: Opiates and Endogenous Opiod Peptides. Elsevier/North Holland Biochemical Press, Amsterdam, The Netherlands. 1976, pp 275-280.
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Gilbert PE, Martin WR: The effects of morphine and morphine-like drugs in the non-dependent morphine-dependent and cyclazocine-dependent chronic spinal dog. J Pharmacol Exp Ther 198:66-82, 1976.
Endorphins, Opiate Receptors and Migraine Headache Federigo Sicuteri, M.D. Department of Clinical Pharmacology, Headache Centre, University of Florence, Florence, Italy Reprint requests to: Department of Clinical Pharmacology, Headache Centre, University of Florence, Clinica Medica Generale, 85, Viale Morgagni, 50134 Florence, Italy (Prof. Sicuteri) Accepted for publication: 10/10/77 (Headache 17:253-256, 1978) NON-ORGANIC central pain (NOCP) refers to a number of painful conditions, the most common being migraine and other idiopathic headache (IH). For these two conditions there is clinical and pharmacologic evidence suggesting a central nature of the pain.1 The term "non-organic" is used to distinguish these conditions from organic pain (thalamic syndrome)2 sustained from vascular, neoplastic and inflammatory lesions of the central nociceptive system. The shifting of pain from side to side to various regions, the fluctuation in time and physiologic or environmental influences strongly suggest a chemical basis for NOCP which involves neurotransmitters.3,4 Thus, pain in IH does not arise from mechanical stimulation of peripheral nociceptors, but from a functional disorder of neurotransmitters in the nociceptive system. Nociception includes antinociception which modulates pain. Antinociception is activated in emergencies in anxiety, terror, rage, sexual excitement and violent pain itself. The activation of this system provokes a physiologic analgesia. The antinociceptive system is also minimally active under normal non-painful conditions, modulating the slight inflow of pain from different regions of the body.5 Impairment of the antinociceptive system renders painful stimuli which are normally painless. More profound disorders of the antinociceptive system allow spontaneous pains to appear. This can be considered akin to sensory hallucinations and similar to organic central pain of the thalamic syndrome.2 The pain in IH has the characteristics of central pain. It is poorly localized, has affective coloration, anesthesia or paresthesia are present and it outlasts the stimulus. Though the patient thinks it is localized to the head, frequent reference to pain in the neck, shoulders, trunk and arms is made. When pain thresholds are studied by ischemic muscular work, post-ischemic congestion of the superior arm and calf compression, a significant depression of the deep pain threshold is found.6 A lowering of the deep pain threshold cannot be explained by a peripheral origin of the pain because pain arising peripherally enhances rather than decreases pain threshold.7 Serotonin has been considered of importance in IH. It is thought that it provokes pain peripherally by stimulating or sensitizing vascular and perivascular nociceptors.8 Antiserotonin drugs improve migraine and IH9 and animal10,11 and clinical12 evidence has shown the role of serotonin as a transmitter of the antinociceptive system. This supports the non-organic central origin theory of the pain in IH. The study of the pathyphysiology and pharmacology of pain has been aided by the discovery of naturally occurring morphine-like factors (MLF: enkephalins and endophins) which act on opiate receptors in the human and animal brain and produce opiate-like analgesia and behavioral modifications.13-15 Because the pain in IH is thought to arise centrally, MLF's could be involved in its genesis.16 I wish to emphasize some clinical and pharmacologic aspects of NOCP and IH, and consider the fundamental role of morphine-like peptidergic neurons in central pain mechanisms. PAIN Pain is the most important phenomenon of IH; it is considered peripheral in origin, caused by vascular-mechanical17 or biochemical (5-HT and kinin) peripheral stimulation of head nociceptors.18 Recently, however, it has been proposed that this pain arises centrally and that it is due to a failure of the antinociceptive system attributed to a deficiency of modulating neurotransmitters.4 MLF's seem to be the main transmitters of the antinociceptive system because they provoke a morphine-like analgesia reversible by naloxone, an opiate antagonist, when inoculated in discrete areas of the
brain.19-21 The highest concentrations of opiate receptors have been found in the amygdala and periacqueductalgray of the brain, and in the medial thalamus and hypothalamus,22 which corresponds to the anatomic extent of the antinociceptive system. The substantia gelatinosa, including laminae 2a and 3a, are rich in opiate receptors. They are also abundant in the spinal trigeminal nucleus which receives painful stimuli from the hand and face through trigeminal, facial, glossopharyngeal and vagus nerves.23 This suggests that pain modulation by MLF's occurs also at spinal and brain stem levels. Morphine loses its analgesic effect in rats depleted of serotonin.10,11 MLF's could exert their analgesic properties through serotoninergic neurons by a deficiency in peptidergic neurons, or an opiate receptor hypersensitivity; a failure of serotoninergic neurons or a defect in both systems. Because morphine is a poor analgesic in IH, the possibility of a serotonin deficiency and/or hyposensitivity of opiate receptors can be postulated. There are no evidences that deficiency of MLF's produces supersensitivity which occurs with deficiency of neurotransmitters. Apparently, chronic administration of morphine does not change the binding capacity of opiate receptors,23 but doubles the neuronal content of MLF's. This suggests a presynaptic mechanism for tolerance and physical dependence.24 Ergotamine is a potent analgesic in migraine, more so than morphine. If the origin of pain in IH is central, one can postulate that ergotamine acts by facilitating the antinociceptive action of serotonin at a central leve.25,26 Hypothetically, ergotamine may facilitate internal opiate binding to specific receptors in the antinociceptive system. The phenomenon of physical dependence on ergotamine and methysergide, which develops in the majority of IH sufferers with dramatic and repeated crises on withdrawal of these drugs, suggests the possibility of a central (MFL and/or serotonin) mechanism of ergotamine analgesia. DEPRESSION IH sufferers are not usually depressed. However, when the pain is severe and frequent they may become depressed. During migraine attacks, temporary acute depression is frequently present. This depression is in part due to pain and also to stress and frustration. Actually it is common for depression to start in the pre-headache phase (depressive aura). It is not surprising, therefore, that impairment in turnover of the same neurotransmitters, mainly serotonin and dopamine, involved in central nociception is also thought to be concerned with mood. MLF's seem to have some importance in behavior. In the cerebrospinal fluid of patients with chronic psychosis, an abnormal concentration of endorphin has been found;27 Naloxone, a morphine antagonist, can reverse auditory hallucinations in schizophrenics.28 This drug, however, has been reported by others to have little or no effect on hallucinations.29 Intracisternal endorphin provokes long-lasting rigidity and immobility, rather like a catatonic state.30 This suggests that impairment of peptidergic neurons could be a mechanism of psychopathology. An abnormal increase in CSF endorphin content was observed also in patients with schizophrenic and manic-depressive psychosis.27 I do not find that pain is the only symptom of depression.31 During a migraine attack concomitant transitory depression occurs and acute depression usually develops together with the pain. In manic-depressives, pain is a frequent symptom.32 Undoubtedly, depression is largely due to pain and it is provocative that serotonin and MLF's are both implicated in depression and IH. VOMITING Vomiting is common during migraine attacks; it might not depend on stress (pain) because it can arise before the start of the pain (emetic aura). IH patients have an enhanced susceptibility of the vomiting centers (CTZ) to normally subemetic doses of apomorphine, I-dopa and 5-hydroxytryptophan.33 This might be due to a super-sensitivity of CTZ dopamine receptors. Opiate receptors are also concentrated in the area postrema of the brain stem which includes the CTZ.34 Vomiting in IH might result from a psychogenic mechanism (repulsion of the imminent attack) or be due to direct stimulation of dopamine receptors of the CTZ (hypersensitivity to I-dopa and apomorphine) or indirectly (tryptophan or serotonin) by a release of dopamine. A direct hypersensitivity of the specific opiate receptors of CTZ is suggested by the facility of provoking nausea and vomiting after administering morphine to IH sufferers. To interpret the sensitivity of CTZ both to dopamine and related drugs (apomorphine and I-dopa) the interactions between these substances on analgesia and locomotor activity in rats have to be considered. Morphine seems to exert some of its central actions by interfering with dopaminergic transmission and initiating a mechanism which resembles denervation supersensitivity. Administration of this drug increases sensitivity to dopamine precursors.35 SEXUAL FUNCTION Ovulation, menstruation, pregnancy, erotic stimulation or intercourse, influence IH. Conversely, severe
NOCP such as daily IH or migraine with frequent severe attacks can provoke sexual deficits and impotence. Pharmacologic manipulation of serotonin and dopamine with fenclonine or serotonin and dopamine precursors can correct sexual deficits in IH sufferers,36,37 but not in other patients.37,38 This shows the precariousness of brain monoamine metabolism in NOCP. Beta-endorphin when inoculated into the lateral ventricles, in rats exposed to estrous females, enhanced the number of mountings; this excitatory effect can be inhibited by naloxone, suggesting that the effect was provoked via opiate receptors.39 CONSTIPATION IH sufferers complain frequently of constipation during a migraine attack or during chronic daily headache. MLF has been found in the intestinal tract. Exogenous and endogenous opiates can reduce or abolish peristaltic activity of the isolated intestine induced by electrical stimulation or through increased intraluminal pressure.40 Guinea-pig ileum spontaneously releases an opiate-like material which inhibits peristaltic activity.41 The possibility suggests itself, therefore, that MLF may participate in the APUD (Amine Precursor Uptake and Decarboxylation) cellular system in the same way as gastrin, somatostatin, vasoactive and intestinal peptides do.23,42 The intestinal symptoms in IH patients (constipation, more rarely diarrhea) could be related to release and depletion of MLF from the intestinal tract. OLIGURIA Oliguria frequently occurs before a migraine attack an terminates with compensatory polyuria after the attack is over. An opiate substance of unknown structure of low molecular-weight, has been extracted from human plasma. This substance induces prolonged analgesia, reversible with naloxone, when injected into rat periaqueductal-gray matter. It differs from enkephalin by its thin layer chromatographic mobility, behavioral effects, induction of long-lasting analgesia and ability to pass the blood-brain barrier. This substance, named anodynin, is probably derived from the pituitary gland because it disappears from the circulation after hypophysectomy.43 The posterior, and to a lesser extent, the anterior pituitary gland, possesses opiate receptors.44 Because opiates stimulate the release of antidiuretic hormones from the posterior pituitary gland, MLF could participate in the modulation of hormonal antidiuresis23 and the fluid retention in migraine attacks could be due to a release of antidiuretic hormones. HALLUCINATIONS Visual scotomata and olfactory or gustatory sensations during the aura or during migraine attacks can be thought of as elementary hallucinations. Sometimes hallucinations in migraine are elaborate and refer to changes in the dimension of some parts of the body. IH sufferers have hypersensitivity to hallucinogenic drugs related to serotonin, such as LSD-25 and psilocybin. Frank hallucinations can be provoked in migraineurs by doses which are not hallucinogenic in controls.45 The antinociceptive system is therefore also implicated in the production of spontaneous and pharmacologic hallucinations. It has been proposed that narcotics act on multiple opiate receptors.46,47 They could have affinity to a morphine receptor (micron) producing analgesia and euphoria by affinity to another receptor (kappa) they could produce sedation and sleep, different types of analgesia and dependence and, finally, through affinity to a sigma receptor, could produce dysphoria and hallucinations.46 I have observed clinically that IH sufferers do not tolerate, or tolerate very poorly, pentazocine. They complain ot disagreeable dysphoria, depersonalization and frank hallucinations more often than non-IH sufferers. Pentazocine acts mainly on sigma receptors, producing dysphoria and hallucinations.48 Idiopathic headache could be the most common expression of central pain, caused by functional disorders of neurotransmitters of antinociception. Thus, IH could be a genetic disorder of the central peptidergic (enkephalins and endorphins) neurons and of serotonin-dopaminergic neurons which seem to be involved in the internal opiate system. This results in painful sensations and functional disorders (nausea, vomiting, oliguria, dysphoria and hallucinations) of discrete areas of the brain which are largely influenced through opiate receptors. Further studies should focus on the turnover of MLF by evaluating neurotransmitters in cerebrospinal fluid in IH. In a pilot study, the level of MLF was lower in IH sufferers than in controls.16 We are also studying the capacity of inactivating labelled enkephalin from CSF of IH sufferers. Pharmacologic investigations of specific receptor binding by using opiate agonists and antagonists could also provide information on the possible role of the opioid peptidergic system in IH and other NOCP which can also be thought of as the pain disease for antonamasia. REFERENCES 1.
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