Cyclical vomiting syndrome - migraine - vasopressin nexus: A new hypothesis for anticipatory nausea and vomiting
Vinod Gupta, Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates
21 April 2005
McRonald and Fleischer [1] discuss the possible role of anticipatory nausea and vomiting (ANV) in cyclical vomiting syndrome (CVS). In January 2004, in response to a previously published article linking CVS, migraine and epilepsy [2], I made possibly the first allusion to a theoretical link between CVS and ANV, particularly with reference to the major subset of migraine-associated CVS; it was suggested that CVS represents another form of anticipatory vomiting seen first in patients undergoing chemotherapy [3].
Although CVS has been known for almost a century and is regarded as a probable manifestation of the migraine diathesis [1,4], the conceptual gap between nausea / vomiting without headache (CVS) and nausea / vomiting with headache (migraine) remains challenging. In other words, if CVS is indeed an expression of the migrainous tendency, we must have a logically defensible explanation for the absence of headache in CVS patients. Linking the pathogenesis of CVS to migraine is hardly reassuring, as the pathophysiology and biology of migraine is itself at its infancy [5-8]. On the management front, the proposal that recognition and management of nausea itself can reduce the risk of a triggering classical conditioning in CVS is attractive but vague; none of the migraine prophylactic drugs recommended for controlling CVS – cyproheptadine, pizotifen, amitriptyline or propranolol – [1] has any direct effect on the management of nausea in the absence of headache. Any medication for modulation of conditioning of ANV must affect central neuronal function and readily cross the blood-brain barrier (BBB).The pharmacological basis of migraine prophylaxis is entirely empirical; if drugs like atenolol, nadolol, or verapamil – that do not freely or readily cross the intact BBB or critically influence brain neuronal function – can prevent migraine headache as well as aura, the role of central neuronal dysfunction as the key or exclusive source of origin of migraine is debatable [5-13]. Remarkably, while atenolol is currently regarded as a first-line prophylactic agent [7], several agents that instantaneously abort migraine aura also do not readily cross the intact BBB, including nifedipine, isoproterenol, and frusemide [12]. McKee et al. [14] found that sustained infusion of magnesium over 24 hours in a cohort with potential BBB disruption produced limited and delayed increases in total and ionized cerebrospinal fluid magnesium concentration, supporting previous studies that indicated only limited brain penetration of magnesium [15]. Also, in contrast to 12-day old rats, magnesium sulphate failed to modulate cortical afterdischarges in hypoxia exposed 25- and 35-day old rats [16]. Clinical hope in limiting thrombotic stroke-related brain damage by early administration of magnesium cannot be allowed to obscure pharmacokinetic absolutes [17]. Moreover, peripheral frontotemporal application of nitroglycerine can precipitate ipsilateral headache without involving any alteration of brain neuronal function [18]. Several lines of evidences indicate an important role for a peripheral source or origin of migraine [19]. In this context, the relevance of migraine prophylactic drugs in preventing secondary Pavlovian conditioning at the level of the brain in CVS becomes questionable.
The pathophysiological concept of CVS is rather abstruse, primarily because of the efforts to delineate it as a separate clinical entity or expression. The confusion is also evident in the putative mechanisms as well as therapeutic approach. If anticipatory nausea / vomiting (ANV) is to be regarded as normal response to severe nausea and not as a primary anxiety disorder, alleviation of anxiety as a definitive mode of therapy, as suggested [1], does not seem a promising approach. Appropriate functioning of the individual is the underlying evolutive goal of both psychodynamic conditioning and behavioural therapy. To a level, anxiety enhances performance by priming the individual for the event; it is only excessive or overwhelming or pathological anxiety that limits performance. Not only is CVS not a feature of the vast majority of patients with anxiety neurosis or thyrotoxicosis but primary anxiolytic medications also have little or no role in long-term management of migraine patients. Again, migraine prophylactic drugs that do not significantly cross the BBB, e.g. atenolol, nadolol, or verapamil, manifest no anxiolytic properties. Also, amitriptyline increases brain and brain stem neuronal catecholamines and serotonin levels, inducing a clinical state of neuronal excitation best seen in its propensity to precipitate mania as well as seizures; nevertheless, this pharmacologic agent is one of the best established anti-migraine agents [20]. While it is true that nausea being an unquantifiable symptom can be overlooked by the therapist with consequent misdiagnosis and stigmatization [1], the pathophysiological link between anxiety, migraine, and CVS is, at best, nebulous. Fear of recurrence of attacks in not unique to CVS, being commonly seen in migraine with aura patients [21]. The fear factor of an impending attack is most pronounced in cluster headache, sometimes to a level predisposing to suicide [22]. Cluster headache is, strikingly and rather paradoxically, not associated with either nausea or vomiting.
Surprisingly, McRonald and Fleischer [1] do not consider the role of arginine vasopressin (AVP) in CVS and ANV [3]. AVP is a key stress-related neurohormone that is principally involved in the pathophysiology of nausea or vomiting or both. Emesis clearly has an antidiuretic action indicating increased AVP release [23, 24]. Similarly, nausea itself -- even without vomiting -- is accompanied by rapid and intense AVP release (usually to plasma concentrations of >20 pmol/l); nausea of a mild degree can distort physiological AVP responses because nausea is a more potent and predominating stimulus to AVP release [24]. Nausea-mediated AVP release dominates over concomitant inhibition by water loading (osmolar) or ethanol (pharmacologic) [23-23, 24]. Further, apomorphine-induced nausea / vomiting leads to a striking release of AVP in human subjects (from 0.9 +/- 0.2 pmol/l to 249 +/- 104 pmol/l at 15 min after the onset of symptoms); on the occasions nausea was not precipitated, apomorphine did not stimulate AVP release [25-28]. Thirdly, the specificity of nausea-mediated AVP release is indicated by the absence of significant increases in plasma AVP -- in contrast to human volunteers -- in rats (which lack an emetic reflex) given relatively large doses of apomorphine [23].
Vomiting itself characteristically remits the headache of migraine, a feature clearly noted over two thousand years ago. Hippocrates (c.460--c.370 BC) described “, vomiting, when it became possible, was able to divert the pain and render it more moderate [29, 30]. In 1790, Tissot wrote: “... vomiting might herald the termination of the headache” [30]. AVP can abort migraine attacks [31, 32]. AVP promotes vasomotor control, antinociception and behavior control; the headache-remitting influence of nausea / vomiting of migraine probably involves spontaneous stimulation of AVP release from neurons in the paraventricular and supraoptic hypothalamic nuclei [3, 32]. Pre-prodromal and prodromal AVP release is probably also responsible, along with systemic and brain parenchymal catecholamine and serotonin release, for the characteristic delay in onset of migraine headache in a wide variety of clinical and experimental situations and circumstances [8]. Vomiting (spontaneous) as well as the chemical emetogenic influence (pharmacologic) of apomorphine both increase AVP bioavailability and can remit migraine headache; this observation has important biological implications. Rather than being simplistically regarded as an accompaniment of migraine headache with an identical pathogenesis, nausea / vomiting should be recognized as a headache-remitting protective force / physiological event [3, 33]. At this stage of comprehension of migraine pathophysiology, there is a critical need to evolve a conceptual divide between physiological processes that predispose to a headache or headache-free state [5, 33]. The conceptual dissociation between the physiological bases of the nausea / vomiting and the headache of migraine marks the first step in this complex endeavor.
“Good medicine is indivisible…has always seen the patient balance between opposing forces pushing him towards health or disease…” [34] The biology of CVS involves elucidation of the matrix of opposing forces (physiological processes) pushing patients towards vomiting (disease) or vomiting-free state (health). I propose that AVP released early and prominently during episodes of cyclical vomiting keeps migraine headache in remission. In effect, CVS represents an “acephalgic” variant of migraine, a subset in which early and protracted vomiting has evolved as an adaptive strategy.
Against this background, it is possible to rationalize the failure of metoclopramide in this patient [1]. Metoclopramide stimulates release of biologically active AVP in normal volunteers who are recumbent, dehydrated, or under steady state water diuresis as well as in insulin-dependent diabetics in good metabolic control [35, 36]. Known mechanisms regulating AVP regulation are not involved, as no alterations in plasma osmolality, heart rate, or blood pressure occurred after metoclopramide administration. Also, other chemically unrelated dopamine antagonists -- sulpiride and haloperidol -- did not increase AVP secretion, de-linking this effect from the anti-dopaminergic property, anti-serotonergic, and/or prolactin-releasing property of metoclopramide [37, 38]. Metoclopramide-induced AVP release in healthy volunteers is unaffected after metergoline, ketanserin or pirenzepine administration but it is abolished by atropine [36]. Cholinergic activation, particularly the M-2 type receptor, may be involved in metoclopramide-induced pharmacological [37, 38] as well as stress / nausea induced physiological AVP release. Supporting this neuronal association, metoclopramide fails to release AVP in patients with multiple system atrophy; hypothalamic cholinergic neurons are often involved in the underlying central neurological degeneration [39].
Nausea / vomiting and metoclopramide both, therefore, stimulate the same neuroendocrinal system, i.e., release of AVP by physiological (adaptive) and chemical (pharmacological) stimulation, respectively. Adaptive mechanisms, nevertheless, operate with limited accuracy and intelligence, e.g., fluid retention precipitates pulmonary venous congestion in left heart failure or decompensation in ascites. Similarly, while this so-called “vegetative” accompaniment probably serves to naturally attenuate headache of migraine, early or cyclical vomiting in migraine can increase the psychosomatic distress or morbidity of migraine as well as retard absorption of abortive anti-migraine agents by decreasing intestinal motility and slowing gastric emptying. Interestingly, injection of AVP into cerebroventricular and cisternal sites also responsive to apomorphine rapidly evokes emesis, suggesting involvement of receptors in the area postrema [40]. Whereas AVP can abort migraine headache, its release in the brain parenchyma may contribute to nausea or emesis itself, a self-reinforcing feedback loop. Drinking copious volumes of water to induce vomiting and to dilute bile and gastric acid (peripheral actions) [1], also has a central component possibly relevant to this syndrome. Water ingestion suppresses AVP release [41], a feature that might decrease occurrence of episodic vomiting; appearance or aggravation of migraine attacks may, however, complicate attempts at water therapy [32,42].
In summary, AVP release appear to have a central role in the CVS, both in the suppression of migraine headaches as well as the pathogenesis of episodic vomiting itself.
4. Li BUK, Balint JP: Cyclic vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr 2000, 47:117-160.
5. Gupta VK: Hidden costs of increasing nosologic sophistication. J Neurol Neurosurg Psychiatry (Published online 31 January 2005), available at: http://jnnp.bmjjournals.com/cgi/eletters/76/2/212#392
6. Gupta VK: Bureaucratisation of migraine. Lancet Neurology 2004, 3:396.
7. Gupta VK: Non-lateralizing brain PET changes in migraine: phenomenology versus pharmacology? Brain 2004, 127:E12.
8. Gupta VK: Stress, adaptation, and traumatic-event headaches: pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004, published online 26 November 2004. Available at: http://www.biomedcentral.com/1471-2377/4/17/comments#106454
9. Gupta VK: Migraine, epilepsy, brain neuronal hyperexcitation, Headache 2004, 45:89. 10. Gupta VK: Cortical spreading depression is neuroprotective: the challenge of basic sciences in migraine research. Headache 2005, 45:177-178.
11. Gupta VK: Management of migraine aura: basic theoretical and clinical reconsiderations. Headache 2005 (In press).
12. Gupta VK: Magnesium therapy for migraine: do we need more trials or more reflection? Headache 2004, 44:445-446.
13. Gupta VK, Migraine, cortical excitability, and evoked potentials: a clinico-pharmacological perspective. Brain 2005 (In press).
14. Mckee JA, Brewer RP, Macy GE, Phillips-Bute B, Campbell K, Borel C, Reynolds J, Warner D: Analysis of the brain bioavailability of peripherally administered magnesium sulphate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 2005, 33:661-666.
15. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulphate does not reduce postoperative analgesic requirements. Anesthesiology 2001, 95:640-646.
16. Kalincik T, Maresova D: Influence of magnesium sulphate on evoked activity of rat brain after exposure to short-term hypoxia. Physiol Res 2004, Nov 15; [Epub ahead of print].
17. Gupta VK: Intravenous magnesium for neuroprotection in acute stroke: clinical hope versus basic neuropharmacology. Stroke 2004, 35:2758-2759.
18. Bonuso S, Marano E, Stasio ED, Sorge F, Barbieri F, Ullucci E: Source of pain and primitive dysfunction in migraine: an identical site? J Neurol Neurosurg Psychiatry, 1989, 52:1351-1354.
19. Gupta VK. Nitric oxide and migraine: another systemic influence postulated to explain a lateralizing disorder. Eur J Neurol 1996, 3:172-173.
20. Gupta VK: Amitriptyline versus cyproheptadine: opposite influences on brain 5-HT function. Headache (In press).
21. Spierings ELH, Reinders MJ, Hoogduin CAL: The migraine aura as a cause of avoidance behavior. Headache 1989, 29:254-5.
23. Rowe JW, Shelton RL, Helderman JH, Vetal RE, Robertson GL: Influence of the emetic reflex on vasopressin release in man. Kidney Int 1979, 16:729-735.
24. Faull CM, Rooke P, Bayliss PH: The effect of a highly specific serotonin agonist on osmoregulated vasopressin secretion in healthy man. Clin Endocrinol 1991, 35:423-430.
25. Nussey SS, Hawthorn J, Page SR, Ang VT, Jenkins JS: Responses of plasma oxytocin and arginine vasopressin to nausea induced by apomorphine and ipecacuanha. Clin Endocrinol, 1988, 28: 297-304.
26. Grant PJ, Hughes JR, Dean HG, Davies JA, Prentice CR: Vasopressin and catecholamine secretion during apomorphine-induced nausea mediate acute changes in haemostatic function in man. Clin Sci, 1986, 71: 621-624.
27. Coiro V, Volpi R, Capretti L, Colla R, Caffarri G, Vescovi PP, Chiodera P: Dopaminergic and cholinergic control of arginine-vasopressin secretion in type I diabetic men. Eur J Clin Invest 1995, 25:412-417.
28. Rossi NF. Dopaminergic control of angiotensin II-induced vasopressin secretion in vitro. Am J Physiol 1998, 275(4 Pt 1):E687-693.
29. Hippocrates, In: Concerning Migraine. A L Allory. Thesis, Paris, 1859.
32. Gupta VK: A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia, 1997, 17: 561-569.
33. Gupta VK: Conceptual divide between adaptive and pathogenetic phenomena in migraine: nausea and vomiting. Brain, 2004, 127: E18.
34. Wall PD, Melzack R. Textbook of Pain. 2nd ed. New York: Churchill Livingstone, 1989.
35. Bevilacqua M, Norbiato G, Chebat E, Raggi U, Cavaiani P, Guzzetti R, Bertora P: Osmotic and nonosmotic control of vasopressin release in the elderly: effect of metoclopramide. J Clin Endocrinol Metab. 1987, 65:1243-1247.
36. Coiro V, Capretti L, Speroni G, Volpi R, Caiazza A, Rossi G, Bianconi L, Chiodera P: Abnormal arginine-vasopressin responses to metoclopramide and insulin-induced hypoglycemia in type I diabetes mellitus. Horm Res, 1990, 33:227-232.
37. Coiro V, Capretti L, Speroni G, Volpi R, Fagnoni F, Bianconi L, Schianchi L, Caiazza A, Chiodera P: Muscarinic cholinergic, but not serotoninergic mediation of arginine vasopressin response to metoclopramide in man. Clin
Endocrinol 1989, 31:491-498.
38. Steardo L, Iovino M, Monteleone P, Bevilacqua M, Norbiato G: Evidence that cholinergic receptors of muscarinic type may modulate vasopressin release induced by metoclopramide. J Neural Transm Gen Sect, 1990, 82:213-217.
39. Norbiato G, Bevilacqua M, Righini V, Chebat E, Vago T, Bertora P, Castelli L, Mangoni A: Altered vasopressin response to metoclopramide in multiple system atrophy: evidence of a cholinergic defect in the hypothalamus. Acta
Neurol Scand, 1992, 85:299-303.
40. Wu M, Harding RK, Hugenholtz H, Kucharczyk J: Emetic effects of centrally administered angiotensin II, arginine vasopressin and neurotensin in the dog. Peptides, 1985, 6 Suppl 1:173-175.
41. Gupta VK: Hypertensive response of water ingestion in chronic autonomic failure: refining underlying mechanism. J Neurol Neurosurg Psychiatry (published online on 7 January 2005), Available at:
Cyclical vomiting syndrome - migraine - vasopressin nexus: A new hypothesis for anticipatory nausea and vomiting
21 April 2005
McRonald and Fleischer [1] discuss the possible role of anticipatory nausea and vomiting (ANV) in cyclical vomiting syndrome (CVS). In January 2004, in response to a previously published article linking CVS, migraine and epilepsy [2], I made possibly the first allusion to a theoretical link between CVS and ANV, particularly with reference to the major subset of migraine-associated CVS; it was suggested that CVS represents another form of anticipatory vomiting seen first in patients undergoing chemotherapy [3].
Although CVS has been known for almost a century and is regarded as a probable manifestation of the migraine diathesis [1,4], the conceptual gap between nausea / vomiting without headache (CVS) and nausea / vomiting with headache (migraine) remains challenging. In other words, if CVS is indeed an expression of the migrainous tendency, we must have a logically defensible explanation for the absence of headache in CVS patients. Linking the pathogenesis of CVS to migraine is hardly reassuring, as the pathophysiology and biology of migraine is itself at its infancy [5-8]. On the management front, the proposal that recognition and management of nausea itself can reduce the risk of a triggering classical conditioning in CVS is attractive but vague; none of the migraine prophylactic drugs recommended for controlling CVS – cyproheptadine, pizotifen, amitriptyline or propranolol – [1] has any direct effect on the management of nausea in the absence of headache. Any medication for modulation of conditioning of ANV must affect central neuronal function and readily cross the blood-brain barrier (BBB).The pharmacological basis of migraine prophylaxis is entirely empirical; if drugs like atenolol, nadolol, or verapamil – that do not freely or readily cross the intact BBB or critically influence brain neuronal function – can prevent migraine headache as well as aura, the role of central neuronal dysfunction as the key or exclusive source of origin of migraine is debatable [5-13]. Remarkably, while atenolol is currently regarded as a first-line prophylactic agent [7], several agents that instantaneously abort migraine aura also do not readily cross the intact BBB, including nifedipine, isoproterenol, and frusemide [12]. McKee et al. [14] found that sustained infusion of magnesium over 24 hours in a cohort with potential BBB disruption produced limited and delayed increases in total and ionized cerebrospinal fluid magnesium concentration, supporting previous studies that indicated only limited brain penetration of magnesium [15]. Also, in contrast to 12-day old rats, magnesium sulphate failed to modulate cortical afterdischarges in hypoxia exposed 25- and 35-day old rats [16]. Clinical hope in limiting thrombotic stroke-related brain damage by early administration of magnesium cannot be allowed to obscure pharmacokinetic absolutes [17]. Moreover, peripheral frontotemporal application of nitroglycerine can precipitate ipsilateral headache without involving any alteration of brain neuronal function [18]. Several lines of evidences indicate an important role for a peripheral source or origin of migraine [19]. In this context, the relevance of migraine prophylactic drugs in preventing secondary Pavlovian conditioning at the level of the brain in CVS becomes questionable.
The pathophysiological concept of CVS is rather abstruse, primarily because of the efforts to delineate it as a separate clinical entity or expression. The confusion is also evident in the putative mechanisms as well as therapeutic approach. If anticipatory nausea / vomiting (ANV) is to be regarded as normal response to severe nausea and not as a primary anxiety disorder, alleviation of anxiety as a definitive mode of therapy, as suggested [1], does not seem a promising approach. Appropriate functioning of the individual is the underlying evolutive goal of both psychodynamic conditioning and behavioural therapy. To a level, anxiety enhances performance by priming the individual for the event; it is only excessive or overwhelming or pathological anxiety that limits performance. Not only is CVS not a feature of the vast majority of patients with anxiety neurosis or thyrotoxicosis but primary anxiolytic medications also have little or no role in long-term management of migraine patients. Again, migraine prophylactic drugs that do not significantly cross the BBB, e.g. atenolol, nadolol, or verapamil, manifest no anxiolytic properties. Also, amitriptyline increases brain and brain stem neuronal catecholamines and serotonin levels, inducing a clinical state of neuronal excitation best seen in its propensity to precipitate mania as well as seizures; nevertheless, this pharmacologic agent is one of the best established anti-migraine agents [20]. While it is true that nausea being an unquantifiable symptom can be overlooked by the therapist with consequent misdiagnosis and stigmatization [1], the pathophysiological link between anxiety, migraine, and CVS is, at best, nebulous. Fear of recurrence of attacks in not unique to CVS, being commonly seen in migraine with aura patients [21]. The fear factor of an impending attack is most pronounced in cluster headache, sometimes to a level predisposing to suicide [22]. Cluster headache is, strikingly and rather paradoxically, not associated with either nausea or vomiting.
Surprisingly, McRonald and Fleischer [1] do not consider the role of arginine vasopressin (AVP) in CVS and ANV [3]. AVP is a key stress-related neurohormone that is principally involved in the pathophysiology of nausea or vomiting or both. Emesis clearly has an antidiuretic action indicating increased AVP release [23, 24]. Similarly, nausea itself -- even without vomiting -- is accompanied by rapid and intense AVP release (usually to plasma concentrations of >20 pmol/l); nausea of a mild degree can distort physiological AVP responses because nausea is a more potent and predominating stimulus to AVP release [24]. Nausea-mediated AVP release dominates over concomitant inhibition by water loading (osmolar) or ethanol (pharmacologic) [23-23, 24]. Further, apomorphine-induced nausea / vomiting leads to a striking release of AVP in human subjects (from 0.9 +/- 0.2 pmol/l to 249 +/- 104 pmol/l at 15 min after the onset of symptoms); on the occasions nausea was not precipitated, apomorphine did not stimulate AVP release [25-28]. Thirdly, the specificity of nausea-mediated AVP release is indicated by the absence of significant increases in plasma AVP -- in contrast to human volunteers -- in rats (which lack an emetic reflex) given relatively large doses of apomorphine [23].
Vomiting itself characteristically remits the headache of migraine, a feature clearly noted over two thousand years ago. Hippocrates (c.460--c.370 BC) described “, vomiting, when it became possible, was able to divert the pain and render it more moderate [29, 30]. In 1790, Tissot wrote: “... vomiting might herald the termination of the headache” [30]. AVP can abort migraine attacks [31, 32]. AVP promotes vasomotor control, antinociception and behavior control; the headache-remitting influence of nausea / vomiting of migraine probably involves spontaneous stimulation of AVP release from neurons in the paraventricular and supraoptic hypothalamic nuclei [3, 32]. Pre-prodromal and prodromal AVP release is probably also responsible, along with systemic and brain parenchymal catecholamine and serotonin release, for the characteristic delay in onset of migraine headache in a wide variety of clinical and experimental situations and circumstances [8]. Vomiting (spontaneous) as well as the chemical emetogenic influence (pharmacologic) of apomorphine both increase AVP bioavailability and can remit migraine headache; this observation has important biological implications. Rather than being simplistically regarded as an accompaniment of migraine headache with an identical pathogenesis, nausea / vomiting should be recognized as a headache-remitting protective force / physiological event [3, 33]. At this stage of comprehension of migraine pathophysiology, there is a critical need to evolve a conceptual divide between physiological processes that predispose to a headache or headache-free state [5, 33]. The conceptual dissociation between the physiological bases of the nausea / vomiting and the headache of migraine marks the first step in this complex endeavor.
“Good medicine is indivisible…has always seen the patient balance between opposing forces pushing him towards health or disease…” [34] The biology of CVS involves elucidation of the matrix of opposing forces (physiological processes) pushing patients towards vomiting (disease) or vomiting-free state (health). I propose that AVP released early and prominently during episodes of cyclical vomiting keeps migraine headache in remission. In effect, CVS represents an “acephalgic” variant of migraine, a subset in which early and protracted vomiting has evolved as an adaptive strategy.
Against this background, it is possible to rationalize the failure of metoclopramide in this patient [1]. Metoclopramide stimulates release of biologically active AVP in normal volunteers who are recumbent, dehydrated, or under steady state water diuresis as well as in insulin-dependent diabetics in good metabolic control [35, 36]. Known mechanisms regulating AVP regulation are not involved, as no alterations in plasma osmolality, heart rate, or blood pressure occurred after metoclopramide administration. Also, other chemically unrelated dopamine antagonists -- sulpiride and haloperidol -- did not increase AVP secretion, de-linking this effect from the anti-dopaminergic property, anti-serotonergic, and/or prolactin-releasing property of metoclopramide [37, 38]. Metoclopramide-induced AVP release in healthy volunteers is unaffected after metergoline, ketanserin or pirenzepine administration but it is abolished by atropine [36]. Cholinergic activation, particularly the M-2 type receptor, may be involved in metoclopramide-induced pharmacological [37, 38] as well as stress / nausea induced physiological AVP release. Supporting this neuronal association, metoclopramide fails to release AVP in patients with multiple system atrophy; hypothalamic cholinergic neurons are often involved in the underlying central neurological degeneration [39].
Nausea / vomiting and metoclopramide both, therefore, stimulate the same neuroendocrinal system, i.e., release of AVP by physiological (adaptive) and chemical (pharmacological) stimulation, respectively. Adaptive mechanisms, nevertheless, operate with limited accuracy and intelligence, e.g., fluid retention precipitates pulmonary venous congestion in left heart failure or decompensation in ascites. Similarly, while this so-called “vegetative” accompaniment probably serves to naturally attenuate headache of migraine, early or cyclical vomiting in migraine can increase the psychosomatic distress or morbidity of migraine as well as retard absorption of abortive anti-migraine agents by decreasing intestinal motility and slowing gastric emptying. Interestingly, injection of AVP into cerebroventricular and cisternal sites also responsive to apomorphine rapidly evokes emesis, suggesting involvement of receptors in the area postrema [40]. Whereas AVP can abort migraine headache, its release in the brain parenchyma may contribute to nausea or emesis itself, a self-reinforcing feedback loop. Drinking copious volumes of water to induce vomiting and to dilute bile and gastric acid (peripheral actions) [1], also has a central component possibly relevant to this syndrome. Water ingestion suppresses AVP release [41], a feature that might decrease occurrence of episodic vomiting; appearance or aggravation of migraine attacks may, however, complicate attempts at water therapy [32,42].
In summary, AVP release appear to have a central role in the CVS, both in the suppression of migraine headaches as well as the pathogenesis of episodic vomiting itself.
References
1. McRonald FE, Fleisher DR: Anticipatory nausea in cyclical vomiting. BMC Pediatr 2005, 5:3.
2. Cupini LM, Santorelli FM, Iani C, Calabresi P: Cyclic vomiting syndrome, migraine, and epilepsy: a common underlying disorder? Headache 2003, 43:407-409.
3. Gupta VK: Cyclic vomiting syndrome: anticipatory stress response in migraine? Headache 2004, 44:106-107.
4. Li BUK, Balint JP: Cyclic vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr 2000, 47:117-160.
5. Gupta VK: Hidden costs of increasing nosologic sophistication. J Neurol Neurosurg Psychiatry (Published online 31 January 2005), available at: http://jnnp.bmjjournals.com/cgi/eletters/76/2/212#392
6. Gupta VK: Bureaucratisation of migraine. Lancet Neurology 2004, 3:396.
7. Gupta VK: Non-lateralizing brain PET changes in migraine: phenomenology versus pharmacology? Brain 2004, 127:E12.
8. Gupta VK: Stress, adaptation, and traumatic-event headaches: pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004, published online 26 November 2004. Available at: http://www.biomedcentral.com/1471-2377/4/17/comments#106454
9. Gupta VK: Migraine, epilepsy, brain neuronal hyperexcitation, Headache 2004, 45:89. 10. Gupta VK: Cortical spreading depression is neuroprotective: the challenge of basic sciences in migraine research. Headache 2005, 45:177-178.
11. Gupta VK: Management of migraine aura: basic theoretical and clinical reconsiderations. Headache 2005 (In press).
12. Gupta VK: Magnesium therapy for migraine: do we need more trials or more reflection? Headache 2004, 44:445-446.
13. Gupta VK, Migraine, cortical excitability, and evoked potentials: a clinico-pharmacological perspective. Brain 2005 (In press).
14. Mckee JA, Brewer RP, Macy GE, Phillips-Bute B, Campbell K, Borel C, Reynolds J, Warner D: Analysis of the brain bioavailability of peripherally administered magnesium sulphate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 2005, 33:661-666.
15. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulphate does not reduce postoperative analgesic requirements. Anesthesiology 2001, 95:640-646.
16. Kalincik T, Maresova D: Influence of magnesium sulphate on evoked activity of rat brain after exposure to short-term hypoxia. Physiol Res 2004, Nov 15; [Epub ahead of print].
17. Gupta VK: Intravenous magnesium for neuroprotection in acute stroke: clinical hope versus basic neuropharmacology. Stroke 2004, 35:2758-2759.
18. Bonuso S, Marano E, Stasio ED, Sorge F, Barbieri F, Ullucci E: Source of pain and primitive dysfunction in migraine: an identical site? J Neurol Neurosurg Psychiatry, 1989, 52:1351-1354.
19. Gupta VK. Nitric oxide and migraine: another systemic influence postulated to explain a lateralizing disorder. Eur J Neurol 1996, 3:172-173.
20. Gupta VK: Amitriptyline versus cyproheptadine: opposite influences on brain 5-HT function. Headache (In press).
21. Spierings ELH, Reinders MJ, Hoogduin CAL: The migraine aura as a cause of avoidance behavior. Headache 1989, 29:254-5.
22. Mathew NT: Advances in cluster headache. Neurol Clin 1990, 4:867-890.
23. Rowe JW, Shelton RL, Helderman JH, Vetal RE, Robertson GL: Influence of the emetic reflex on vasopressin release in man. Kidney Int 1979, 16:729-735.
24. Faull CM, Rooke P, Bayliss PH: The effect of a highly specific serotonin agonist on osmoregulated vasopressin secretion in healthy man. Clin Endocrinol 1991, 35:423-430.
25. Nussey SS, Hawthorn J, Page SR, Ang VT, Jenkins JS: Responses of plasma oxytocin and arginine vasopressin to nausea induced by apomorphine and ipecacuanha. Clin Endocrinol, 1988, 28: 297-304.
26. Grant PJ, Hughes JR, Dean HG, Davies JA, Prentice CR: Vasopressin and catecholamine secretion during apomorphine-induced nausea mediate acute changes in haemostatic function in man. Clin Sci, 1986, 71: 621-624.
27. Coiro V, Volpi R, Capretti L, Colla R, Caffarri G, Vescovi PP, Chiodera P: Dopaminergic and cholinergic control of arginine-vasopressin secretion in type I diabetic men. Eur J Clin Invest 1995, 25:412-417.
28. Rossi NF. Dopaminergic control of angiotensin II-induced vasopressin secretion in vitro. Am J Physiol 1998, 275(4 Pt 1):E687-693.
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Competing interests
None declared