cholecystokinin and Migraine-Disorders

Cholecystokinin (CCK) peptides are involved in the control of multiple functions both in the central nervous system (CNS) and in the gastrointestinal tract where they act as neurotransmitters and regulate digestive functions. This review deals with the role of CCK peptides as vasoactive mediators. Recent work from our group demonstrates that CCK peptides induce neurogenic vasodilatation both in cerebral and mesenteric vessels. Such an effect is mediated by nitric oxide and seems to be presynaptic. These findings suggest that endogenous CCK peptides could be relevant vasodilatory agents involved in regulating both cerebral and splanchnic blood flow. We hypothesize here how such an effect could be useful in the interpretation of, in a new conceptual frame, the eventual contribution of CCK to some physiological and physiopathological events, such as splanchnic postprandial hyperaemia, panic attack or migraine.

Topics: Animals; Blood Vessels; Cerebrovascular Circulation; Cholecystokinin; Humans; Migraine Disorders; Models, Cardiovascular; Nitric Oxide; Panic Disorder; Receptors, Cholecystokinin; Splanchnic Circulation; Vasodilation

Vascular headaches are among the most prevalent yet poorly understood problems in clinical neurology. Headaches may develop in association with hypertension, seizures, stroke or without a recognizable pathophysiology such as during migraine and cluster headaches. Cephalic blood vessels (pial and dural vessels) are implicated as the most important source for all headaches and are innervated by sensory fibers which arise from ganglia innervating the forehead, scalp and neck. Sensory fibers contain vasoactive neuropeptides which become released from peripheral (perivascular) and central terminations to mediate vasodilation and pain, respectively. The presence of vascular headache implies activation of this final common pain pathway which we have termed the trigeminovascular system. The presence of vascular headache implies activation of this final common pain pathway which we have termed the trigeminovascular system. The existence of such a system a) clarifies certain pain patterns which develop following stimulation of cephalic blood vessels, b) suggests a mechanism to explain the referral of pain to the forehead, c) provides a mechanism to explain the action of certain antimigraine drugs, d) suggests a local mechanism which enhances blood flow under certain pathological conditions. Hence, this review will update existing knowledge about the trigeminovascular system and its role in headache pathophysiology.

Topics: Animals; Calcitonin Gene-Related Peptide; Cerebrovascular Circulation; Cholecystokinin; Circle of Willis; Dura Mater; Guinea Pigs; Humans; Migraine Disorders; Neuropeptides; Pain; Peptide Fragments; Rats; Subarachnoid Hemorrhage; Tachykinins; Trigeminal Ganglion; Trigeminal Nerve; Vascular Headaches

Neuropeptides are sufficiently stable to allow valid radioimmunoassay of peptide concentrations in post-mortem human nervous tissue and in human cerebrospinal fluid. Studies have now documented abnormalities of peptide concentrations in degenerative diseases of the brain. Somatostatin concentration is reduced in the hippocampus and neocortex of patients dying with Alzheimer's type dementia. In Huntington's disease, there are reduced concentrations of substance P, met-enkephalin and cholecystokinin in the basal ganglia; in contrast the concentrations of somatostatin and TRH are increased. Immunocytochemical and experimental lesion studies are underway in an attempt to localize the peptide-containing cells affected by these disorders; and the potential role of alterations in neuropeptide function in the pathogenesis, clinical manifestations and therapy of these illnesses is of great interest. Although alterations of CSF peptide concentrations have been reported in a variety of human diseases, interpretation of these results requires knowledge of the origin and disposition of CSF peptides. Future research into the pathology of peptidergic systems will depend on the development of specific peptide antagonists to probe dynamic aspects of peptide function and on the application of the tools of molecular biology, such as specific mRNA assays, to human material.

Topics: Alzheimer Disease; Animals; Brain; Cholecystokinin; Choline O-Acetyltransferase; Endorphins; Epilepsy; Forecasting; Histocytochemistry; Humans; Huntington Disease; Migraine Disorders; Nerve Tissue Proteins; Nervous System Diseases; Pain; Parkinson Disease; Radioimmunoassay; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Tissue Distribution; Vasopressins

Migraine is a disabling neurovascular disorder, which increases risk of cardiovascular events and is a social burden worldwide. The present first-line anti-migraine medications can cause overwhelming side-effects, of which one includes the onset of cardiovascular disease. As one of the marketed Tibetan drugs, Ru-yi-Zhen-bao Pills (RYZBP) have been clinically used to treat cardiovascular disorders and as anti-migraine medication. However, there is currently no research exploring the anti-migraine actions of RYZBP.. The current research was designed to assess the anti-migraine roles of RYZBP and explore the underlying mechanisms in a nitroglycerin (NTG)-induced migraine rat model trial.. 120 rats were randomly divided into the following six groups of 20 rats each: normal control group, model control group, positive control group, and RYZBP high/medium/low-dose groups (Ru-yi-Zhen-bao Pills; TH 1.00 g/kg, TM 0.50 g/kg and TL 0.25 g/kg). All rats were administered intragastrically for 7 consecutive days, which were subcutaneously injected with the NTG (10 mg/kg) after the last gavage (except in the normal control group). 3min after NTG treatment, 30 rats (5 rats from each group) were anesthetized and devoted to electroencephalogram(EEG) testing, which was used to evaluate the analgesic effect of RYZBP. One hour after NTG treatment, the rest of the 90 rats (15 rats from each group) were anesthetized and midbrain tissue sample was dissected. The dissection was then washed with physiological saline and collected. The histopathological changes in the periaqueductal gray(PAG) of 5 tissue samples were determined by aematoxylin-eosin (H&E) staining, as well as an estimation of substance P (SP) and neurokinin 1 receptor (NK1R) expression through immunohistochemically staining(IHC). Another 5 midbrain preparations were carried out to evaluate calcitonin gene-related peptide (CGRP), proenkephalin (PENK), SP, and cholecystokinin (CCK) expressions by real-time quantitative polymerase chain reaction (RT-qPCR). The rest of the 5 brainstem tissues were then used to measure CCK, CGRP, and opioid peptide receptor (DORR) levels by western blotting(WB).. In the EEG test, RYZBP (TM 0.50 g / kg) treatment transformed the EEG pain-wave of the NTG-induced migraine model rats in different time period. In the mechanism assay, compared with the model control group, RYZBP pretreatment reduced inflammatory cell infiltration, fibrosis and vacuolation of neuronal cells of PAG tissue seen by HE staining. IHC experiments further showed that RYZBPTM up-regulated SP expression levels and enhanced NK1R levels in the NTG-induced migraine rats (P < 0.05). Therapeutic administration of RYZBP also increased PENK mRNA expression and DORR protein level. Both RT-qPCR and western blotting trials indicated that RYZBP treatment significantly decreased CCK and CGRP expression levels (P < 0.01 or P < 0.05) in the NTG-induced migraine rats.. RYZBP has the potential to be an effective anti-migraine treatment through suppressing the EEG pain-wave, increasing the levels of SP, PENK, DORR and reducing expression of CCK and CGRP. Mediating the PAG anti-nociceptive channel and inhibiting central sensitization were the two potential mechanisms, which offers further evidence for clinical therapy.

Topics: Animals; Calcitonin Gene-Related Peptide; Cholecystokinin; Disease Models, Animal; Drugs, Chinese Herbal; Electroencephalography; Enkephalins; Humans; Male; Medicine, Tibetan Traditional; Migraine Disorders; Nitroglycerin; Nociception; Periaqueductal Gray; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Opioid

Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P<0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine.

Topics: Animals; Calcitonin Gene-Related Peptide; Cholecystokinin; Female; Male; Migraine Disorders; Periaqueductal Gray; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; RNA, Messenger; Serotonin 5-HT1 Receptor Agonists; Triazoles; Tryptamines

A common complaint among pain patients is that they lose their appetite. These accounts are anecdotal, however, and the neural mechanism underlying pain-induced loss of appetite remains unknown. In this study, we documented the occurrence of appetite loss in patients under migraine attack and investigated the neuronal substrate of pain-induced anorexia in our animal model of intracranial pain. We found that loss of appetite during the migraine attack in humans coincided strongly with the onset and duration of the head pain in 32/39 cases, and that brief noxious stimulation of the dura in conscious rats produced a transient suppression of food intake. Mapping of neuronal activation in the rat showed that noxious dural stimulation induced a 3- to 4-fold increase in the number of Fos-positive neurons in medullary dorsal horn areas that process nociceptive signals (laminae I, V) and in parabrachial and hypothalamic neurons positioned to suppress feeding behavior. In the parabrachial area, activated neurons were localized in the superior-lateral subnucleus, and 40% of them expressed the mRNA encoding the anorectic neuropeptide cholecystokinin. In the hypothalamus, activated Fos-positive neurons were found in the dorsomedial area of the ventromedial nucleus, and 76% of them expressed the mRNA for cholecystokinin type-B receptor. Based on these findings, we suggest that at least one of several groups of hypothalamic neurons that normally inhibit appetite in response to metabolic cues is positioned to mediate the suppression of food intake by pain signals.

Topics: Animals; Anorexia; Brain Stem; Cholecystokinin; Dura Mater; Eating; Electric Stimulation; Humans; In Situ Hybridization; Male; Migraine Disorders; Nerve Tissue Proteins; Neurons; Nociceptors; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Trigeminal Nuclei; Ventromedial Hypothalamic Nucleus

Topics: Adrenergic Fibers; Calcitonin Gene-Related Peptide; Cerebral Arteries; Cerebrovascular Circulation; Cholecystokinin; Cholinergic Fibers; Gastrin-Releasing Peptide; Histamine; Humans; Migraine Disorders; Muscle, Smooth, Vascular; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Peptides; Serotonin; Substance P; Vasoactive Intestinal Peptide