oxytocin and Migraine-Disorders

Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

Topics: Analgesics; Female; Gonadal Steroid Hormones; Humans; Male; Migraine Disorders; Oxytocin; Pain; Prolactin; Receptors, Oxytocin; Receptors, Prolactin

Migraine is ranked as the second highest cause of disability worldwide and the first among women aged 15-49 years. Overall, the incidence of migraine is threefold higher among women than men, though the frequency and severity of attacks varies during puberty, the menstrual cycle, pregnancy, the postpartum period and menopause. Reproductive hormones are clearly a key influence in the susceptibility of women to migraine. A fall in plasma oestrogen levels can trigger attacks of migraine without aura, whereas higher oestrogen levels seem to be protective. The basis of these effects is unknown. In this Review, we discuss what is known about sex hormones and their receptors in migraine-related areas in the CNS and the peripheral trigeminovascular pathway. We consider the actions of oestrogen via its multiple receptor subtypes and the involvement of oxytocin, which has been shown to prevent migraine attacks. We also discuss possible interactions of these hormones with the calcitonin gene-related peptide (CGRP) system in light of the success of anti-CGRP treatments. We propose a simple model to explain the hormone withdrawal trigger in menstrual migraine, which could provide a foundation for improved management and therapy for hormone-related migraine in women.

Topics: Adolescent; Adult; Calcitonin Gene-Related Peptide; Estrogens; Female; Hormones; Humans; Incidence; Male; Middle Aged; Migraine Disorders; Oxytocin; Young Adult

To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM).. MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking.. We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords.. OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack.. Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.

Topics: Estrogens; Female; Humans; Menstrual Cycle; Menstruation Disturbances; Migraine Disorders; Oxytocin; Receptors, Oxytocin

The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.

Topics: Animals; Clinical Trials as Topic; Humans; Hypothalamus; Migraine Disorders; Neuropeptide Y; Nociception; Orexins; Oxytocin; Pituitary Adenylate Cyclase-Activating Polypeptide; Treatment Outcome

This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs-studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, "as needed" dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.

Topics: Administration, Intranasal; Animals; Humans; Migraine Disorders; Oxytocics; Oxytocin; Trigeminal Ganglion

Rising evidence indicate that oxytocin and IL-1β impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls.. 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS.. nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p < 0.01). Inter-ictal saliva oxytocin and IL-1β were significantly elevated pre- as well as post-nVNS compared to healthy controls (p < 0.01) and similarly showed changes that may reflect the observed clinical effects.. Our results add to accumulating evidence for a therapeutic efficacy of adjunct cervical non-invasive vagus nerve stimulation in migraine patients. This study failed to provide an evidence-derived conclusion addressed to the predictive value and usefulness of saliva assays due to its uncontrolled study design. However, saliva screening of mediators associated with trigemino-nociceptive traffic represents a novel approach, thus deserve future targeted headache research. Trial registration This study was indexed at the German Register for Clinical Trials (DRKS No. 00011089) registered on 21.09.2016.

Topics: Adult; Aged; Cervical Vertebrae; Depression; Female; Humans; Inflammation; Interleukin-1beta; Middle Aged; Migraine Disorders; Oxytocin; Pain; Quality of Life; Saliva; Sleep; Vagus Nerve Stimulation

Hypothalamus is a key region in migraine attacks. In addition, women are disproportionately affected by migraine. The calcitonin gene-related peptide (CGRP) system is an important key player in migraine pathophysiology. CGRP signaling could be a target of hormones that influence migraine. Our aim is to identify the expression of vasopressin and its receptors in the brain and in the trigeminovascular system with focus on the migraine-related regions and, furthermore, to examine the role of sex on the expression of neurohormones in the trigeminal ganglion.. Rat brain and trigeminal ganglia were carefully harvested, and protein and mRNA levels were analyzed by immunohistochemistry and real-time PCR, respectively.. Vasopressin and its receptors immunoreactivity were found in migraine-related areas within the brain and, in the trigeminal ganglion, predominantly in neuronal cytoplasm. There were no differences in the number of positive immunoreactivity cells expression of CGRP and vasopressin in the trigeminal ganglion between male and female rats. In contrast, the number of RAMP1 (CGRP receptor), oxytocin (molecular relative to vasopressin), oxytocin receptor and vasopressin receptors (V1aR and V1bR) immunoreactive cells were higher in female compared to male rats. Vasopressin and its receptors mRNA were expressed in both hypothalamus and trigeminal ganglion; however, the vasopressin mRNA level was significantly higher in the hypothalamus.. A better understanding of potential hormonal influences on migraine mechanisms is needed to improve treatment of female migraineurs. It is intriguing that vasopressin is an output of hypothalamic neurons that influences areas associated with migraine. Therefore, vasopressin and the closely related oxytocin might be important hypothalamic components that contribute to migraine pathophysiology.

Topics: Animals; Calcitonin Gene-Related Peptide; Female; Male; Migraine Disorders; Oxytocin; Rats; RNA, Messenger; Vasopressins

Central sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity.. A CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining.. Our results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899.. Our findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.

Topics: Animals; Central Nervous System Sensitization; Mice; Migraine Disorders; Neuronal Plasticity; Oxytocin; Receptors, Oxytocin

Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level. The present study was designed to test the above hypothesis in a well-established electrophysiological model of migraine. Using anesthetized rats, we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation. Furthermore, pretreatment with L-368,899 (a selective oxytocin receptor antagonist, OTR) abolished the oxytocin-induced inhibition of trigeminovascular neuronal responses. This study provides the first direct evidence that oxytocin, probably by OTR activation at TCC level inhibited dural nociceptive-evoked action potential in this complex. Thus, targeting OTR at TCC could represent a new avenue to treat migraine.

Topics: Action Potentials; Animals; Dura Mater; Electric Stimulation; Migraine Disorders; Nociception; Oxytocin; Rats; Rats, Wistar; Synaptic Transmission; Trigeminal Nuclei

Recent work, both clinical and experimental, suggests that the hypothalamic hormone oxytocin (OT) and its receptor (OTR) may be involved in migraine pathophysiology. In order to better understand possible central actions of OT in migraine/headache pathogenesis, we mapped the distribution of OT and OTR in nerve cells and fibers in rat brain with a focus on areas related to migraine attacks and/or shown previously to contain calcitonin gene related peptide (CGRP), another neuropeptide involved in migraine.. Distribution of OT and OTR in the adult, rat brain was qualitatively examined with immunohistochemistry using a series of well characterized specific antibodies.. As expected, OT was extensively localized in the cell somas of two hypothalamic nuclei, the supraoptic (SO or SON) and paraventricular nuclei (Pa or PVN). OT also was found in many other regions of the brain where it was localized mainly in nerve fibers. In contrast, OTR staining in the brain was mainly observed in cell somas with very little expression in fibers. The most distinct OTR expression was found in the hippocampus, the pons and the substantia nigra. In some regions of the brain (e.g. the amygdala and the hypothalamus), both OT and OTR were expressed (match). Mismatch between the peptide and its receptor was primarily observed in the cerebral and cerebellar cortex (OT expression) and hippocampus (OTR expression).. We compared OT/OTR distribution in the CNS with that of CGRP and identified regions related to migraine. In particular, regions suggested as "migraine generators", showed correspondence among the three mappings. These findings suggest central OT pathways may contribute to the role of the hypothalamus in migraine attacks.

Topics: Amygdala; Animals; Brain; Hypothalamus; Male; Migraine Disorders; Neurons; Oxytocin; Rats; Receptors, Oxytocin

The current study examined pain and neurogenic inflammation responses to topical capsaicin during the interictal period (between headache) and their relationship with plasma oxytocin in individuals with migraine.. Individuals with migraine can experience generalized (extracephalic) hyperalgesia, which can persist even between headache attacks. Elevated levels of plasma and cerebrospinal fluid oxytocin have been observed during migraine attacks, oxytocin levels being positively associated with the intensity of migraine symptoms. However, whether oxytocin plays a role in the mechanisms of generalized pain sensitization and neurogenic inflammation during the interictal period has not been studied yet. Understanding migraineurs' interictal pain phenotype and endogenous oxytocin might help identify individuals who would benefit from intranasal oxytocin treatment.. Thirty-two subjects with migraine and 26 healthy controls underwent pain testing. The current study compared capsaicin-induced pain, central sensitization (areas of secondary mechanical allodynia and hyperalgesia), and neurogenic inflammation (capsaicin-induced flare) responses on the nondominant volar forearm between migraineurs and healthy controls. Additionally, we studied plasma oxytocin levels and their relationship to migraine symptoms, experimental pain and affect.. The results indicated a significant group effect (P = .019): Migraineurs reported greater capsaicin-induced pain unpleasantness (M = 1.2, SD = 1.4) on a 0-10 scale and showed larger areas of flare (LnM = 2.8, SD = 0.4) than healthy controls (M = 0.5, SD = 0.8; LnM = 2.6, SD = 0.4; ps < .032). In a subgroup analysis, enhanced capsaicin-induced pain unpleasantness was found in the chronic (P = .007), but not the episodic (Ps > .200), migraineurs. The oxytocin levels were elevated in migraineurs and accounted for 18% of the group difference in capsaicin-induced pain unpleasantness. Within migraineurs, interictal oxytocin levels were negatively associated with psychological distress (Ps < .030). However, during the interictal period, pain sensitivity in extracephalic regions and plasma oxytocin levels were unrelated to migraine symptom parameters (Ps > .074). Lastly, the results found no group difference in areas of secondary mechanical allodynia and hyperalgesia (Ps >.298).. The current study revealed that individuals with migraine exhibit enhanced extracephalic capsaicin-induced pain unpleasantness and flare responses during interictal periods. In addition, migraineurs, especially those with chronic migraine, had slightly elevated interictal oxytocin levels compared to controls, which was associated with their affective component of experimental pain. Therefore, treatment targeting affective pain during the interictal period may help to reduce generalized pain in migraine. Furthermore, endogenous increases in oxytocin may be a compensatory mechanism that may help decrease affective distress in migraineurs. The therapeutic effects of intranasal oxytocin may benefit migraineurs by reducing their affective distress.

Topics: Adolescent; Capsaicin; Cross-Sectional Studies; Female; Humans; Hyperalgesia; Male; Migraine Disorders; Oxytocin; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Sensory System Agents; Statistics, Nonparametric; Surveys and Questionnaires; Time Factors; Young Adult

Topics: Brain; Humans; Migraine Disorders; Oxytocin; Pilot Projects; Probiotics

Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective and cognitive functions. Our overall goal is to define an anatomical framework for conceptualizing how a 'decision' is made on whether a trigeminovascular thalamic neuron fires, for how long, and at what frequency. To begin answering this question, we determine which neuropeptides/neurotransmitters are in a position to modulate thalamic trigeminovascular neurons. Using a combination of in-vivo single-unit recording, juxtacellular labeling with tetramethylrhodamine dextran (TMR) and in-vitro immunohistochemistry, we found that thalamic trigeminovascular neurons were surrounded by high density of axons containing biomarkers of glutamate, GABA, dopamine and serotonin; moderate density of axons containing noradrenaline and histamine; low density of axons containing orexin and melanin concentrating hormone (MCH); but not axons containing CGRP, serotonin 1D receptor, oxytocin or vasopressin. In the context of migraine, the findings suggest that the transmission of headache-related nociceptive signals from the thalamus to the cortex may be modulated by opposing forces (i.e., facilitatory, inhibitory) that are governed by continuous adjustments needed to keep physiological, behavioral, cognitive and emotional homeostasis.

Topics: Animals; Anxiety; Biomarkers; Brain Stem; Calcitonin Gene-Related Peptide; Dopamine; Eating; Glutamates; Histamine; Hypothalamic Hormones; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Melanins; Migraine Disorders; Neurons; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Orexins; Oxytocin; Pituitary Hormones; Rats, Sprague-Dawley; Serotonin; Sleep; Stress, Psychological; Thalamus; Trigeminal Nerve; Vasopressins

We present 2 cases, one adult and one pediatric, of acute migraine headache promptly relieved by intravenous oxytocin. Both cases were typical flares of a chronic intermittent headache pattern with classic vascular symptoms. Pain relief in both cases was rapid and temporally related to oxytocin administration. Vascular headache pathophysiology and possible oxytocin mechanisms of action are discussed.

Topics: Acute Disease; Adult; Analgesics; Child; Female; Humans; Injections, Intraventricular; Male; Migraine Disorders; Oxytocin

Six subjects with a history of increased urinary frequency during migraine were studied. In each case there was a marked diuresis and natriuresis within 12 hours of onset of the headache. This was associated with a significant fall in urinary arginine vasopressin (AVP) (p less than 0.01). Migraine may be associated with altered hypothalamic activity resulting in reduced AVP secretion.

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Female; Humans; Middle Aged; Migraine Disorders; Oxytocin; Water-Electrolyte Balance