Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation.

Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

Shaoyao Gancao decoction alleviates the central hyperalgesia of recurrent NTG-induced migraine in rats by regulating the NGF/TRPV1/COX-2 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shaoyao Gancao Decoction (SGD) is well known as an effective prescription for analgesia composed of two herbs, and is noted as traditional Chinese medicine morphine. It is widely used in various conditions causing pain, including migraine. However, there is currently no research exploring the mechanism of action in the treatment of migraines. AIM OF THE STUDY: The current research was devised to determine the underlying regulatory mechanism of SGD, by verifying its role in the NGF/TRPV1/COX-2 signal pathway. MATERIALS AND METHODS: The active components in SGD were identified by UHPLC-MS. A migraine model was prepared by subcutaneous (s.c.) injection of nitroglycerin (NTG) into the neck to detect migraine-like behavior, orbital hyperalgesia threshold changes, and the therapeutic effect of SGD. The mechanism of SGD in remedying migraine was studied through transcriptome sequencing (RNA-seq), which was further validated utilizing Elisa, Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) experiments. RESULTS: In the SGD chemical composition analysis, 45 components were identified including gallic acid, paeoniflorin and albiforin. In the behavioral experiments, SGD treatment significantly decreased the score of migraine-like head scratching in the NTG-induced migraine model (Mod) rats, while the hyperalgesia threshold increased outstandingly on days 10, 12, and 14 (P < 0.01, P < 0.001 or P < 0.0001). In migraine biomarkers experiment, compared with the Mod group, the 5-hydroxytryptamine (5-HT) contents were outstandingly enhanced by SGD treatment, while nitric oxide (NO) contents were markedly declined (P < 0.01). In the RNA-seq test, the down-regulated genes of SGD inhibiting hyperalgesia migraine included the neurotrophic factor (NGF) and transient receptor potential vanillic acid subfamily protein 1 receptor (TRPV1). The down-regulation pathway is the inflammatory mediator regulation of TRP channels. In gene set enrichment analysis (GSEA), SGD decreased the over-expression of protooncogene tyrosine-protein kinase Src (SRC) and TRPV1 in this pathway, and the two genes clustered at its lower end, with similar functions. PPI network results show that NGF interacts with TRPV1. Further verification shows that when compared with Mod group, the plasma cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) protein expression levels and the dura mater calcitonin gene-related peptide (CGRP), extracellular signal-regulated kinase (ERK), p-ERK, SRC and NGF protein expression levels in the SGD group were remarkably decreased (P < 0.01, P < 0.001 or P < 0.0001), and the expression level of TRPV1 protein showed a downward trend (P = 0.06). The expression levels of COX-2, NO, CGRP, TRPV1, SRC and NGF mRNA in the dura mater was overtly down-regulated (P < 0.05, P < 0.01 or P < 0.001). CONCLUSIONS: SGD has a significant inhibitory effect on the NGF/TRPV1/COX-2 signaling pathway that mediates central hyperalgesia migraine, thus suggesting the molecular mechanism of SGD in improving the symptoms of migraine may be related to the central hyperalgesia neurotransmitter that regulates the pathogenesis of migraine.

Changes in gamma-aminobutyric acid and glutamate/glutamine levels in the right thalamus of patients with episodic and chronic migraine: A proton magnetic resonance spectroscopy study.

OBJECTIVE: To explore gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the right thalamus of patients with episodic migraine (EM) and chronic migraine (CM) and their effects on the chronification of migraine. BACKGROUND: Migraine affects approximately 1 billion people worldwide, with 2.5%-3% of people with EM progressing to CM each year. Magnetic resonance spectroscopy studies have revealed altered GABA and Glx levels in the thalamus of patients with migraine without aura, but these neurometabolic concentrations are underexplored in the thalamus of patients with CM. METHODS: In this cross-sectional study, patients with EM and CM were recruited. Mescher-Garwood point resolved spectroscopy sequence was used to acquire neurotransmitter concentrations in the right thalamus of patients with EM and CM and matched healthy controls (HCs). RESULTS: A total of 26 patients (EM, n = 11; CM, n = 15) and 16 age- and sex-matched HCs were included in the analysis. There were significantly lower GABA+/Water levels in the right thalamus of the CM group (mean ± standard deviation: 2.27 ± 0.4 [institutional units]) than that of the HC group (2.74 ± 0.4) (p = 0.026; mean difference [MD] = -0.5 [i.u.]), and lower Glx/Cr levels in the EM group (mean ± SD: 0.11 ± < 0.1) than in the HCs (0.13 ± < 0.1) and CM group (0.13 ± < 0.1) (p = 0.023, MD < -0.1, and p = 0.034, MD < -0.1, respectively). The GABA+/Glx ratio was lower in the CM group (mean ± SD: 0.38 ± 0.1) compared to the EM group (0.47 ± 0.1) (p = 0.024; MD = -0.1). The area under the curve for GABA+/Water levels in differentiating patients with CM from HCs was 0.83 (95% confidence interval 0.68, 0.98; p = 0.004). Correlation analyses within the migraine group revealed no significant correlation between metabolite concentration levels and headache characteristics after Bonferroni correction. CONCLUSION: Reduced GABA+/Water levels and imbalance of excitation/inhibition in the right thalamus may contribute to migraine chronification.

FKN/CX3CR1 axis facilitates migraine-Like behaviour by activating thalamic-cortical network microglia in status epilepticus model rats.

BACKGROUND: The incidence of migraines is higher among individuals with epilepsy than in healthy individuals, and these two diseases are thought to shared pathophysiological mechanisms. Excitation/inhibition imbalance plays an essential role in the comorbidity of epilepsy and migraine. Microglial activation is crucial for abnormal neuronal signal transmission. However, it remains unclear whether and how microglia are activated and their role in comorbidities after being activated. This study aimed to explore the characteristics and mechanism of microglial activation after seizures and their effect on migraine. METHODS: Model rats of status epilepticus (SE) induced by intraperitoneal injection of lithium chloride (LiCl)-pilocarpine and migraine induced by repeated dural injections of inflammatory soup (IS) were generated, and molecular and histopathologic evidence of the microglial activation targets of fractalkine (FKN) signalling were examined. HT22-BV2 transwell coculture assays were used to explore the interaction between neurons and microglia. LPS (a microglial agonist) and FKN stimulation of BV2 microglial cells were used to evaluate changes in BDNF levels after microglial activation. RESULTS: Microglia were specifically hyperplastic and activated in the temporal lobe cortex, thalamus, and spinal trigeminal nucleus caudalis (sp5c), accompanied by the upregulation of FKN and CX3CR1 four days after seizures. Moreover, SE-induced increases in nociceptive behaviour and FKN/CX3CR1 axis expression in migraine model rats. AZD8797 (a CX3CR1 inhibitor) prevented the worsening of hyperalgesia and microglial activation in migraine model rats after seizures, while FKN infusion in migraine model rats exacerbated hyperalgesia and microglial activation associated with BDNF-Trkb signalling. Furthermore, in neuron-microglia cocultures, microglial activation and FKN/CX3CR1/BDNF/iba1 expression were increased compared with those in microglial cultures alone. Activating microglia with LPS and FKN increased BDNF synthesis in BV2 microglia. CONCLUSIONS: Our results indicated that epilepsy facilitated migraine through FKN/CX3CR1 axis-mediated microglial activation in the cortex/thalamus/sp5c, which was accompanied by BDNF release. Blocking the FKN/CX3CR1 axis and microglial activation are potential therapeutic strategies for preventing and treating migraine in patients with epilepsy.

Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain.

The pro-nociceptive role of glutamate in the CNS in migraine pathophysiology is well established. Glutamate, released from trigeminal afferents, activates second order nociceptive neurons in the brainstem. However, the function of peripheral glutamate receptors in the trigeminovascular system suggested as the origin site for migraine pain, is less known. In the current project, we used calcium imaging and patch clamp recordings from trigeminal ganglion (TG) neurons, immunolabelling, CGRP assay and direct electrophysiological recordings from rat meningeal afferents to investigate the role of glutamate in trigeminal nociception. Glutamate, aspartate, and, to a lesser extent, NMDA under free-magnesium conditions, evoked calcium transients in a fraction of isolated TG neurons, indicating functional expression of NMDA receptors. The fraction of NMDA sensitive neurons was increased by the migraine mediator CGRP. NMDA also activated slowly desensitizing currents in 37% of TG neurons. However, neither glutamate nor NMDA changed the level of extracellular CGRP. TG neurons expressed both GluN2A and GluN2B subunits of NMDA receptors. In addition, after removal of magnesium, NMDA activated persistent spiking activity in a fraction of trigeminal nerve fibers in meninges. Thus, glutamate activates NMDA receptors in somas of TG neurons and their meningeal nerve terminals in magnesium-dependent manner. These findings suggest that peripherally released glutamate can promote excitation of meningeal afferents implicated in generation of migraine pain in conditions of inherited or acquired reduced magnesium blockage of NMDA channels and support the usage of magnesium supplements in migraine.

Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain.

Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. PERSPECTIVE: This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.

Migraine and Sleep-An Unexplained Association?

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.

Carnitine Responsive Migraine Headache Syndrome: Case Report and Review of the Literature.

PURPOSE OF REVIEW: To review carnitine's role in migraine and headache, present a case of a patient with intractable chronic migraine refractory to medications but exquisitely responsive to mitochondrial cofactors with a particularly prompt response to L-carnitine supplementation with dose response, and suggest scenarios where L-carnitine could be considered for prophylactic treatment in migraine and intractable headache with migraine features. RECENT FINDINGS: Multiple treatments modalities are used to treat migraine, including nutraceutical therapies. Mitochondrial supplements are often used to treat migraine, based on controlled trials. One of the nutraceutical therapies used in neurological and non-neurological conditions is L-carnitine. A few studies have examined the effect of carnitine in patients with migraine. We present a case of a patient with chronic migraine-like headaches found to have carnitine deficiency whose headaches greatly improved with carnitine supplementation. This case suggests that secondary carnitine deficiency may cause chronic migraine. Energy deficiency states occur with migraine, and replenishment of energy substrates has demonstrated some improvement in migraine. Recent studies suggest that L-carnitine with other mitochondrial cofactors may be migraine preventives. The exact link between carnitine and migraine is unknown. Perhaps carnitine deficiency should be in the differential for refractory migraine. Supplementation with L-carnitine merits exploration as a nutraceutical treatment of chronic migraine. Our case suggests that there may be a dose-dependent response to L-carnitine.

The association between melatonin and episodic migraine: A pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy.

Although exogenous melatonin supplementation has been suggested to be effective for episodic migraine prophylaxis, there is no conclusive evidence comparing the efficacy of exogenous melatonin supplementation to the other FDA-approved pharmacotherapy for episodic migraine prophylaxis. The aim of the current network meta-analysis (NMA) was to compare the efficacy of exogenous melatonin supplementation in patients with episodic migraine. The randomized placebo-controlled trials or randomized controlled trials (RCTs) incorporating a placebo in the study designs were included in our analyses. All of the NMA procedures were conducted under the frequentist model. The primary outcome was changes in frequency of migraine days and response rate after migraine prophylaxis with melatonin supplementation or pharmacological interventions. We included 25 RCTs in total with 4499 patients (mean age = 36.0 years, mean female proportion = 78.9%). The NMA demonstrated that migraine prophylaxis with oral melatonin 3 mg/d (immediate-release) at bedtime was associated with the greatest improvement in migraine frequency [mean difference = -1.71 days, 95% confidence interval (CI): -3.27 to -0.14 days compared to placebo] and the second highest response rate (odds ratio = 4.19, 95% CI = 1.46 to 12.00 compared to placebo). Furthermore, oral melatonin 3 mg (immediate-release) at bedtime was the most preferred pharmacological intervention among all of the investigated interventions when improvements in migraine frequency, response rate, dropout rate, and rates of any adverse events were taken into account. This pilot NMA suggests the potential prophylactic role of exogenous melatonin supplementation in patients with episodic migraine.

Evodiamine via targeting nNOS and AMPA receptor GluA1 inhibits nitroglycerin-induced migraine-like response.

ETHNOPHARMACOLOGICAL RELEVANCE: Evodiamine (EVO) is a natural compound derived from Tetradium ruticarpum (A.Juss.) T.G.Hartley used to treat pain and migraine in traditional Chinese medicine. EVO is the primary active ingredient of Tetradium ruticarpum. However, the preventive effect of EVO against migraine remains unexplored. AIM OF THE STUDY: To investigate the preventive effect of EVO against nitroglycerin (NTG)-induced acute migraine in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were intragastrically administered EVO (45 or 90 mg/kg) for nine days. To establish an acute migraine model, we subcutaneously injected rats with a 10 mg/kg NTG solution. The migraine-like behavior of the rats was evaluated via the formalin test and the warm water tail-withdrawal assay. The periaqueductal gray (PAG) and serum samples were collected from the rats and used to determine the effect of EVO on the levels of serum nitric oxide (NO), CGRP, c-Fos, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor GluA1. RESULTS: The formalin test and the warm water tail-withdrawal assay showed that EVO inhibited the licking foot/shaking response and reversed the shortened tail-withdrawal latency in NTG-treated rats. Additionally, EVO suppressed serum NO levels and reduced the mRNA/protein expression of c-Fos and nNOS, but not iNOS, in the PAG. Furthermore, EVO suppressed total protein expression of the AMPA receptor GluA1 and its phosphorylation at Ser831 and Ser845. CONCLUSIONS: This study showed that EVO inhibits the migraine-like pain response and that this beneficial effect might be attributed to the regulation of nNOS and suppression of the AMPA receptor GluA1. We suggest that EVO has the potential to treat migraine as a lead compound of natural origin.

The distribution of oxytocin and the oxytocin receptor in rat brain: relation to regions active in migraine.

BACKGROUND: 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. METHODS: Distribution of OT and OTR in the adult, rat brain was qualitatively examined with immunohistochemistry using a series of well characterized specific antibodies. RESULTS: 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). CONCLUSIONS: 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.

Episodic primary migraine headache: supplementary prophylaxis with Pycnogenol® prevents attacks and controls oxidative stress.

BACKGROUND: This registry study investigated the supplement Pycnogenol® on migraine headache attacks and oxidative stress in otherwise healthy subjects with migraine and moderate headache (MH). METHODS: To manage MH, these subjects used only a few drugs (antiemetics, analgesics on demand) and lifestyle changes; only very occasionally they used other, more specific products such as triptans. Study groups: one group used only standard management (SM), basically, management on demand. Oral magnesium and riboflavin (vitamin B2) were used with lipoic acid as they are considered useful to improve MH. Another group used the supplement Pycnogenol® (150 mg/day for 8 weeks) in addition to SM. These two groups were compared to a third (non-parallel, observational) group using topiramate (50 mg/day). If needed, subjects were allowed to use rescue medications. RESULTS: Forty-six subjects were included in the study. Twenty-two used the standard management and 24 were supplemented with Pycnogenol® in association with SM. In addition, 21 subjects were treated with topiramate. Safety with Pycnogenol® was very good. The two main management groups and the third non-parallel group had comparable baseline characteristics. The number of migraine attacks were significantly reduced during the observation period with Pycnogenol® (P<0.05) in comparison with SM. Supplementation was more effective in reducing the use of rescue medications (P<0.05) including analgesics compared to SM. At 8 weeks, the pain score was lower with Pycnogenol in comparison with SM (P<0.05). The working incapacity was significantly lower with Pycnogenol® than in the SM group (P<0.05). The number of migraine attacks was lower with topiramate compared to SM. Pain score, working incapacity and use of rescue medication were lower with topiramate than in SM. However, adverse effects with topiramate, included paresthesia, fatigue, dizziness and nausea even at low dosages complicated management. Some 50% of these side effects require a form of further treatment including medications. Oxidative stress: all included subjects had high oxidative stress at baseline. At 8 weeks, the level of plasma free radicals was significantly lowered with Pycnogenol® (P<0.05), but not in the SM or topiramate group. CONCLUSIONS: Pycnogenol® used as prophylaxis appears to reduce pain and the number and severity of symptoms in MH in parallel with a reduction of oxidative stress.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Traditional and Novel Migraine Therapy in the Aging Population.

Migraine is a common disabling disorder that affects 36 million Americans. The clinical features of migraine are less typical in the people above age 60, making the diagnosis and treatment difficult in this group. In this review, we will discuss migraine-specific drugs and their use in populations about age 60 who suffer from migraine. This discussion will include an overview of traditional treatments for the acute and preventive treatment of migraine, and considerations for their use in patient populations above age 60. In addition, we will discuss newer agents that show a more promising safety profile.

Electroacupuncture exerts an anti-migraine effect via modulation of the 5-HT7 receptor in the conscious rat.

BACKGROUND: Acupuncture has been recommended as an alternative therapy for migraine. Emerging evidence suggests that the 5-HT7 receptor (5-HT7R) plays a significant facilitatory role in descending modulation in migraine pathophysiology, and that activation of 5-HT7R in the descending pathway is involved in migraine central sensitisation. OBJECTIVE: To investigate the ability of electroacupuncture (EA) to ameliorate central sensitisation via modulation of 5-HT7R in the descending pain pathways using a rat model of migraine induced by repetitive dural electrical stimulation (DES). DESIGN: 64 male Sprague-Dawley rats were randomly divided into four groups: Normal group; DES group (receiving dural electrical stimulation only); DES+GB20 group (DES model group treated with EA at GB20); and DES+Sham group (DES model group treated with EA at a non-traditional (sham) acupuncture point). The presence of cutaneous allodynia was determined by measuring facial and hind-paw withdrawal latencies to electronic von-Frey. The expression of 5-HT7R in the descending pathways (periaqueductal grey, raphe magnus nucleus, and trigeminal nucleus caudalis) was assessed using immunofluorescence and Western blotting. RESULTS: Facial and hind-paw withdrawal thresholds were significantly increased in the DES+GB20 group compared with the untreated DES group. The expression of 5-HT7R was significantly decreased in the DES+GB20 group compared with the DES group (one-way analysis of variance (ANOVA), P<0.05). No significant differences in behaviour or expression were found between the rats in the DES+Sham group and the untreated DES group (one-way ANOVA, P>0.05). CONCLUSION: EA at GB20 may ameliorate central sensitisation in migraine by inhibiting the activation of 5-HT7 receptors in the descending pain pathway in a rat model of migraine.

Alkaloids from the rhizomes of Ligusticum striatum exert antimigraine effects through regulating 5-HT1B receptor and c-Jun.

ETHNOPHARMACOLOGICAL RELEVANCE: Migraine is a prevalent, complex, painful, and disabling neurovascular disorder that places an enormous social and economic burden on patients. Rhizome Chuanxiong (RCX), the dried rhizomes of Ligusticum striatum DC., has been widely used in the clinic for the treatment of migraine for centuries in China. Total alkaloids (TAs) are considered to be important effective ingredients of L. striatum, especially for cardiovascular and cerebrovascular diseases. However, there has been no study published, to date, reporting the antimigraine effects of TAs from RCX (RCXTAs). AIM OF THE STUDY: The present study was designed to evaluate the antimigraine effects of RCXTAs and explore the underlying mechanisms in an experimental migraine rat model. MATERIALS AND METHODS: RCXTAs were prepared in accordance with our previous optimized preparation process. A nitroglycerin-induced migraine model in rats and a reserpine-induced migraine model in mice were established to investigate the effects of RCXTAs on monoamine neurotransmitters in brain tissue, including 5-hydroxytryptamine (5-HT) and its metabolite (5-HIAA). Migraine rats or mice were divided into six groups as follows: control; model; zolmitriptan (1.67 mg/kg); and low-, medium-, and high-dose RCXTAs (12.5, 25, and 50 mg/kg, respectively). The levels of 5-HT and 5-HIAA in the brains of rats and mice were determined by using the enzyme-linked immunosorbent assay method. Pathological changes in the brains of migraine rats were examined by immunohistochemistry. The protein expression of 5-HT1B receptor, c-Fos, and c-Jun in the periaqueductal gray (PAG) of migraine rats was measured by Western blot. RESULTS: After preventive administration of RCXTAs to the nitroglycerin-induced migraine rats, the levels of 5-HT and 5-HIAA in the brain tissue were generally upregulated in all three RCXTA dose groups, a finding that was similar to that observed in the control group. Additionally, the 5-HT and 5-HIAA levels were significantly increased in the medium- and high-dose RCXTA groups when compared with the model group (p < 0.01). Therapeutical administration of RCXTAs to reserpine-induced migraine mice also inhibited the reduction of 5-HT and 5-HIAA in the brain (p < 0.01). Both immunohistochemistry and Western blot tests showed that RCXTAs pretreatment has significantly upregulated 5-HT1B receptor expression and downregulated c-Jun expression in the nitroglycerin-induced migraine rats. CONCLUSIONS: RCXTAs exerted significant preventive and therapeutic effects on migraine via increasing the levels of 5-HT and 5-HIAA. Upregulation of the expression of monoamine neurotransmitter 5-HT1B receptor and downregulation of the expression of c-Jun were the possible mechanisms.

The Neuromodulatory Effects of ω-3 Fatty Acids and Nano-Curcumin on the COX-2/ iNOS Network in Migraines: A Clinical Trial Study from Gene Expression to Clinical Symptoms.

BACKGROUND: Migraine is a common neuroinflammatory disorder characterized by recurrent attacks of pain. Human and experimental models of migraine studies have demonstrated the role played by COX-2/ iNOS in migraine's neuroinflammatory pathogenesis. COX-2 and iNOS are closely linked and both contribute to inflammation and neurogenic pain in the central nervous system. Omega- 3 fatty acids and curcumin, an active polyphenol of turmeric, have anti-inflammatory and neuroprotective effects through several mechanisms, including the suppression of COX-2 and iNOS gene expression, as well as their serum levels. The aim of the present study is to evaluate the nutrigenomic effects of ω-3 fatty acids, nano-curcumin, and a combination of the two, on neuroinflammation and clinical symptoms in migraine patients. METHODS: This study reports the results of a clinical trial over a 2-month period, involving 74 episodic migraine patients who received ω-3 fatty acids, nano-curcumin, a combination of them, or a placebo. At the start and end of the study, the expression of COX-2/iNOS (in peripheral mononuclear blood cells isolated from patients) and COX-2/iNOS serum levels were measured, using real-time PCR and ELISA respectively. The frequency, severity and duration of pain attacks were also recorded. RESULTS: The results of the present trial showed that ω-3 fatty acids and nano-curcumin can reinforce each other's effects in the downregulation of COX-2/iNOS mRNA, as well as reduce their serum levels. In addition, the combination of ω-3 and nano-curcumin significantly reduced the frequency, severity and duration of headaches (P<0.05). CONCLUSION: These findings indicate that combination therapy of ω-3 fatty acids and nano-curcumin can be considered as a promising new approach in migraine prevention.

Emerging relevance of circadian rhythms in headaches and neuropathic pain.

Circadian rhythms of physiology are the keys to health and fitness, as dysregulation, by genetic mutations or environmental factors, increases disease risk and aggravates progression. Molecular and physiological studies have shed important light on an intrinsic clock that drives circadian rhythms and serves essential roles in metabolic homoeostasis, organ physiology and brain functions. One exciting new area in circadian research is pain, including headache and neuropathic pain for which new mechanistic insights have recently emerged. For example, cluster headache is an intermittent pain disorder with an exceedingly precise circadian timing, and preliminary evidence is emerging linking several circadian components (eg, Clock and Nr1d1) with the disease. In this review, we first discuss the broad metabolic and physiological relevance of the circadian timing system. We then provide a detailed review of the circadian relevance in pain disease and physiology, including cluster headache, migraine, hypnic headache and neuropathic pain. Finally, we describe potential therapeutic implications, including existing pain medicines and novel clock-modulating compounds. The physiological basis for the circadian rhythms in pain is an exciting new area of research with profound basic and translational impact.

Long-chain omega-3 fatty acids and headache in the U.S. population.

The objective of this study was to assess whether dietary intake of long-chain omega-3 polyunsaturated fatty acids (PUFAs) is associated with lower prevalence of headache in the U.S. POPULATION: This cross-sectional study used data for a nationally representative sample of 12,317 men and women aged ≥ 20 years participating in the National Health and Nutrition Examination Surveys of 1999-2004. Interviewers recorded self-report of severe headache or migraine in the past three months. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were quantified from 24-hour dietary recall using the U.S. Department of Agriculture National Nutrient Database. Serum concentration of C-reactive protein, a marker of inflammation and potential mediator of PUFA's analgesic properties, was quantified by latex-enhanced nephelometry. Multivariable generalized linear models estimated prevalence ratios (PR) with 95% confidence limits (CL) for severe headache or migraine adjusting for NHANES cycle, sociodemographic characteristics, body mass index and total energy intake. The unadjusted prevalence of severe headache or migraine was 22.0% (females 28.2%, males 15.5%). In multivariable analysis, greater intake of omega-3 PUFAs was associated with lower prevalence of severe headache or migraine: PR 0.94 (95% CL: 0.88, 0.99, p = 0.035) per log unit increase in EPA, and PR 0.94 (95% CL: 0.90, 0.99, p = 0.023) per log unit increase in DHA. The strength of association was greater for non-Mexican Hispanics than for other racial/ethnic groups but was not attenuated after adjustment for C-reactive protein. In conclusion, higher dietary intakes of EPA and DHA were associated with lower prevalence of headache supporting the hypothesis that omega-3 PUFAs may prevent or reduce headache.

Increased thalamic glutamate/glutamine levels in migraineurs.

BACKGROUND: Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexcitability has been reported. Levels of regional excitatory and inhibitory neurotransmitters are related to cortical excitability and hence may play a role in the origin of the disease. Consequently, a mismatch of the excitatory-inhibitory neurotransmitter network might contribute to local hyperexcitability and the onset of migraine attacks. In this study we sought to assess local levels of glutamate / glutamine (GLX) and gamma-aminobutyric acid (GABA) in the occipital cortex and right thalamus of migraineurs and healthy subjects. METHODS: We measured interictally local biochemical concentrations in the occipital lobe and the right thalamus in patients with migraine (without aura) and healthy controls (HCs) using proton magnetic resonance spectroscopy at 3 T. GLX levels were acquired using PRESS and GABA levels using the GABA-sensitive editing sequence MEGA-PRESS. Regional GLX and GABA levels were compared between groups. RESULTS: Statistical analyses revealed significantly increased GLX levels in both the primary occipital cortex and thalamus. However, we found no group differences in GABA levels for these two regions. Correlation analyses within the migraine group revealed no significant correlations between pain intensity and levels of GLX or GABA in either of the two brain regions. CONCLUSIONS: Further research is needed to investigate the role of GABA/GLX ratios in greater depth and to measure changes in neurotransmitter levels over time, i.e. during migraine attacks and interictally.