Preventive Treatment for Episodic Migraine.

Episodic migraine is a debilitating condition. Preventive therapy is used to reduce frequency, duration, or severity of attacks. This review discusses principles of preventive treatment with a focus on preventive treatment options for people with episodic migraine. Specifically discussed is evidence and use of new migraine-specific treatment options for episodic migraine, such as calcitonin gene-related peptide monoclonal antibodies, a noninvasive transcutaneous electrical nerve stimulation device, and a single-pulse transcranial magnetic stimulator device. Also discussed are evidence-based updates from the 2012 American Academy of Neurology and the American Headache Society guidelines regarding major medication classes recommended for preventive episodic migraine treatment.

Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor.

CONTEXT: Calcitonin gene-related peptide (CGRP), substance P and nerve growth factor play an important role in inflammatory pain in various somatic pain models but their role in chronic pancreatitis has not been well studied. OBJECTIVES: The aim of this study was to investigate the effects of intrathecal administration of calcitonin gene-related peptide antagonist and substance P receptor antagonist on pain behavior in a rat model of chronic pancreatitis and to determine whether nerve growth factor drives the up-regulation of expression of these neuropeptides in sensory neurons. METHODS: Pancreatitis was induced by retrograde infusion of trinitobenzene sulfonic acid into the pancreatic duct of adult rats. Three weeks post infusion continuous intrathecal infusion of the calcitonin gene-related peptide antagonist alpha CGRP8-37 or neurokinin-1 receptor antagonist CP-96345 or its inactive enantiomer CP-96344 was administered for seven days. The effects of treatment on pancreatic hyperalgesia were assessed by sensitivity of the abdominal wall to von Frey filament probing as well as by the nocifensive response to electrical stimulation of the pancreas. In a separate experiment chronic pancreatitis was induced and pancreas specific dorsal root ganglion neurons labeled with DiI were assessed for calcitonin gene-related peptide and substance P immunoreactivity. RESULTS: Intrathecal infusion of calcitonin gene-related peptide and neurokinin-1 receptor antagonists significantly attenuated behavioral pain responses in rats with chronic pancreatitis. Further, treatment of chronic pancreatitis rats with nerve growth factor antibody significantly reduced pancreas specific neurons expressing calcitonin gene-related peptide and substance P in thoracic dorsal root ganglion. CONCLUSIONS: Calcitonin gene-related peptide and substance P mediate pancreatic hyperalgesia in chronic pancreatitis and nerve growth factor in turn sustains the up-regulation of these neuropeptides in pancreatic sensory neurons.

Centrally administered adrenomedullin 5 activates oxytocin-secreting neurons in the hypothalamus and elevates plasma oxytocin level in rats.

We examined the effects of i.c.v. administration of adrenomedullin 5 (AM5) on the brain of conscious rats. We used porcine AM5 in the present study because rat AM5 has not been detected. We observed Fos-like immunoreactivity (LI) in the hypothalamus and brainstem of conscious rats after i.c.v. administration of AM5 (2 nmol/rat). Fos-LI, measured at 90 min post-AM5 injection, was observed in various brain areas, including the supraoptic (SON) and the paraventricular nuclei (PVN). Dual immunostaining for Fos/oxytocin (OXT) and Fos/arginine vasopressin (AVP) revealed that OXT-LI neurones predominantly colocalized Fos-LI compared with AVP-LI neurones in the SON and the PVN. Plasma OXT levels were significantly increased 5 min after i.c.v. administration of AM5 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 15 and 30 min without changes in plasma AVP levels at any time. In situ hybridization histochemistry showed that i.c.v. administration of AM5 (0.2, 1 and 2 nmol/rat) caused a marked induction of the expression of the c-fos gene in the SON and the PVN. This induction was significantly but not completely reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37; 3 nmol/rat) and the AM receptor antagonist AM-(22-52; 27 nmol/rat). Although porcine AM5 has not been detected yet in the brain, these results suggest that centrally administered porcine AM5 may activate OXT-secreting neurosecretory cells in the hypothalamus partly through AM/CGRP receptors and elicit secretion of OXT into the systemic circulation in conscious rats.

Adrenomedullin 2 (AM2)/intermedin is a more potent activator of hypothalamic oxytocin-secreting neurons than AM possibly through an unidentified receptor in rats.

Central administration of either adrenomedullin 2 (AM2) or adrenomedullin (AM) activates hypothalamic oxytocin (OXT)-secreting neurons in rats. We compared AM2 with AM, given intracerebroventricularly (icv), across multiple measures: (1) plasma OXT levels in conscious rats; (2) blood pressure, heart rate and circulating catecholamine levels in urethane-anesthetized rats; and (3) the expression of the c-fos gene in the supraoptic (SON) and the paraventricular nuclei (PVN). We also tested the effects of the AM receptor antagonist, AM(22-52) and calcitonin gene-related peptide (CGRP) antagonist, CGRP(8-37) on these measures. Plasma OXT levels at 10 min after icv injection of AM (1 nmol/rat) were increased (compared with vehicle), but OXT levels after AM2 (1 nmol/rat) were nearly double the levels seen after AM injection. OXT levels remained elevated at 30 min. Pretreatment with AM(22-52) (27 nmol/rat) and CGRP(8-37) (3 nmol/rat), nearly abolished the increase in plasma OXT level after AM injection, but partially blocked OXT level changes due to AM2. Increases in blood pressure, heart rate and circulating catecholamines were all greater in response to central AM2 than to AM at the same dose. In situ hybridization histochemistry showed that both AM2 and AM induced expression of the c-fos gene in the SON and the PVN, but AM(22-52)+CGRP(8-37) could only nearly abolish the effects of centrally administered AM. These results suggest that the more potent central effects of AM2 and only partial blockade by AM/CGRP receptor antagonists may result from its action on an additional, as yet unidentified, specific receptor in the central nervous system.

A protective role for calcitonin gene-related peptide in water-immersion stress-induced gastric ulcers in rats.

This study investigated the role of endogenous and exogenous calcitonin gene-related peptide (CGRP) in water immersion stress (WIS)-induced gastric ulcers in rats. WIS produced gastric ulcers which were inversely correlated to the decrease in CGRP-like immunoreactivity observed in the whole thickness of the corpus stomach but not in its mucosal layers. Systemic administration of CGRP (100 micrograms kg-1 s.c.) produced a significant decrease in lesion index of WIS-ulcers and this protection was inhibited by functional ablation of afferent neurons induced by capsaicin pretreatment (100 mg kg-1 s.c. in two days, a week before the experiments). These findings suggest that sensory endogenous CGRP plays a defensive role in WIS-ulcers.

Inhibition by actinomycin D of neurogenic mouse ear oedema.

We have investigated the effects of actinomycin D on mouse ear oedema induced by capsaicin, neuropeptides, and established inflammatory mediators. Actinomycin D (0.5 mg/kg, i.v.) significantly (P < 0.01) inhibited ear oedema induced by topical application of capsaicin, while adriamycin (6.0 mg/kg, i.v.) and cycloheximide (6.0 mg/kg, i.v.) had no effect on oedema. The ear oedema induced by intradermal injection of neuropeptides such as mammalian tachykinins, calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP), was markedly (P < 0.05, P < 0.01 or P < 0.001) suppressed by actinomycin D. The drug was also effective (P < 0.01 or P < 0.001) in inhibiting bradykinin (BK)- and compound 48/80-induced ear oedema, but did not inhibit oedema induced by histamine, 5-HT, leukotriene C4 (LTC4), and platelet activating factor (PAF) at a dose of 1 mg/kg. In mast cell-deficient W/WV mice, actinomycin D (1.0 mg/kg, i.v.) failed to inhibit substance P (SP)-induced ear oedema whereas spantide (0.5 mg/kg, i.v.) was an effective (P < 0.01) inhibitor of oedema formation. Furthermore, actinomycin D (10-100 microM) dose-dependently prevented histamine release from rat peritoneal mast cells evoked by SP, compound 48/80, and the ionophore A23182, respectively. These results strongly suggest that an inhibitory effect of actinomycin D on neurogenic inflammation is due primarily to the prevention of mast cell activation mediated by neuropeptides, rather than an interaction with DNA or receptors of neuropeptides.

Plasma protein extravasation into the rat knee joint induced by calcitonin gene-related peptide.

In previous experiments, intra-articular administration of calcitonin gene-related peptide (CGRP) failed to elicit plasma protein extravasation into synovial fluid. In the present study, using a sensitive technique to assay protein in synovial fluid, intra-articular perfusion of CGRP (10(-6) M) was found to produce protein extravasation which was sustained throughout the period of infusion. Both lower (10(-7) M) and higher (10(-5) M) concentrations of CGRP failed to produce extravasation. This failure at the highest concentration of CGRP was the likely consequence of a significant fall in arterial blood pressure which occurred with administration of CGRP at this concentration. In the presence of arterial hypotension induced by an alpha-adrenoceptor antagonist, 10(-6) M CGRP failed to produce extravasation. Plasma extravasation induced by CGRP was a specific effect and not merely a consequence of its potent vasodilator properties as similar vasodilator responses induced by a beta-adrenoceptor agonist failed to induce protein leakage. These findings indicate that CGRP can alter blood vessel permeability and therefore could additionally contribute to neurally mediated inflammatory responses.

Microinjection of alpha-calcitonin gene-related peptide into the hypothalamus activates sympathetic outflow in rats.

Effect of rat alpha-calcitonin gene-related peptide (alpha-CGRP) microinjected into various hypothalamic nuclei on plasma levels of catecholamines and arterial blood pressure were investigated in urethane-anesthetized rats. alpha-CGRP (0.05 and 0.25 nmol) microinjected into the hypothalamic paraventricular nucleus (PVN) increased the plasma level of noradrenaline (NA), but not that of adrenaline (AD), in a dose-dependent manner. A similar increase in plasma level of NA was also observed by alpha-CGRP (0.05 nmol) microinjected into the preoptic area (POA), anterior hypothalamus (AH), dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). A significant increase in arterial blood pressure was observed by microinjection of alpha-CGRP (0.05 nmol) into the PVN, POA, AH and DMH, and the most prominent increase was caused by its microinjection into the PVN. Microinjection of the same dose of this peptide into the VMH, lateral hypothalamic area and posterior hypothalamus was without effect. The increase in plasma level of NA induced by alpha-CGRP (0.05 nmol) into the PVN was not affected by bilateral adrenalectomy. Electrical stimulation of the PVN elicited increases in plasma levels of both NA and AD. This increase in NA was abolished by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.v., 3 days before experiments). These results suggest that activation of the PVN by electrical stimulation elicits both sympathetic and adrenomedullary outflow. alpha-CGRP microinjected into the PVN selectively activates the sympathetic outflow.

Peptides in the parabrachial nucleus modulate visceral input to the thalamus.

The role of neuropeptides in ascending visceral pathways was investigated by recording the changes in the response of thalamic neuronal activity evoked by vagal stimulation before and after peptide injection in the parabrachial nucleus (PB). Male Wistar rats (n = 25) were anesthetized with chloral hydrate and ventilated, and blood pressure and heart rate were continuously monitored. The left cervical vagus nerve was stimulated at submaximal current intensities to elicit changes in single and multiunit activity in the parvocellular visceral relay nuclei in the ventral basal thalamus. Peristimulustime histograms of thalamic activity were made before and after 200-nl injections of peptides or artificial cerebrospinal fluid (CSF) controls in the PB. Injection of calcitonin gene-related peptide (CGRP) at 5 mM or substance P (SP) at 2 mM into the PB significantly attenuated the evoked response of thalamic neuronal activity by 87-100% and 85-100%, respectively. Injections of somatostatin (SOM; 1 mM) did not significantly alter the response evoked by vagal stimulation but significantly inhibited the spontaneous firing of thalamic units, resulting in a 10-fold increase in the response-to-background ratio. This suggests that SOM in the PB inhibits cells in a parallel pathway that terminates on thalamic visceral neurons but that are not part of the ascending visceral sensory pathway. Spontaneous thalamic neuronal activity and vagally evoked responses were significantly enhanced (278-508%) by injection of 1 mM neurotensin (NT) in the PB. Cholecystokinin (CCK) at low doses (0.0002-0.2 mM) attenuated while the highest dose, 2 mM, briefly excited the spontaneous activity of thalamic units before inhibiting their activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Tests of adipsia and conditioned taste aversion following the intrahypothalamic injection of amylin.

Intrahypothalamic injection of amylin (AMY) was shown to reduce the intake of rat chow and water for 8 and 4 h, respectively, in schedule-fed rats. Amylin also reduced water intake to a much lesser degree in 24-h water-deprived rats. A test of the ability of AMY to form a conditioned taste aversion yielded no change in saccharin preference, as compared to controls treated with vehicle. These results suggest that although AMY has adipsic effects, the reduction in water is not of sufficient magnitude to cause the anorexia. In addition, the failure of AMY to support a conditioned taste aversion suggests that AMY does not cause anorexia by inducing malaise. Therefore, in addition to other metabolic effects, AMY may be involved in the control of food and water intake.

Calcitonin gene-related peptide depresses the growth and secretory activity of rat adrenal zona glomerulosa.

The bolus ip. injection of rat calcitonin gene-related peptide (CGRP) (5 pm. kg-1) significantly lowered plasma aldosterone concentration (PAC) in rats, despite a mild rise in plasma renin activity. Natremia, kalaemia and the blood levels of ACTH or corticosterone were not affected. Similar results were obtained after prolonged (5 days) sc. infusion of rats with CGRP (1 pm. kg-1. h-1). Moreover, CGRP infusion caused a notable atrophy of the zona glomerulosa (ZG) and its parenchymal cells, as well as a clearcut reduction in the surge of PAC evoked by a bolus injection of a high dose of angiotensin-II (100 micrograms. kg-1). From these results it is suggested that CGRP exerts an inhibitory effect on the growth and secretory activity of ZG in rats.