The hypothalamic orexinergic system: pain and primary headaches.
ABSTRACT The primary headaches are a group of distinct individually characterized attack forms, which although varying in presentation, share some common anatomical basis responsible for the pain component of the attack. The hypothalamus is known to modulate a multitude of functions and has been shown to be involved in the pathophysiology of a variety of primary headaches including cluster headache and chronic migraine. It seems likely that it may be involved in other primary headache disorders due to their episodic nature and may underlie many of their diverse symptoms. We discuss the hypothalamic involvement in the modulation of trigeminovascular processing and examine the involvement of the hypothalamic orexinergic system as a key regulator of this function.
Article: Animal models of chronic migraine.[Show abstract] [Hide abstract]
ABSTRACT: Many animal models of migraine have been described. Some of them have been useful in the development of new therapies. All of them have their shortcomings. Animal models of chronic migraine have been relatively less frequently described. Whether a rigid distinction between episodic and chronic migraine is useful when their underlying pathophysiology is likely to be the same and that migraine frequency probably depends on complex polygenic influences remains to be determined. Any model of chronic migraine must reflect the chronicity of the disorder and be reliable and validated with pharmacological interventions. Future animal models of chronic migraine are likely to involve recurrent activation of the trigeminal nociceptive system. Valid models would provide a means for investigating pathophysiological mechanism of the transformation from episodic to chronic migraine and may also be used to test the efficacy of potential preventive medications.Current Pain and Headache Reports 01/2015; 19(1):467. · 2.26 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Migraine is the most common neurological disorder and one of the most common chronic pain conditions. Despite its prevalence, the pathophysiology leading to migraine is poorly understood and the identification of new therapeutic targets has been slow. Several processes are currently thought to contribute to migraine including altered activity in the hypothalamus, cortical-spreading depression (CSD), and afferent sensory input from the cranial meninges. Decreased extracellular pH and subsequent activation of acid-sensing ion channels (ASICs) may contribute to each of these processes and may thus play a role in migraine pathophysiology. Although few studies have directly examined a role of ASICs in migraine, studies directly examining a connection have generated promising results including efficacy of ASIC blockers in both preclinical migraine models and in human migraine patients. The purpose of this review is to discuss the pathophysiology thought to contribute to migraine and findings that implicate decreased pH and/or ASICs in these events, as well as propose issues to be resolved in future studies of ASICs and migraine. This article is part of a Special Issue entitled 'ASIC Channels'. Copyright © 2015. Published by Elsevier Ltd.Neuropharmacology 01/2015; · 4.82 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: OBJECT Spontaneous intracranial hypotension is an increasingly recognized cause of headaches. Pituitary enlargement and brain sagging are common findings on MRI in patients with this disorder. The authors therefore investigated pituitary function in patients with spontaneous intracranial hypotension. METHODS Pituitary hormones were measured in a group of 42 consecutive patients with spontaneous intracranial hypotension. For patients with hyperprolactinemia, prolactin levels also were measured following treatment. Magnetic resonance imaging was performed prior to and following treatment. RESULTS The study group consisted of 27 women and 15 men with a mean age at onset of symptoms of 52.2 ± 10.7 years (mean ± SD; range 17-72 years). Hyperprolactinemia was detected in 10 patients (24%), ranging from 16 ng/ml to 96.6 ng/ml in men (normal range 3-14.7 ng/ml) and from 31.3 ng/ml to 102.5 ng/ml in women (normal range 3.8-23.2 ng/ml). In a multivariate analysis, only brain sagging on MRI was associated with hyperprolactinemia. Brain sagging was present in 60% of patients with hyperprolactinemia and in 19% of patients with normal prolactin levels (p = 0.02). Following successful treatment of the spontaneous intracranial hypotension, hyperprolactinemia resolved, along with normalization of brain MRI findings in all 10 patients. CONCLUSIONS Spontaneous intracranial hypotension is a previously undescribed cause of hyperprolactinemia. Brain sagging causing distortion of the pituitary stalk (stalk effect) may be responsible for the hyperprolactinemia.Journal of Neurosurgery 11/2014; · 3.23 Impact Factor
CURRENT REVIEW: BASIC SCIENCE
The Hypothalamic Orexinergic System:
Pain and Primary Headaches
Philip Holland, PhD; Peter J. Goadsby, MD, PhD
The primary headaches are a group of distinct individually
characterized attack forms, which although varying in
presentation, share some common anatomical basis
responsible for the pain component of the attack. The
hypothalamus is known to modulate a multitude of functions
and has been shown to be involved in the pathophysiology of
a variety of primary headaches including cluster headache and
chronic migraine. It seems likely that it may be involved in
other primary headache disorders due to their episodic nature
and may underlie many of their diverse symptoms. We
discuss the hypothalamic involvement in the modulation of
trigeminovascular processing and examine the involvement of
the hypothalamic orexinergic system as a key regulator of this
Key words: hypothalamus, primary headache, orexin
Abbreviations: TTH tension type headache, CH cluster headache,
TAC’s trigeminal autonomic cephalalgias, NPY neuropeptide Y, NA
noradrenaline, ATP adenosine triphosphate, VIP vasoactive
intestinal peptide, PHI peptide histidine isoleucine, AChe
acetylcholinesterase, PHM peptide histidine methionine 27, PACAP
pituitary cyclase-activating peptide, SP substance P, CGRP
calcitonin gene-related peptide, NKA neurokinin A, TNC
trigeminal nucleus caudalis, PAG periaqueductal gray, NST nucleus
tractus solitarius, RVM rostroventromedial medulla, NRM nucleus
raphe magnus, MPO medial preoptic nucleus, PVN paraventricular
nucleus, SCN suprachiasmatic nucleus, SUNCT short-lasting
unilateral neuralgiform headache with conjunctival injection and
tearing, OX1R orexin 1 receptor, OX2R orexin 2 receptor, VLM
ventrolateral reticular formation, PBN parabrachial nucleus,
N-(2-Methyl-6-benzoxazolyl)-N-1,5-naphthyridin-4-yl urea, DRN
dorsal raphe nucleus
For CME, visit http://www.headachejournal.org
From Headache Group, Institute of Neurology, The National Hospital for Neurology and
Neurosurgery, London, UK (Drs. Holland and Goadsby); Department of Neurology, Univer-
sity of California, San Francisco, San Francisco CA, USA (Dr. Goadsby).
Address all correspondence to Dr. Peter J. Goadsby, Institute of Neurology, Queen Square,
London, WC1N 3BG, UK.
Accepted for publication March 21, 2007.
C ?2007 the Authors
Journal compilation C ?2007 American Headache Society
The primary headaches are a group of distinct individually char-
acterized attack forms including migraine, tension type headache
(TTH), cluster headache (CH), and other trigeminal autonomic
cephalalgias (TAC’s).1It is now widely believed that the primary
Ray and Wolff initially identified that a variety of stimuli could
rise to the majority of afferent fibers innervating the head, face,
and dural vasculature and for this reason it is of great importance
to primary headaches.3,4
The rich innervation of the vasculature and meninges of the brain
provides a dense plexus of mainly unmyelinated fibers that arise
from the trigeminal ganglion and to a lesser extent the upper cer-
of the anatomy and physiology of the pain-producing structures.
The peripheral branch consisting of the cranial circulation and
dura mater receives sympathetic, parasympathetic, and sensory
ters (Fig. 1). Sympathetic nerve fibers arising from the superior
cervical ganglion supply the cranial vasculature with neuropep-
tide Y (NPY), noradrenaline (NA), and adenosine triphosphate
(ATP). Parasympathetic nerve fibers arising from the sphenopala-
tine and otic ganglia as well as the carotid miniganglia, supply
the cranial vasculature with vasoactive intestinal peptide (VIP),
peptide histidine isoleucine (PHI), acetylcholinesterase (AChE),
cyclase-activating peptide (PACAP), and other VIP-related pep-
tides.5Sensory nerve fibers arising from the trigeminal ganglion
supply the cranial vasculature with substance P (SP), calcitonin
gene-related peptide (CGRP), neurokinin A (NKA), and PACAP.
Bipolar trigeminovascular afferents innervating the cranial struc-
trigeminal nucleus caudalis (TNC), which is the key relay cen-
ter for transmission of nociceptive information to higher brain
ASCENDING NOCICEPTIVE PROJECTIONS
FROM THE TNC
Nociceptive stimulation activates neurons in the TNC, which
project to multiple brainstem, thalamic, hypothalamic, and
952 HeadacheJune 2007
Fig 1.—The 3 separate systems of perivascular nerve fibers inner-
vating the cranial circulation.
telencephalic sites that in sequence distribute sensory infor-
mation to multiple cortical regions.7These pathways can be
either monosynaptic, as with the trigeminohypothalamic and
trigeminothalamic tracts, or polysnaptic, like the spinomesen-
cephalic tract, projecting to other brain regions en route to higher
centers. Together they play a major role in the modulation and
experience of pain, integrating both sensory discriminative and
affective-cognitive aspects of nociceptive processing.8
The hypothalamus contributes only 0.5% of the brain,9but is
involved in a multitude of brain functions. It is known to be in-
system, thermoregulation, determining biological rhythms, emo-
tional behavior, arousal, and the cardiovascular system.10Afferent
and efferent nerve fibers connect the hypothalamus to a variety
of structures including the cerebral cortex, thalamus, hippocam-
cord. The hypothalamus also receives a dense blood supply and
of chemical messengers from the blood and cerebrospinal fluid,
and neurotransmitters from other neurons.
THE HYPOTHALAMUS AND NOCICEPTIVE
The hypothalamus is not traditionally associated with nociceptive
processing; however, it does have direct ascending and descending
connections with the dorsal horn.11,12It has afferent and efferent
connections with many structures, including the nucleus tractus
solitarius (NST), rostroventromedial medulla (RVM), PAG, and
date numerous hypothalamic nuclei have been implicated in the
descending modulation of pain and nociceptive processing. The
medial preoptic nucleus (MPO) has clear projections to the PAG,
NRM, and the RVM,13,14all areas involved in nociceptive pro-
response to pain, and stimulation of the MPO inhibits the re-
sponses of spinal neurons to noxious stimuli.15Stimulation of the
to noxious peripheral stimuli,16-18as does lateral hypothalamic
stimulation.16,19,20Electrical stimulation of the paraventricular
nucleus (PVN) has also demonstrated antinociceptive effects.21
Stimulation of the anterior hypothalamus is also known to sup-
press the response of wide dynamic range neurons in the dorsal
horn to noxious stimulation16,22and opioid injections into the
posterior, preoptic, and arcuate nuclei of the hypothalamus elicits
THE HYPOTHALAMUS AND THE
AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system is regulated by nuclei of the hy-
pothalamus and limbic system via the NTS onto the brain stem
nuclei and spinal autonomic ganglia. The brain stem nuclei and
spinal autonomic ganglia receive afferent input from the periph-
route to the hypothalamus and limbic system. The integration of
the trigeminal nerve gives rise to the trigeminal-autonomic reflex,
which is considered to underlie the cranial autonomic features
displayed in certain TAC’s including rhinorrhoea, conjunctival
infection, lacrimation, and nasal congestion.25-27
THE HYPOTHALAMUS AND CIRCADIAN
The hypothalamus is intrinsically linked with the control of body
rhythms and metabolic function. The most obvious circadian
rhythm is the sleep wake cycle, however, many other body sys-
tems demonstrate a circadian pattern, including feeding behavior,
ter of biological rhythms is the suprachiasmatic nucleus (SCN),
which orchestrates the many physiological systems influenced by
tions and diffusible signals to influence other regions of the brain
and direct projections have been identified to the lateral hypotha-
projections of the SCN can in turn further influence endocrine
and autonomic function via monosynaptic or polysynaptic con-
nections as demonstrated by the rapid decrease in plasma corti-
costerone initiated by a light pulse in rats.31
THE HYPOTHALAMUS AND PRIMARY
Hypothalamus and Cluster Headache.—
The fact that the hypothalamus plays a major role in cluster
headache is now widely accepted. Initial observations indicat-
ing a seasonal and circadian rythmicity of attacks point firmly
to the involvement of the suprachiasmatic nucleus.32Further ev-
idence is gained from the close correlation with sleep33and the
953 HeadacheJune 2007
presence of cranial autonomic symptoms. PET and fMRI stud-
ies have identified hypothalamic activation during spontaneous,
as well as triggered cluster attacks and short-lasting unilateral
neuralgiform headache with conjunctival injection and tearing
(SUNCT),34-37accompanied by the presence of permanent sub-
the treatment of chronic cluster headache has proved a successful
intervention strategy providing strong evidence for the involve-
ment of the hypothalamus in cluster headache.39-41
Hypothalamus and Migraine.—
As with cluster headache, clinical evidence indicating endocrine
abnormalities in chronic migraine implicate the hypothalamus in
to 48 hours preceding the onset of an attack indicate an underly-
ing the presence of similar symptoms following glyceryl trinitrate
triggered attacks.45Akin to cluster headache, migraine attacks
demonstrate a striking circadian rythmicity46-48and are linked to
hormonal fluctuation,49further implicating the hypothalamus.
HYPOTHALAMUS AND SHORT-LASTING
UNILATERAL NEURALGIFORM HEADACHE
WITH CONJUNCTIVAL INJECTION
SUNCT is a member of the larger group of TAC’s with clus-
ter headache and paroxysmal hemicrania; like the other members
SUNCT demonstrates clear autonomic symptoms pointing to a
disinhibition of the trigeminal-autonomic reflex. Ipsilateral hy-
pothalamic activation has also been reported during attacks50in
ing to a similar mechanism.
FOR HYPOTHALAMIC INVOLVEMENT
IN PRIMARY HEADACHES
Although the wide array of accompanying symptoms seen in pri-
it is clear that the trigeminal nerve and its peripheral and central
connections are of great importance to the pain component of
attacks. To date no acceptable animal model has been developed
to investigate the many sensory and autonomic symptoms, which
are so characteristic of primary headaches, such as migraine and
cluster headache. However, modeling the nociceptive component
remains an achievable goal with current experimental models.
Experimental evidence for the involvement of the hypothala-
mus in trigeminovascular nociception has been provided from a
variety of studies. Malick et al. demonstrated that stimulation of
the dura mater in the rat produced Fos expression in the ventro-
medial, PVN, and dorsomedial hypothalamic nuclei, resulting in
suppression of appetite and increases in arterial blood pressure.51
The findings indicate a complex relationship between nociceptive
trigeminal neuronal activation and suppression of food intake at
the level of the hypothalamus, consistent with clinical observa-
tions of loss of appetite in migraine.51Stimulation of the superior
sagittal sinus in the cat has also demonstrated hypothalamic ac-
tivation with upregulation of Fos protein-like immunoreactivity
in the supraoptic and posterior hypothalamic nucleus, consistent
with a role for hypothalamic structures in modulation of nocicep-
acid precursor peptide, prepro-orexin, by proteolytic cleavage. A
single gene located on chromosome 17q21 in humans is responsi-
ble for encoding prepro-orexin.53,54Following proteolytic cleav-
age both orexin peptides are posttransationally modified, with the
addition of N-terminal pyroglutamyl cyclisation and C-terminal
amidation for orexin A and only C-terminal amidation for orexin
B (Fig. 2).55Mature orexin A is a 33-residue neuropeptide con-
are essential for functional potency57,58as are the 19 C-terminal
residues.58Mature orexin B is a 28-residue neuropeptide contain-
ing 2 α-helices linked by a flexible loop.55Orexin A and B are
46% homologous, and the sequence of orexin A is fully conserved
across rat, mouse, pig, cow, and human.54,59,60Orexin B shows a
slight variation across species, with the rat/mouse isoforms differ-
ing by 2 amino acids compared with the human sequence60and
porcine orexin B has a single serine-to-proline substitution.59
Fig 2.—Schematic representation of the orexin system. Orexin A
and B are cleaved from a common precursor peptide, prepro-orexin.
The orexins act on 2 G protein-coupled receptors, OX1R and OX2R.
teins, whereas OX2R couples with Gi/oand/or Gq. OX1R is selective
for orexin A, whereas OX2R is nonselective for both orexin A and
954 Headache June 2007
Fig 3.—Orexinergic pathways and orexin receptor mRNA distribution in the rat brain. A summary of the major orexinergic pathways
and receptor mRNA distribution in the rat brain. Not all pathways and sites are shown and the level of expression may be varied between
areas, adapted from the references.54,62-76Arcn = arcuate nucleus; CA1–3 = areas of hippocampus; CC = cingulate cortex; CMN =
centromedial nucleus; DRN = dorsal raphe; LC = locus coeruleus; MRN = median raphe nucleus; NST = nucleus of solitary tract;
olfB = olfactory bulb; olfT = olfactory tubercle; PVN = paraventricular nucleus; NRM = nucleus raphe magnus; RO = nucleus raphe
VAMN = ventral anteromedial nuclei.
The orexins bind to 2 G-protein coupled receptors, termed
OX1R and OX2R.77The 2 receptors are 64% homologous and
are most closely related (26%) to the NPY2 receptor.54The rat
and human versions of the OX1R and OX2R demonstrate a 94%
and 95% homology, respectively, suggesting a high level of con-
servation across mammalian species.54Orexin A has equal affinity
for both the OX1R and OX2R, with orexin B demonstrating a
10-fold higher affinity for the OX2R than the OX1R. Activation
of either OX1R or OX2R results in elevated levels of intracellular
Ca2+concentrations,78,79which results in the enhancement of
the Gq-mediated stimulation of phospholipase C.
to its implication in a variety of functions including feeding, sleep
wake cycle, cardiovascular function, neuroendocrine, and auto-
nomic function80-83as well as a more recent implication in the
modulation of nociceptive processing.84-87The orexinergic sys-
tem projects to many areas involved in nociceptive processing and
autonomic regulation, including the hypothalamus, PAG, ven-
trolateral reticular formation (VLM), PVN, parabrachial nucleus
(PBN), NTS, and lamina I, II, and X of the spinal and trigeminal
dorsal horns.76,88,89In general the orexin receptor expression is in
of the posterior hypothalamus in rats results in transient hyperal-
gesia indicating a possible hypothalamic role in the maintenance
of a basal nociceptive threshold.91Bingham et al. postulated a
novel descending orexinergic inhibitory system in the rat raising
may be orexin driven.84
ulating nociceptive processing is both complimentary and contra-
dictory. Bingham et al. reported that orexin A is antinociceptive
in the thermal and visceral nociceptive tests in the rat and mouse
and antihyperalgesic in the mouse carrageenan-induced thermal
hyperalgesia test when given intravenously or intracerebroventric-
urea (SB-334867) a selective nonpeptide OX1R antagonist re-
versed the orexin A effects as well as demonstrating hyperalgesic
orexinergic inhibitory system that is activated under inflamma-
tory conditions. The responses observed were independent of the
endogenous opiate system, despite having similar effects as mor-
Yamamoto et al. also demonstrated the analgesic effects of
orexin A and proposed a spinal cord mechanism.92Orexin B had
955 HeadacheJune 2007
no effect on any of the aspects studied and SB-334867 was again
able to antagonize the effects of orexin A, however, no change was
seen when given alone. Thus it is possible that the descending
inhibitory system proposed by Bingham et al. is only activated
during inflammatory conditions, such as the mouse carrageenan-
or acute nociceptive stimuli such as the rat formalin or hot plate
Further discrepancies in the roles of orexin A and B in differ-
ent models of nociception exist. Suyama et al. demonstrated that
orexin A but not orexin B inhibits heat-evoked hyperalgesia in the
rat when given intrathecally.93Orexin A also reduces mechanical
Under normal baseline conditions there was no difference in pain
thresholds between knockout and wild type mice. However, fol-
lowing the induction of peripheral inflammation prepro-orexin
knock out mice demonstrated a greater degree of hyperalgesia
and lowered stress-induced analgesia than their wild type coun-
terparts. It would appear that the orexinergic system facilitates an
increase in pain thresholds under inflammatory conditions and
this is likely to be mediated within the CNS.94Peripheral in-
flammation is known to activate ascending pain pathways, which
project to higher structures including the hypothalamus. Watan-
abe et al.94demonstrated that under inflammatory conditions
be a result of the ascending nociceptive input or as a result of the
activation of endogenous descending inhibitory pathways.95The
distribution of the orexinergic system from the hypothalamus to
the PAG and spinal cord present the possibility for either the
modulation of descending inhibitory pathways or the direct re-
lease of orexin at the spinal cord. Thus suppressing nociceptive
inputs at the second order relay neurons as demonstrated by the
antinociceptive effects of spinal as well as intracerebroventricular
The orexins have only very recently been linked with a possible
role in primary headache disorders and the evidence as such is
circumstantial. An obvious generic link is the anatomical distri-
bution of the orexins and the discovery that they could influence
nociceptive processing. A link between both migraine and cluster
headache with sleep has long been established. Attacks are com-
mon during rapid eye movement sleep periods and many patients
find sleeping to be the preferred method to abort an attack. Nar-
colepsy is a disorder of the sleep–wake cycle with a prevalence of
approximately 0.05% in the general population.98It is character-
ized by excessive daytime somnolence, overwhelming episodes of
sleep, disturbed nocturnal sleep, hypnagogic hallucinations, sleep
paralysis, and cataplexy.98The orexinergic system is known to
play a key role in the pathophysiology of narcolepsy, via a loss of
It has been shown that narcoleptic patients have a greatly in-
creased prevalence of migraine. In a study of 68 narcoleptic pa-
tients 64% of women and 35% of men were found to suffer from
migraine attacks100fulfilling all the International Headache Soci-
in narcoleptic patients was later confirmed in a larger study, with
44% of women and 23% of men suffering from migraine.107
One interesting finding is the late onset of migraine in nar-
coleptic patients, demonstrating that narcolepsy appears to put
people at an increased risk for migraine compared to the general
population.108The neuroanatomical base of both disorders may
raphe nucleus (DRN) combined with activation of the serotoner-
gic DRN and noradrenergic locus coeruleus, all point to a role of
ical role in rapid eye movement sleep, a regulatory disturbance of
which is thought to underline narcolepsy.98,113Further evidence
ies in cluster headache. The 1246 G > A polymorphism of the
risk of cluster headache. Patients homozygous for the G allele, in
comparison to the remaining genotypes, are 5-fold more likely to
the pathophysiology of cluster headache, paroxysmal hemicrania,
and SUNCT35,36,50,115and the same may be true of migraine116
and other primary headaches. The orexinergic system provides
a novel sexually dimorphic117,118descending pathway through
which the hypothalamus could modulate numerous processes in-
cluding sensory processing of pain at various levels exerting both
excitatory and inhibitory effects.
Clinical evidence for a role of the orexinergic system in the
modulation of primary headaches has not yet been investigated.
However, in an animal model of trigeminovascular nociception,
systemically administered orexin A significantly inhibits nocicep-
mater surrounding the middle meningeal artery.119The orexin-
ergic trigeminal modulatory effect is further evidenced, via the
of the OX1R and OX2R in the posterior hypothalamus has been
shown to differentially modulate nociceptive dural inputs to the
TNC.121Activation of the OX1R elicits an antinociceptive effect
whereas OX2R activation elicits a pronociceptive effect. Experi-
mental evidence indicates that regulation of autonomic and neu-
roendocrine functions as well as nociceptive processing is closely
coupled in the hypothalamus122and recent data point to the in-
volvement of orexinergic mechanisms.123Thus, the orexinergic
system is a posterior hypothalamic mechanism that is involved
in central pain modulating of dural input and could be a possi-
ble link between the pain of primary neurovascular headaches
956 HeadacheJune 2007
and the symptomatology that is suggestive of a hypothalamic
dysfunction.124The first orally available orexinergic antagonist
ACT-078537 is currently under trial for sleep disorders,125the
development of a specific OX1R agonist may prove beneficial in
the treatment of a variety of conditions including the primary
headaches and narcolepsy.
DIRECT ACTIONS OF A HYPOTHALAMIC
OREXINERGIC DYSFUNCTION ON
to terminate in the spinal and trigeminal dorsal horns.62,64,76,126
Although the orexins are on the whole excitatory, they have been
shown to produce antinociceptive effects at the level of the spinal
cord.97The densest orexinergic projections to the dorsal horn ter-
minate in lamina IIo and in the border region of laminae IIo/IIi,
an area classically associated with inhibitory interneurons. It has
been shown that as well as a direct excitatory projection on to
second order relay neurons, the orexinergic fibers also form ex-
citatory synapses with inhibitory interneurons.81Thus a gated
mechanism exists via which the hypothalamic orexinergic projec-
tions could facilitate or inhibit the activation of these ascending
sensory neurons (Fig. 4).
modulatory mechanism for the orexins, which allows a differen-
Fig 4.—Orexinergic projections of importance to the modulation of nociceptive processing. Schematic drawing of a sagittal section through
the rat brain, summarizing the hypothalamic orexinergic projections involved in the modulation of nociceptive processing. Acb = nucleus
accumbens; olfT = olfactory tract; CC = corpus callosum; CM = centromedian nucleus of the thalamus; VM = ventral midbrain; dR =
dorsal raphe; PAG = periaqueductal gray; LDT = laterodorsal tegmental and pedunculopontine; LC = locus coeruleus; 5 HT = serotonin.
Adapted from reference.81
tial level of inhibition or excitation depending on the presence
of other inputs on to the target cell. For example at low doses
centrations they begin to excite presynaptic GABAergic neurons,
also resulting in inhibition.127It is therefore possible, due to the
nature of the orexinergic terminations, that their effect is depen-
dant on the inputs into the inhibitory cell. For example, it is
possible that at the level of the spinal cord the orexins are di-
rectly exciting the postsynaptic cell and simultaneously exciting
a GABAergic/glycinergic cell that inhibits that postsynaptic cell.
ing pathways had activated excitatory inputs into the inhibitory
cell. This form of direct and indirect opposing modulation al-
lows the orexinergic system great flexibility over the responses it
elicits and provides a mechanism by which relatively weak inputs
can be amplified to produce a much larger effect in postsynaptic
INDIRECT ACTION OF OREXINS
VIA MODULATION OF OTHER
ulation of other neurotransmitter systems throughout the CNS.
Orexin A and B have been shown to act on a variety of neu-
rotransmitter systems including the dopaminergic, histaminergic
957 Headache June 2007
Fig 5.—Summary of the different direct and indirect mechanisms
via which the orexinergic system can modulate the serotonergic sys-
tem. The orexins synthesized in the lateral hypothalamus (LH) have
direct excitatory projections to the serotonergic (5-HT) neurons in
the dorsal raphe nucleus (DRN) as well as indirect inhibitory pro-
jections via the excitation of GABAergic interneurons in the DRN. A
ergic neurons of the tuberomammilary nucleus as well as the LH and
the norepinephrine (NE) expressing neurons of the locus coeruleus
(LC). The 5-HT neurons of the DRN form a negative feedback path-
way via direct projections to the LH.
It is important to realize that there are also other mechanisms
via which the orexins could be exerting their effects. Bingham
et al.84postulated a possible peripheral mechanism via activa-
tion of peripheral OX1R, and based on the recent findings of
the orexins ability to excite GABAergic neurons it is possible that
their antinociceptive activities may be via activation of functional
GABAergic inhibitory projections from the hypothalamus and
HOW DOES THE OREXINERGIC SYSTEM FIT
A CONSTRUCT OF THE DIVERSE
SYMPTOMS OF THE PRIMARY HEADACHES?
and periventricular hypothalamic nuclei, from here orexinergic
projections extend throughout the entire length of the neuroaxis
to varying degrees. It is crucial to remember that the primary
headache disorders are multifactorial syndromes that are divided
into a number of symptoms, including sensory disturbances, au-
tonomic features, and pain. The orexins, as well as demonstrat-
ing the ability to modulate trigeminal nociceptive processing, are
the hypothalamic-pituitary-adrenal axis and modulate the secre-
tion of a variety of hormones.80It has also been demonstrated via
anatomical and experimental studies that they can modulate the
autonomic nervous system.76,80
OTHER HYPOTHALAMIC PEPTIDE
Somatostatin is another hypothalamic peptide hormone that has
as well as affecting neurotransmission via activation of G-protein
coupled somatostatin receptors and inhibition of a variety of hor-
mones. It is secreted by cells in the PVN and delta cells in the
stomach, intestine, and pancreas. Upon release it can bind to 1 of
5 somatostatin receptors (sst1−5), which are distributed through-
out the body138,139including the hypothalamus, PAG, NRM,
anterior cingulate cortex, and the spinal and trigeminal dorsal
horns140-144as well as nonneuronal tissue.
Clinical data for a variety of pain syndromes has provided evi-
dence for somatostatins involvement in the generation of analge-
properties in postoperative pain,145cancer pain,146arthritis and
the primary headaches migraine, and cluster headache.147,148Ex-
perimental in-vivo and in-vitro evidence points to an inhibitory
effect at the level of the spinal and trigeminal dorsal horns.149-151
NRM, and caudate putamen152,153while intracerebroventricular
administration of octreotide, an analog of somatostatin reduces
Fos expression in the TNC following noxious corneal stimulation
in the rat.154
Manipulation of the posterior hypothalamic somatostatin re-
ceptors modulates dural and facial trigeminal nociceptive trans-
mission in the TNC. Microinjection of cyclo-somatostatin into
the posterior hypothalamus inhibited both A- and C-fiber re-
to noxious thermal facial stimulation.155
Somatostatin has proven trigeminovascular modulatory func-
metabolic, neuroendocrine, and autonomic functions. It is there-
fore a possible key component in the link between dural nocicep-
diverse symptomatology which accompanies the pain component
of a variety of primary headache disorders.
The hypothalamus is critically important in the brain, only the
cerebral cortex is involved in as many diverse functions. As such
958 Headache June 2007
it is likely to play an important role in the pathophysiology of
a variety functional disorders, including primary headache syn-
dromes. The evidence for the involvement of the hypothalamus
in certain subtypes including cluster headache, migraine, chronic
migraine, and SUNCT is compelling. The exact role it plays has
yet to be elucidated, that is does the hypothalamus actively con-
remote “generator?” Evidence from the sleep disorder narcolepsy,
which is clearly linked to hypothalamic orexinergic dysfunction,
points to a gating or switching mechanism. It is possible that
the hypothalamus has a similar role in primary headaches, act-
ing as a balance between a variety of systems that could underlie
the symptoms of the individual attack. Thus a dysfunction in a
hypothalamic circuit, for example the orexinergic system, would
allow the destabilization of the pro- and anti-nociceptive inputs
on the trigeminovascular system accompanied by autonomic and
sensory disturbances. This could be as a result of direct actions on
and higher autonomic centers including the PVN. The episodic
nature of many attack syndromes points to a crucial role of the
SCN, which influences many other hypothalamic, thalamic, and
is orchestrated by the SCN, which would help to explain both the
autonomic and endocrine abnormalities, which are characteristics
of many primary headaches.
Conflict of Interest: None
1. Headache Classification Committee of the International
Headache Society. The International Classification of Headache
Disorders, 2nd edn. Cephalalgia. 2004;24(suppl 1):9-160.
2. Ray BS, Wolff HG. Experimental studies on headache. Pain
sensitive structures of the head and their significance in
headache. Arch Surg. 1940;41:813-856.
3. Messlinger K, Burstein R. Anatomy of the central nervous
system pathways related to head pain. In: Olesen J,
Tfelt-Hansen P, Welch KMA, eds. The Headaches,
Philadelphia: Lippincott Williams & Wilkins; 2000:55-76.
4. Go JL, Kim PE, Zee CS. The trigeminal nerve. Semin
Ultrasound CT MR. 2001;22(6):502-520.
5. Olesen J, Edvinsson L. Cephalic neurovascular transmitters and
receptors. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The
headaches, Philadelphia: Lippincott Williams & Wilkins;
6. Moskowitz MA. The neurobiology of vascular head pain. Ann
7. Goadsby PJ, Lipton RB, Ferrari MD. Migraine–current
understanding and treatment. N Engl J Med.
8. Craig AD. Emotional aspects of pain. In: Wall PD, Melzack R,
eds. Textbook of Pain, Edinburgh: Churchill Livingston;
9. Kiernan J. The Human Nervous System: An Anatomical View
Point, 7th edn. New York: Lippincott – Raven; 1998:518.
10. Settle M. The hypothalamus. Neonatal Netw. 2000;19(6):9-
11. Giesler J, Glenn J. Evidence of direct nociceptive projections
from the spinal cord to the hypothalamus and telencephalon.
Semin Neurosci. 1995;7(4):253-261.
12. Millan MJ. The induction of pain: An integrative review. Prog
13. Jiang M, Behbehani MM. Physiological characteristics of the
projection pathway from the medial preoptic to the nucleus
raphe magnus of the rat and its modulation by the
periaqueductal gray. Pain. 2001;94(2):139-147.
14. Murphy AZ, Rizvi TA, Ennis M, Shipley MT. The organization
of preoptic-medullary circuits in the male rat: Evidence for
interconnectivity of neural structures involved in reproductive
behavior, antinociception and cardiovascular regulation.
15. Lumb BM. Hypothalamic influences on viscero-somatic
neurones in the lower thoracic spinal cord of the anaesthetized
rat. J Physiol. 1990;424:427-444.
16. Carstens E. Hypothalamic inhibition of rat dorsal horn neuronal
responses to noxious skin heating. Pain. 1986;25(1):95-107.
17. Carstens E. Inhibition of spinal dorsal horn neuronal responses
to noxious skin heating by medial hypothalamic stimulation in
the cat. J Neurophysiol. 1982;48(3):808-822.
18. Culhane ES, Carstens E. Medial hypothalamic stimulation
suppresses nociceptive spinal dorsal horn neurons but not the
tail-flick reflex in the rat. Brain Res. 1988;438(1-2):137-144.
19. Carstens E, Fraunhoffer M, Suberg SN. Inhibition of spinal
dorsal horn neuronal responses to noxious skin heating by
lateral hypothalamic stimulation in the cat. J Neurophysiol.
20. Holden JE, Naleway E. Microinjection of carbachol in the
lateral hypothalamus produces opposing actions on nociception
mediated by alpha(1)- and alpha(2)-adrenoceptors. Brain Res.
21. Miranda-Cardenas Y, Rojas-Piloni G, Martinez-Lorenzana G,
et al. Oxytocin and electrical stimulation of the paraventricular
hypothalamic nucleus produce antinociceptive effects that are
reversed by an oxytocin antagonist. Pain.
22. Workman BJ, Lumb BM. Inhibitory effects evoked from the
anterior hypothalamus are selective for the nociceptive responses
of dorsal horn neurons with high- and low-threshold inputs.
J Neurophysiol. 1997;77(5):2831-2835.
23. Yaksh TL. Central pharmacology of nociceptive transmission.
In: Wall PD, Melzack R, eds. Textbook of Pain, Edinburgh:
Churchill Livingston; 1999:253-308.
24. Manning BH, Franklin KB. Morphine analgesia in the formalin
test: Reversal by microinjection of quaternary naloxone into the
posterior hypothalamic area or periaqueductal gray. Behav Brain
25. Goadsby PJ. Trigeminal autonomic cephalalgias.
Pathophysiology and classification. Rev Neurol (Paris).
26. Goadsby PJ. Trigeminal autonomic cephalalgias: Fancy term or
constructive change to the IHS classification? J Neurol
Neurosurg Psychiatry. 2005;76(3):301-305.
959 HeadacheJune 2007
27. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias,
SUNCT syndrome and other short-lasting headaches with
autonomic feature, including new cases. Brain. 1997;120(Pt
28. Panda S, Hogenesch JB. It’s all in the timing: Many clocks,
many outputs. J Biol Rhythms. 2004;19(5):374-387.
29. Davidson AJ, Yamazaki S, Menaker M. SCN: Ringmaster of the
circadian circus or conductor of the circadian orchestra? Novartis
Found Symp. 2003;253:110-121; discussion 121-125, 281-284.
30. Moore RY. Organization and function of a central nervous
system circadian oscillator: The suprachiasmatic hypothalamic
nucleus. Fed Proc. 1983;42(11):2783-2789.
31. Buijs RM, Wortel J, Van Heerikhuize JJ, et al. Anatomical and
functional demonstration of a multisynaptic suprachiasmatic
nucleus adrenal (cortex) pathway. Eur J Neurosci.
32. Pringsheim T. Cluster headache: Evidence for a disorder of
circadian rhythm and hypothalamic function. Can J Neurol Sci.
33. Dodick DW, Eross EJ, Parish JM. Clinical, anatomical, and
physiologic relationship between sleep and headache. Headache.
34. May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET
and MRA findings in cluster headache and MRA in
experimental pain. Neurology. 2000;55(9):1328-1335.
35. May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ.
Hypothalamic activation in cluster headache attacks. Lancet.
36. Sprenger T, Boecker H, Tolle TR, et al. Specific hypothalamic
activation during a spontaneous cluster headache attack.
37. Sprenger T, Valet M, Hammes M, et al. Hypothalamic
activation in trigeminal autonomic cephalgia: Functional
imaging of an atypical case. Cephalalgia. 2004;24(9):753-757.
38. May A, Ashburner J, B¨ uchel C, et al. Correlation between
structural and functional changes in brain in an idiopathic
headache syndrome. Nat Med. 1999;5(7):836-838.
39. Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic
deep brain stimulation for intractable chronic cluster headache:
A 3-year follow-up. Neurol Sci. 2003;24(suppl 2):S143-S145.
40. Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the
posterior hypothalamus for treatment of chronic intractable
cluster headaches: First reported series. Neurosurgery.
2003;52(5):1095-1099; discussion 1099-1101.
41. Leone M, Franzini A, Bussone G. Stereotactic stimulation of
posterior hypothalamic gray matter in a patient with intractable
cluster headache. N Engl J Med. 2001;345(19):1428-1429.
42. Peres MF, Sanchez del Rio M, Seabra ML, et al. Hypothalamic
involvement in chronic migraine. J Neurol Neurosurg Psychiatry.
43. Giffin NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms
in migraine: An electronic diary study. Neurology.
44. Kelman L. The premonitory symptoms (prodrome): A tertiary
care study of 893 migraineurs. Headache. 2004;44(9):865-
45. Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers
premonitory symptoms in migraineurs. Pain.
46. Zurak N. Role of the suprachiasmatic nucleus in the
pathogenesis of migraine attacks. Cephalalgia.
47. Solomon GD. Circadian rhythms and migraine. Cleve Clin J
48. Fox AW, Davis RL. Migraine chronobiology. Headache.
49. MacGregor A. Migraine associated with menstruation. Funct
Neurol. 2000;15(suppl 3):143-153.
50. May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional
magnetic resonance imaging in spontaneous attacks of SUNCT:
Short-lasting neuralgiform headache with conjunctival injection
and tearing. Ann Neurol. 1999;46(5):791-794.
51. Malick A, Jakubowski M, Elmquist JK, Saper CB, Burstein R. A
neurohistochemical blueprint for pain-induced loss of appetite.
Proc Natl Acad Sci U S A. 2001;98(24):14186-14186.
52. Benjamin L, Levy MJ, Lasalandra MP, et al. Hypothalamic
activation after stimulation of the superior sagittal sinus in the
cat: A Fos study. Neurobiol Dis. 2004;16(3):500-505.
53. Sakurai T. Reverse pharmacology of orexin: From an orphan
GPCR to integrative physiology. Regul Pept.
54. Sakurai T, et al. Orexins and orexin receptors: A family of
hypothalamic neuropeptides and G protein-coupled receptors
that regulate feeding behavior (vol 92, pg 573, 1998). Cell.
55. Lee JH, Bang E, Chae KJ, et al. Solution structure of a new
hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur
J Biochem. 1999;266(3):831-839.
56. Soll R, Beck-Sickinger AG. On the synthesis of orexin A: A
novel one-step procedure to obtain peptides with two
intramolecular disulphide bonds. J Pept Sci. 2000;6(8):387-
57. Okumura T, Takeuchi S, Motomura W, et al. Requirement of
intact disulfide bonds in orexin-A-induced stimulation of gastric
acid secretion that is mediated by OX1 receptor activation.
Biochem Biophys Res Commun. 2001;280(4):976-981.
58. Darker JG, Porter RA, Eggleston DS, et al. Structure-activity
analysis of truncated orexin-A analogues at the orexin-1
receptor. Bioorg Med Chem Lett. 2001;11(5):737-740.
59. Dyer CJ, Touchette KJ, Carroll JA, Allee GL, Matteri RL.
Cloning of porcine prepro-orexin cDNA and effects of an
intramuscular injection of synthetic porcine orexin-B on feed
intake in young pigs. Domest Anim Endocrinol.
60. Shibahara M, Sakurai T, Nambu T, et al. Structure, tissue
distribution, and pharmacological characterization of Xenopus
orexins. Peptides. 1999;20(10):1169-1176.
61. Kim HY, Hong E, Kim JI, Lee W. Solution structure of human
orexin-A: Regulator of appetite and wakefulness. J Biochem Mol
62. Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA.
Gene expression and protein distribution of the orexin-1
960 HeadacheJune 2007
receptor in the rat brain and spinal cord. Neuroscience.
63. Trivedi P, Yu H, MacNeil DJ, Van Der Ploeg LH, Guan XM.
Distribution of orexin receptor mRNA in the rat brain. FEBS
64. Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential
expression of orexin receptors 1 and 2 in the rat brain. J Comp
65. Chen CT, Dun SL, Kwok EH, Dun NJ, Chang JK. Orexin
A-like immunoreactivity in the rat brain. Neurosci Lett.
66. Cutler DJ, Morris R, Sheridhar V, et al. Differential
distribution of orexin-A and orexin-B immunoreactivity in the
rat brain and spinal cord. Peptides. 1999;20(12):1455-1470.
67. Date Y, Mondal MS, Matsukura S, Nakazato M. Distribution
of orexin-A and orexin-B (hypocretins) in the rat spinal cord.
Neurosci Lett. 2000;288(2):87-90.
68. Date Y, Ueta Y, Yamashita H, et al. Orexins, orexigenic
hypothalamic peptides, interact with autonomic,
neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci
U S A. 1999;96(2):748-753.
69. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins:
Hypothalamus-specific peptides with neuroexcitatory activity.
Proc Natl Acad Sci U S A. 1998;95(1):322-327.
70. Harrison TA, Chen CT, Dun NJ, Chang JK. Hypothalamic
orexin A-immunoreactive neurons project to the rat dorsal
medulla. Neurosci Lett. 1999;273(1):17-20.
71. Horvath TL, Diano S, Van Den Pol AN. Synaptic interaction
between hypocretin (orexin) and neuropeptide Y cells in the
rodent and primate hypothalamus: A novel circuit implicated in
metabolic and endocrine regulations. J Neurosci.
72. Horvath TL, Peyron C, Diano S, et al. Hypocretin (orexin)
activation and synaptic innervation of the locus coeruleus
noradrenergic system. J Comp Neurol. 1999;415(2):145-159.
73. Horvath TL, Warden CH, Hajos M, et al. Brain uncoupling
protein 2: Uncoupled neuronal mitochondria predict thermal
synapses in homeostatic centers. J Neurosci.
74. Mondal MS, Nakazato M, Matsukura S. Characterization of
orexin-A and orexin-B in the microdissected rat brain nuclei
and their contents in two obese rat models. Neurosci Lett.
75. Mondal MS, Nakazato M, Date Y, et al. Widespread
distribution of orexin in rat brain and its regulation upon
fasting. Biochem Biophys Res Commun. 1999;256(3):495-499.
76. Van Den Pol AN. Hypothalamic hypocretin (orexin): Robust
innervation of the spinal cord. J Neurosc.
77. Foord SM, Bonner TI, Neubig RR, et al. International Union
of Pharmacology. XLVI. G protein-coupled receptor list.
Pharmacol Rev. 2005;57(2):279-288.
78. Lund PE, Shariatmadari R, Uustare A, et al. The orexin OX1
receptor activates a novel Ca2+influx pathway necessary for
coupling to phospholipase C. J Biol Chem.
79. Smart D, Jerman JC, Brough SJ, et al. Characterization of
recombinant human orexin receptor pharmacology in a Chinese
hamster ovary cell-line using FLIPR. Br J Pharmacol.
80. Ferguson AV, Samson WK. The orexin/hypocretin system: A
critical regulator of neuroendocrine and autonomic function.
Front Neuroendocrinol. 2003;24(3):141-150.
81. Siegel JM. Hypocretin (orexin): Role in normal behavior and
neuropathology. Annu Rev Psychol. 2004;55:125-148.
82. Samson WK, Taylor MM, Ferguson AV. Non-sleep effects of
hypocretin/orexin. Sleep Med Rev. 2005;9(4):243-252.
83. Sakurai T. Roles of orexin/hypocretin in regulation of
sleep/wakefulness and energy homeostasis. Sleep Med Rev.
84. Bingham S, Davey PT, Babbs AJ, et al. Orexin-A, an
hypothalamic peptide with analgesic properties. Pain.
85. Cheng JK, Chou RC, Hwang LL, Chiou LC. Antiallodynic
effects of intrathecal orexins in a rat model of postoperative
pain. J Pharmacol Exp Ther. 2003;307(3):1065-1071.
86. Kajiyama S, Kawamoto M, Shiraishi S, et al. Spinal orexin-1
receptors mediate anti-hyperalgesic effects of
intrathecally-administered orexins in diabetic neuropathic pain
model rats. Brain Res. 2005;1044(1):76-86.
87. Yamamoto T, Saito O, Shono K, Aoe T, Chiba T.
Anti-mechanical allodynic effect of intrathecal and
intracerebroventricular injection of orexin-A in the rat
neuropathic pain model. Neurosci Lett. 2003;347(3):183-186.
88. Peyron C, Tighe DK, Van Den Pol AN, et al. Neurons
containing hypocretin (orexin) project to multiple neuronal
systems. J Neurosci. 1998;18(23):9996-10015.
89. Zhang JH, Sampogna S, Morales FR, Chase MH. Distribution
of hypocretin (orexin) immunoreactivity in the feline pons and
medulla. Brain Res. 2004;995(2):205-217.
90. Backberg M, Hervieu G, Wilson S, Meister B. Orexin
receptor-1 (OX-R1) immunoreactivity in chemically identified
neurons of the hypothalamus: Focus on orexin targets involved
in control of food and water intake. Euro J Neuros.
91. Millan MJ, Przewlocki R, Millan MH, Herz A. Evidence for a
role of the ventro-medial posterior hypothalamus in nociceptive
processes in the rat. Pharmacol Biochem Behav.
92. Yamamoto T, Nozaki-Taguchi N, Chiba T. Analgesic effect of
intrathecally administered orexin-A in the rat formalin test and
in the rat hot plate test. Br J Pharmacol. 2002;137(2):170-176.
93. Suyama H, Kawamoto M, Shiraishi S, et al. Analgesic effect of
intrathecal administration of orexin on neuropathic pain in rats.
In Vivo. 2004;18(2):119-123.
94. Watanabe S, Kuwaki T, Yanagisawa M, Fukuda Y, Shimoyama
M. Persistent pain and stress activate pain-inhibitory orexin
pathways. Neuroreport. 2005;16(1):5-8.
95. Millan MJ. Descending control of pain. Prog Neurobiol.
96. Mobarakeh JI, Takahashi K, Sakurada S, et al. Enhanced
antinociception by intracerebroventricularly and
961 HeadacheJune 2007
intrathecally-administered orexin A and B (hypocretin-1 and -2)
in mice. Peptides. 2005;26(5):767-777.
97. Yamamoto T, Saito O, Shono K, Hirasawa S. Activation of
spinal orexin-1 receptor produces anti-allodynic effect in the rat
carrageenan test. Eur J Pharmacol. 2003;481(2-3):175-180.
98. Aldrich MS. Narcolepsy. N Engl J Med. 1990;323(6):389-394.
99. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of
early onset narcolepsy and a generalized absence of hypocretin
peptides in human narcoleptic brains. Nat Med.
100. Dahmen N, Querings K, Grun B, Bierbrauer J. Increased
frequency of migraine in narcoleptic patients. Neurology.
101. Bigal ME, Lipton RB, Stewart WF. The epidemiology and
impact of migraine. Curr Neurol Neurosci Rep.
102. Breslau N, Davis GC, Andreski P. Migraine, psychiatric
disorders, and suicide attempts: An epidemiologic study of
young adults. Psychiatry Res. 1991;37(1):11-23.
103. MacGregor EA, Brandes J, Eikermann A. Migraine prevalence
and treatment patterns: The global migraine and zolmitriptan
evaluation survey. Headache. 2003;43(1):19-26.
104. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of
headache in a general population—a prevalence study. J Clin
105. Rasmussen BK, Olesen J. Migraine with aura and migraine
without aura: An epidemiological study. Cephalalgia.
1992;12(4):221-228; discussion 186.
106. Stewart WF, Simon D, Shechter A, Lipton RB. Population
variation in migraine prevalence: A meta-analysis. J Clin
107. Dahmen N, Kasten M, Wieczorek S, et al. Increased frequency
of migraine in narcoleptic patients: A confirmatory study.
108. Gobel H, Soyka D. [Migraine and tension headache. New
procedures for objective differentiation]. Fortschr Med.
109. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from
perturbation of brain. Headache. 1987;27(8):416-420.
110. Weiller C, May A, Limmroth V, et al. Brain stem activation in
spontaneous human migraine attacks. Nat Med.
111. Afridi S, Goadsby PJ. New onset migraine with a brain stem
cavernous angioma. J Neurol Neurosurg Psychiatry.
112. Afridi SK, Matharu MS, Lee L, et al. A PET study exploring the
laterality of brainstem activation in migraine using glyceryl
trinitrate. Brain. 2005;128(Pt 4):932-939.
113. Datta S. Cellular basis of pontine ponto-geniculo-occipital wave
generation and modulation. Cell Mol Neurobiol.
114. Rainero I, Gallone S, Valfre W, et al. A polymorphism of the
hypocretin receptor 2 gene is associated with cluster headache.
115. Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ. Posterior
hypothalamic activation in paroxysmal hemicrania. Ann Neurol.
116. Denuelle M, Fabre N, Payoux P, Chollet F, GG. Brainstem and
hypothalamic activation in spontaneous migraine attacks.
117. Johren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P.
Prepro-orexin and orexin receptor mRNAs are differentially
expressed in peripheral tissues of male and female rats.
118. Johren O, Neidert SJ, Kummer M, Dominiak P. Sexually
dimorphic expression of prepro-orexin mRNA in the rat
hypothalamus. Peptides. 2002;23(6):1177-1180.
119. Holland PR, Akerman S, Goadsby PJ. Modulation of
nociceptive dural input to the trigeminal nucleus caudalis via
activation of the orexin 1 receptor in the rat. Eur J Neurosci.
120. Holland PR, Akerman S, Goadsby PJ. Orexin 1 receptor
activation attenuates neurogenic dural vasodilation in an animal
model of trigeminovascular nociception. J Pharmacol Exp Ther.
121. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential
modulation of nociceptive dural input to [hypocretin] orexin A
and B receptor activation in the posterior hypothalamic area.
122. Buijs RM, Van Eden CG. The integration of stress by the
hypothalamus, amygdala and prefrontal cortex: Balance
between the autonomic nervous system and the neuroendocrine
system. Prog Brain Res. 2000;126:117-132.
123. Smart D. Orexins: A new family of neuropeptides. Br J Anaesth.
124. Overeem S, van Vliet JA, Lammers GJ, et al. The hypothalamus
in episodic brain disorders. Lancet Neurol. 2002;1(7):437-444.
125. Brisbare-Roch C, Dingemanse J, Koberstein R, et al. Promotion
of sleep by targeting the orexin system in rats, dogs and humans.
Nat Med. 2007;13:150-155. Epub 2007 Jan 28.
126. Cluderay JE, Harrison DC, Hervieu GJ. Protein distribution of
the orexin-2 receptor in the rat central nervous system. Regul
127. Liu RJ, Van Den Pol AN, Aghajanian GK. Hypocretins
(orexins) regulate serotonin neurons in the dorsal raphe nucleus
by excitatory direct and inhibitory indirect actions. J Neurosci.
128. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A
excites serotonergic neurons in the dorsal raphe nucleus of the
rat. Neuropharmacology. 2001;40(3):457-459.
129. Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent
excitation of dorsal raphe serotonin neurons by multiple arousal
systems (orexin/hypocretin, histamine and noradrenaline). J
130. Bubser M, Fadel JR, Jackson LL, et al. Dopaminergic regulation
of orexin neurons. Eur J Neurosci. 2005;21(11):2993-3001.
131. Hirota K, et al. Orexin A and B evoke noradrenaline release
from rat cerebrocortical slices. Br J Pharmacol.
132. Ishizuka T, Yamamoto Y, Yamatodani A. The effect of orexin-A
and -B on the histamine release in the anterior hypothalamus in
rats. Neuroscience Letters. 2002;323(2):93-96.
133. Kohlmeier KA, Inoue T, Leonard CS. Hypocretin/Orexin
peptide signalling in the ascending arousal system: Elevation of
962 HeadacheJune 2007
intracellular calcium in the mouse dorsal raphe and laterodorsal
tegmentum. J Neurophysiol. 2004.
134. Korotkova TM, Eriksson KS, Haas HL, Brown RE. Selective
excitation of GABAergic neurons in the substantia nigra of the
rat by orexin/hypocretin in vitro. Regul Pept.
135. Russell SH, Kim MS, Small CJ, et al. Central administration of
orexin A suppresses basal and domperidone stimulated plasma
prolactin. J Neuroendocrinol. 2000;12(12):1213-1218.
136. Van Den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov
AB. Presynaptic and postsynaptic actions and modulation of
neuroendocrine neurons by a new hypothalamic peptide,
hypocretin/orexin. J Neurosci. 1998;18(19):7962-7971.
137. Eriksson KS, Sergeeva OA, Selbach O, Haas HL. Orexin
(hypocretin)/dynorphin neurons control GABAergic inputs to
tuberomammillary neurons. Eur J Neurosci.
138. Raulf F, Perez J, Hoyer D, Bruns C. Differential expression of
five somatostatin receptor subtypes, SSTR1-5, in the CNS and
peripheral tissue. Digestion. 1994;55(suppl 3):46-53.
139. Schindler M, Humphrey PP, Emson PC. Somatostatin receptors
in the central nervous system. Prog Neurobiol. 1996;50(1):9-47.
140. Beaudet A, Greenspun D, Raelson J, Tannenbaum GS. Patterns
of expression of SSTR1 and SSTR2 somatostatin receptor
subtypes in the hypothalamus of the adult rat: Relationship to
neuroendocrine function. Neuroscience. 1995;65(2):551-561.
141. Del Fiacco M, Quartu M. Somatostatin, galanin and peptide
histidine isoleucine in the newborn and adult human trigeminal
ganglion and spinal nucleus: Immunohistochemistry, neuronal
morphometry and colocalization with substance P. J Chem
142. Lazarov N, Chouchkov C. Localization of somatostatin-like
immunoreactive fibres in the trigeminal principal sensory
nucleus of the cat. Acta Histochem. 1990;89(1):91-97.
143. Handel M, Schulz S, Stanarius A, et al. Selective targeting of
somatostatin receptor 3 to neuronal cilia. Neuroscience.
144. Schindler M, Holloway S, Hathway G, et al. Identification of
somatostatin sst2(a) receptor expressing neurones in central
regions involved in nociception. Brain Res.
145. Chrubasik J, Meynadier J, Scherpereel P, Wunsch E. The effect
of epidural somatostatin on postoperative pain. Anesth Analg.
146. Mollenholt P, Rawal N, Gordh T, Jr, Olsson Y. Intrathecal and
epidural somatostatin for patients with cancer. Analgesic effects
and postmortem neuropathologic investigations of spinal cord
and nerve roots. Anesthesiology. 1994;81(3):534-542.
147. Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous
octreotide in cluster headache: Randomized placebo-controlled
double-blind crossover study. Ann Neurol. 2004;56(4):488-
148. Kapicioglu S, Gokce E, Kapicioglu Z, Ovali E. Treatment of
migraine attacks with a long-acting somatostatin analogue
(octreotide, SMS 201-995). Cephalalgia. 1997;17(1):27-30.
149. Murase K, Nedeljkov V, Randic M. The actions of
neuropeptides on dorsal horn neurons in the rat spinal cord slice
preparation: An intracellular study. Brain Res.
150. Randic M, Miletic V. Depressant actions of
methionine-enkephalin and somatostatin in cat dorsal horn
neurones activated by noxious stimuli. Brain Res.
151. Chapman V, Dickenson AH. The effects of sandostatin and
somatostatin on nociceptive transmission in the dorsal horn of
the rat spinal cord. Neuropeptides. 1992;23(3):147-152.
152. Tashev R, Belcheva S, Milenov K, Belcheva I. Antinociceptive
effect of somatostatin microinjected into caudate putamen.
153. Helmchen C, Fu QG, Sandkuhler J. Inhibition of spinal
nociceptive neurons by microinjections of somatostatin into the
nucleus raphe magnus and the midbrain periaqueductal gray of
the anesthetized cat. Neurosci Lett. 1995;187(2):137-
154. Bereiter DA. Morphine and somatostatin analogue reduce c-fos
expression in trigeminal subnucleus caudalis produced by
corneal stimulation in the rat. Neuroscience.
155. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Inhibition of
nociceptive dural input in the trigeminal nucleus caudalis by
somatostatin receptor blockade in the posterior hypothalamus.