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The cardinal symptom of migraine is headache pain. In this paper we review the neurobiology of this pain as it is currently understood. In recent years, we discovered that the network of neurons that sense pain signals from the dura changes rapidly during the course of a single migraine attack and that the treatment of an attack is a moving target. We found that if the pain is not stopped within 10–20 minutes after it starts, the first set of neurons in the network, those located in the trigeminal ganglion, undergo molecular changes that make them hypersensitive to the changing pressure inside the head, which explains why migraine headache throbs and is worsened by bending over and sneezing. We found that if the pain is not stopped within 60–120 minutes, the second group of neurons in the network, those located in the spinal trigeminal nucleus, undergoes molecular changes that convert them from being dependent on sensory signals they receive from the dura by the first set of neurons, into an independent state in which they themselves become the pain generator of the headache. When this happens, patients notice that brushing their hair, taking a shower, touching their periorbital skin, shaving, wearing earrings, etc become painful, a condition called cutaneous allodynia. Based on this scenario, we showed recently that the success rate of rendering migraine patients pain-free increased dramatically if medication was given before the establishment of cutaneous allodynia and central sensitization. The molecular shift from activity-dependent to activity-independent central sensitization together with our recent conclusion that triptans have the ability to disrupt communications between peripheral and central trigeminovascular neurons (rather than inhibiting directly peripheral or central neurons) explain their clinical effects. Both our clinical and pre-clinical findings of the last five years point to possible short- and long-term advantages in using an early-treatment approach in the treatment of acute migraine attacks.
Peripheral sensitization is thought to be a major contributor to hypersensitivity in many painful syndromes including migraine headaches [2,51,91]. It generally refers to a state where primary afferent nociceptive neurons exhibit increased responsiveness to external mechanical or thermal stimuli at the original site of inflammation or injury. Such changes can be manifested as a novel response to previously ineffective stimulus intensities, indicating decreased activation thresholds [20, 52,61,81,104], and increased response magnitude to suprathreshold stimuli either with or without a noticeable change in threshold [2,16,30,92] In addition to marked changes in their stimulus response properties, peripheral sensitization can also be manifested as an increased level of ongoing discharge (i.e. spontaneous activity) in the absence of externally applied stimuli.
Among the common symptoms of peripheral sensitization during migraine are the throbbing of the headache and its aggravation during routine physical activities that increase intracranial pressure such as coughing and bending over [7,74]. Such intracranial hypersensitivity involves the sensitization of nociceptors that innervate the meninges . Accordingly, fluctuations in intracranial pressure  associated with normal vascular pulsation (4–10 mmHg), as well as those associated with bending over or coughing (4–25 mmHg), effectively activate meningeal nociceptors during migraine, when they are sensitized, but not in the absence of migraine, when they are not sensitized.
A large number of chemical mediators produced at the site of tissue injury and inflammation can promote the excitation and sensitization of nociceptors. Mediators such as bradykinin, histamine, serotonin (5-HT), and prostaglandin E2, (PGE2) have been shown to produce both excitation and mechanical sensitization of somatic  and meningeal nociceptors [52,91]. Other inflammatory mediators known to promote peripheral sensitization are cytokines, most notably interleukins 1, 6 and 8 (IL-1, IL-6, IL-8) and tumor necrosis factor-alpha (TNF-alpha) [67,79]. These mediators are believed to promote nociceptor sensitization through the endogenous release of eicosanoids and sympathetic amines . Additional inflammatory mediators proposed to promote peripheral sensitization include protons, proteases and nitric oxide. Increased levels of protons (acidic pH) found in inflamed tissues, produce not only activation and sensitization of meningeal nociceptors , but also enhance the effects of other inflammatory mediators . Inflammatory proteases, especially tryptase and trypsins, activate protease-activated receptors (PARs) on nociceptors, most notably PAR-2 . Nitric oxide has been shown to produce local inflammation within the meninges , sensitize meningeal nociceptors , and induce headache or migraine in patients .
Most sensitizing agents activate receptors that are coupled to second-messenger cascades which, in turn, modulate voltage-gated ion channels. Other potential targets for the actions of sensitizing agents on nociceptors may also include direct action on sensory transduction elements. Mechanical and thermal sensitivity can be modulated independently in individual nociceptors, suggesting the existence of separate, possibly multiple, transduction mechanisms [5,71]. For example, increased thermal skin sensitivity can be mediated by the transient receptor potential ion channel 1 (TRPV1), a transducer of noxious heat [72,96] when its threshold is lowered by bradykinin, PAR-2 agonist, and protons [18, 78,93]. The mechanism underlying increased mechanical sensitivity remains largely unknown as transducers of noxious mechanical stimuli are yet to be identified.
Peripheral sensitization can also be promoted by changes in the properties of voltage-gated ion channels, such as the TTX-resistant sodium channel (TTX-R). Inflammatory agents such as PGE2 and 5-HT are thought to sensitize sensory neurons by modulating TTX-R sodium currents  through activation of the cAMP-PKA second messenger cascade . Such action may be involved in sensitization of mechanosensitive meningeal nociceptors, as they express the TTX-R channels  and are sensitized by the cAMP-PKA cascade . The cAMP-PKA cascade is also likely to be involved in mechanical sensitization through the suppression of the sustained (delayed rectifier) outward K+ current that is thought to modulate the firing threshold [24,25] and the enhancement of Ih, the hyperpolarization-activated cation current that is thought to facilitate repetitive firing . Another second messenger cascade that may promote mechanical sensitization is the cGMP-PKG cascade that is activated by nitric oxide. The sensitizing action of nitric oxide on meningeal nociceptors may involve the activation of this cascade probably through the facilitation of Ca+2-activated potassium (BK) channels .
The proximate factors that cause local release of sensitizing chemicals during migraine remain unknown. One presumed factor is cortical spreading depression –a slowly propagating wave of neural inhibition and excitation associated with extracellular release of excitatory agents such as potassium and glutamate. Bolay et al.  have shown that cortical spreading depression activates the trigeminovascular system. One of the potential consequences of sensory fiber activation is the release of neuropeptides such as substance P (SP) and calcitonin gene–related peptide (CGRP) from the peripheral terminals of meningeal nociceptors which, in turn, promotes vasodilatation and plasma extravasation [15,50,85]. CGRP and SP are thought to sensitize nociceptors indirectly by inducing the release of sensitizing inflammatory mediators such as histamine, 5HT, BK, TNF-alpha and nitric oxide from other immune cells, especially mast cells, in a process known as mast cell degranulation [77,94,112]. The trigeminovascular system also innervates the inner ear, and auditory brainstem [17,86,99–103,114]. These pathways may play a role in the vertigo, hearing loss, tinnitus, and aural fullness experienced by some migraineurs during their attacks, and which can mimic Meniere’s disease.
Central sensitization in somatosensory pain pathways was first discovered in the rat spinal cord, where it was shown to play a role in post-injury pain hypersensitivity , and later documented in several animal models and in humans [33,49,57,75,87,97]. Central sensitization refers to a condition where nociceptive neurons in the dorsal horn of the spinal cord exhibit increased excitability, increased synaptic strength, and enlargement of their receptive fields beyond the original site of inflammation or injury [64,109,110]. Central sensitization is triggered by sensory input arriving from sensitized nociceptors that supply the affected site. Once initiated, central sensitization may remain dependent on incoming input (i.e., activity-dependent) or become self-sufficient altogether (i.e., activity independent). Sensitized dorsal horn nociceptors become responsive to innocuous (i.e., previously sub-threshold) sensory signals that arrive from areas outside the affected site, resulting in expansion of their receptive fields. Clinically, central sensitization is manifested as decreased pain threshold and exaggerated pain response that is referred outside the original pain site.
Among the common symptoms of central sensitization during migraine is the phenomenon of allodynia, where patients become irritated by mundane mechanical and thermal stimulation of the scalp and facial skin [6,14,22,27,41–43,54,55,83,95,103]. This hypersensitivity is manifested in response to activities such as combing, shaving, breathing cold air, wearing eyeglasses, contact lenses, earrings, or necklaces. Such allodynia involves the sensitization of nociceptive trigeminovascular neurons of the medullary dorsal horn that receive converging sensory input from the dura and skin . Accordingly, innocuous skin stimuli evoke dramatic activity in central trigeminovascular neurons during migraine, when they are sensitized, but produce little or no response in the absence of migraine, when they are not sensitized.
There is good evidence that central sensitization can also be produced in trigeminovascular neurons in the deep laminae of the medullary dorsal horn, and that these sensitized neurons may play a role in the pathogenesis of migraine headache . Topical application of inflammatory agents on the exposed rat dura, which activates the trigeminovascular pathway for many hours [13,23,82], induces long-lasting sensitization in medullary dorsal horn neurons that receive convergent intracranial input from the dura and extracranial input from the periorbital skin. This neuronal sensitization is manifested as increased responsiveness to mechanical stimulation of the dura increased responsiveness to mechanical and thermal stimulation of the skin decreased response thresholds and increased response magnitude to dural and skin stimulation, and expansion of dural and cutaneous receptive fields .
The history of migraine literature is dotted with accounts of increased skin sensitivity during migraine. In 1873, Edward Living  quoted Tissot in his seminal book “on Megrim” as saying: “so painful is this hyperasthesia in a certain stage of the seizure with some people that, he (the patient) could not bear anything to touch his head”. In 1953, Harold Wolff  found that in cranial tissue, deep-pain thresholds were high during headache-free periods and low during the headache, that the zone of low-threshold expanded to include areas on the non-painful side of the head, that the deep-pain threshold begun to decrease several hours after the onset of headache, and that commonly, this hypersensitivity outlasted the headache for hours and even days. In 1960, James Lance  found that about 2/3 (317/500) of migraine patients experienced scalp tenderness during migraine.
Assuming that migraine in humans is associated with sensitization of medullary dorsal horn neurons as observed in the rat, it is reasonable to predict that it should also be associated with allodynia in the periorbital skin. Using quantitative sensory testing technique, it was shown recently that 79% of the patients developed mechanical and/or thermal allodynia on the facial skin ipsilateral to the migraine pain 1–2 hours after onset of the attack . By 4 hours, allodynia frequently extended outside the referred pain area to the skin over the contralateral head and both arms . A standardized questionnaire can now be used to reliably identify patients as allodynic or non-allodynic [3,40].
Central sensitization can be divided into two distinct phases, the initiation phase and the maintenance phase, each mediated by different mechanisms.
Initiation of sensitization in the spinal cord depends on the input from nociceptive neurons of the dorsal horn that receive from signals C-fiber nociceptors that contain the excitatory amino acid glutamate and neuropeptides such as substance P and CGRP . Once activated from the periphery (leading to action potential invasion of the central terminals), calcium inflow into the central terminals of C-fiber nociceptors causes them to release a number of neuropeptides in the superficial layers of the medullary dorsal horn. Consequently, activation of C-fibers elicits slow synaptic potentials [66,88], leading to cumulative depolarization of dorsal horn neurons. C-fiber input can also contribute to the progression and establishment of sustained depolarization in dorsal horn neurons by recruiting L-type calcium plateau currents .
Maintenance of sensitization in spinal cord neurons can be activity-dependent or activity-independent . Activity-dependent central sensitization is the consequence of neurotransmitter (glutamate) and neuromodulator (substance P, brain-derived neurotrophic factor, ephrin-B ligand) induced activation of multiple intra-cellular signaling pathways in dorsal horn neurons by virtue of activation of ligand-gated ion channels (NM-DA, AMPA/Kainate), G-protein coupled metabotropic receptors (NK1, mGluR) and tyrosine kinase receptors (TrkB, EphR). Enhanced neuronal excitability in this form of central sensitization involves phosphorylation of intracellular (PKA, PKC) and extracellular (ERK) kinases and enhanced production of cyclooxygenase in the spinal cord. PKA and PKC activation leads to the phosphorylation of ionotropic glutamate receptors (NMDA and AMPA), which increases synaptic efficacy by altering channel open-time and promoting the trafficking of receptors to the synaptic membrane [58, 111]. ERK phosphorylation increases A-type K+ current via Kv4.2 channels regulation . Increased cyclooxygenase level in the dorsal horn activates EP receptors to facilitate transmitter release from nociceptor central terminals , produce a direct depolarization of dorsal horn neurons , and reduce glycine receptor activity . Activity-dependent central sensitization is displayed by many cells in both the superficial and deep laminae of the dorsal horn, but its contribution to pain sensitivity appears to be mediated by lamina I neurons, particularly those expressing the NK1 receptor [36,60].
Activity-independent central sensitization develops slowly over several hours and lasts for prolonged periods. This form of sensitization, like the activity dependent form, is initiated by intense activity in nociceptors , which induces activation of NMDA, mGlu, NK1 and trkB receptors in the central neurons. This, in turn, activates PKA, PKC and ERK as described above, but it also increases production of the cytokine interleukins-1β (IL-1βpgn endothelial cells and spinal microglia . Central sensitization shifts from activity-dependent mode to activity-independent mode upon widespread increase in expression of transcription factor genes such as CRE-binding protein [46,47], immediate early genes such as c-fos and COX-2 [34, 80], and late-response genes encoding prodynorphine, NK1 and trkB [33,42,56,60]. Interestingly, these genes share cAMP-response element (CRE) sites in their promoter region [44,84].
Migraine patients with and without allodynia exhibit different responses to abortive migraine treatments. Treatment of acute or chronic pain is generally more complicated to treat with triptans in the presence of allodynia. Patients who do not exhibit allodynia during migraine are highly responsive to triptans; they are typically rendered pain-free within 2 hours of treatment . Patients whose migraine headache is accompanied by cutaneous allodynia become increasingly resistant to triptan therapy with the progression of the attack . These patients are highly likely to be rendered pain-free by triptan treatment early in the attack, when they have not yet exhibited signs of allodynia, or even in the early presence of allodynia. The same patients, however, would fail to respond to triptans if treatment were delayed until they have fully developed allodynia over a period of several hours . These observations can be explained by the effects of triptans on central trigeminovascular neurons that mediate allodynia during migraine.
In the rat, sensitization in central trigeminovascular neurons induced by topical application of “inflammatory soup” (histamine/bradykinin/prostaglandin E2 in Hepes buffer) to the dura is blocked by co-administration of sumatriptan (i.e., early treatment paradigm). In contrast, sumatriptan intervention several hours after inflammatory soup application (i.e., late treatment paradigm) could not reverse the ongoing sensitization in the central neurons . Therefore, central trigeminovascular neurons appear to be unequipped to respond to triptans directly. A similar experimental paradigm showed that early triptan treatment cannot prevent the induction of sensitization in meningeal nociceptors, and that late treatment has no effect at the ongoing state of peripheral sensitization . Collectively, these data suggest that the action of triptans in the dorsal horn is mediated mainly by presynaptic inhibition of signal transmission between peripheral (first-order) and central (second-order) trigeminovascular neurons (Fig. 1). This conclusion is consistent with the selective presence of presynaptic 5HT1D receptors on central terminals of peripheral nociceptors in the dorsal horn . Accordingly, termination of migraine headache and the associated allodynia using triptan treatment is possible as long as the excitability of the central neurons remains driven by incoming signals from the meninges, but not after they develop autonomous activity .
Most patients testify that triptans are much more likely to render them pain-free when taken early rather than late, but routinely delay treatment until attacks are fully developed or the pain is severe. Justifying the delayed treatment are concerns about side effects, addiction, limits on supply imposed by prescribers, cost, and most commonly waiting to see if headache develops into a severe migraine attack . For these patients, one way to terminate migraine with allodynia and fully developed central sensitization is parenteral administration of COX1/COX2 inhibitors . Infusion of the COX1/COX2 inhibitor ketorolac in allodynic patients who already missed the critical period for triptan therapy terminated both the headache and the allodynia provided that the patient had no history of using opioids to treat her/his migraines. In the rat, infusion of COX-1/COX-2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons, suggesting that parenteral NSAID administration acts in the dorsal horn to inhibit the central neurons directly and reduce the synaptic input from the peripheral trigeminovascular neuron [38,39].
Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department. Patients who use an opioid therapy over an extended period of time are at high risk of developing medication-overuse headache and low response to non-narcotic drugs. The rational for recommending against the use of opioids in allodynic migraine patients is based on evidence that opioids can facilitate sensitization in the dorsal horn [62, 69,73,105] through: (a) upregulation of NMDA receptors, (b) downregulation of glutamate transporters, (c) production of nitric oxide, (d) activation of spinal glia, and (e) increased extracellular kevel of prostaglandins.
We have presented a review of some of the current information regarding the neural pathways of pain symptoms in migraine. Peripheral senistization refers to a state where primary afferent nociceptive neurons exhibit increased responsiveness to external mechanical or thermal stimuli at the original site of inflammation or injury. Common symptoms of peripheral sensitization during migraine are the throbbing of the headache and its aggravation during routine physical activities that increase intracranial pressure such as coughing and bending over. These effects are mediated by bradykinin, histamine, serotonic, prostaglandin E2 and a number of cytokines and other inflammatory mediators. In contrast, central sensitization refers to a condition where nociceptive neurons in the dorsal horn of the spinal cord exhibit increased excitability, increased synaptic strength, and enlargement of their receptive fields beyond the original site of inflammation or injury. Allodynia is the archetypical manifestation of central sensitization. It is mediated by central trigeminovascular neurons. Central sensitization undergoes an initiation phase and a maintenance phase, each mediated by different neurons. Once initiated, maintenance of central sensitization can be activity-dependent or activity-independent. The activity-dependent form is the consequence of neurotransmitter and neuromodulator induced activation of multiple intracellular signalling pathways. Activity-independent sensitization develops slowly over several hours and lasts for prolonged periods. The pathways and time course of central sensitization have clinical relevance. Early in a migraine attack, triptans are highly effective abortives. However, in patients whose migraine is accompanied by allodynia, the patient becomes increasingly resistant to triptan therapy as the allodynia develops.
There are a host of other migraine symptoms that have not been studied as thoroughly as allodynia. In some cases, distortion or intensification of other sensory modalities, as seen in photophobia, phonophobia, osmophobia, and vestibular symptoms, may be mediated by the same pathways and could have similar response or resistance to therapy. For example, thalamic neurons may have dual innervation and be modulated by normally non-nociceptive modalities. In the case of vestibular symptoms in particular, the trigeminovascular pathways have been shown to affect inner ear bloodflow, which could conceivably create peripheral vestibular dysfunction as a downstream consequence of central sensitization. Both basic and clinical research will be needed to dissect these phenomena and lead to more appropriate and effective treatments.
Supported by NIH grants NS051484 and NS069847 from NINDS.