Headache. 2004 Nov;44(10):1063-1065. [No authors listed] D'Andrea G, Terrazzino S, Leon A, Fortin D, Perini F, Granella F, Bussone G. Elevated levels of circulating trace amines in primary headaches. Neurology. 2004;62: 1701-1705.

Background: Trace amines, including tyramine, octopamine, and synephrine, are closely related to classic biogenic amines. They have been hypothesized to promote migraines and other types of primary headaches, but there is no direct evidence supporting this hypothesis.

Methods: Using a multichannel electrochemical high-performance liquid chromatography system, the authors evaluated whether changes in circulating trace amines occur in subjects with migraine (with or without aura) during headache-free periods as well as in patients with cluster headache (CH) during the remission and active phases as compared with healthy control subjects.

Results: Plasma levels of all trace amines were significantly higher in CH patients, in both the remission and the active phases, when compared with control subjects or subjects with migraine. In addition, intraplatelet levels of octopamine, synephrine, and tyramine were higher in CH patients than in control subjects. In migraine patients, plasma levels of octopamine and synephrine were higher compared with controls, although in migraine with aura, the difference was not significant.

Conclusions: Whereas the elevation of plasma trace amine levels in both migraine and CH supports the hypothesis that disorders of biogenic amine metabolism may be a characteristic biochemical trait in primary headache sufferers, the observation that such alterations are more prominent in patients with CH than migraine patients suggests that they may reflect sympathetic or hypothalamic dysfunction.

Comment: Dr. D'Andrea's conclusion are consistent with the fact that the putative generator for cluster, discovered by May, Goadsby et al is in the hypothalamus.-Stewart J. Tepper This is an important clinico-pathological paper from Professor Bussone's group. For me it raises important questions. Do these vasoactive amines provide the basis for separating out a more "vascular" type of headache, such as Cluster with its nasal congestion, conjunctival injection, and lacrimation? Might these amines be transported via platelets to act as surrogate false transmitters when taken up by sympathetic nerves? These complimentary studies are important alongside the imaging work in order to complete the jigsaw puzzle.

-David S. Millson Bardoni R, Torsney C, Tong CK, Prandini M, MacDermott AB. Presynaptic NMDA receptors modulate glutamate release from primary sensory neurons in rat spinal cord dorsal horn. J Neurosci. 2004;24:2774-2781.

NMDA receptors have the potential to produce complex activity-dependent regulation of transmitter release when localized presynaptically. In the somatosensory system, NMDA receptors have been immunocytochemically detected on presynaptic terminals of primary afferents, and these have been proposed to drive release of substance P from central terminals of a subset of nociceptors in the spinal cord dorsal horn. Here, we report that functional NMDA receptors are indeed present at or near the central terminals of primary afferent fibers. Furthermore, we show that activation of these presynaptic receptors results in an inhibition of glutamate release from the terminals. Some of these NMDA receptors may be expressed in the preterminal axon and regulate the extent to which action potentials invade the extensive central arborizations of primary sensory neurons.

Comment: We assume that when a glutamate antagonist works to abort migraine, it works postsynaptically (see the Sang et al, abstract above). NMDA antagonists have so far been too toxic to use to abort migraine, but the idea of targeting presynaptic inhibitory receptors is very attractive. -Stewart J. Tepper

Shigetomi E, Kato F. Action potential-independent release of glutamate by Ca(2+) entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network. J Neurosci. 2004;24:3125-3135.

P2X receptors are ATP-gated channels permeable to cations including Ca(2+). In acute slices containing the nucleus of the solitary tract, in which neuronal ATP release and ATP-elicited physiological responses are demonstrated in vivo, we recorded spontaneous action potential-independent EPSCs (miniature EPSCs [mEPSCs]). Activation of presynaptic P2X receptors with alpha,beta-methylene ATP (alphabetamATP) triggered Ca(2+)-dependent glutamate release that was resistant to blockade of voltage-dependent calcium channels but abolished by P2X receptor antagonists. mEPSCs elicited with alphabetamATP were of larger amplitude than basal mEPSCs and resulted in postsynaptic firing caused by temporal summation of miniature events. The large-amplitude mEPSCs provoked by alphabetamATP were likely to result from highly synchronized multivesicular release of glutamate at single release sites. Neither alphabetamATP nor ATP facilitated GABA release. We conclude that this facilitated release and consequent postsynaptic firing underlie the profound autonomic responses to activation of P2X receptors observed in vivo.

Comment: This article describes another form of calcium channel, the P2X receptors, the activation of which releases glutamate. The glutamate release is not blocked by traditional voltage-dependent calcium channel blockers. Please see the abstract above by Sang et al, which shows that an AMPA-kainate glutamate blocker works to abort migraine. -Stewart J. Tepper

Pardutz A, Szatmari E, Vecsei L, Schoenen J. Nitroglycerin-induced nNOS increase in rat trigeminal nucleus caudalis is inhibited by systemic administration of lysine acetylsalicylate but not of sumatriptan. Cephalalgia. 2004;24:439-445.

Systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor, in migraineurs triggers after several hours an attack of which the precise mechanisms are unknown. We found previously in rats that nitroglycerin (10 mg/kg s.c.) is able to increase significantly after 4 hour the number of neuronal nitric oxide synthase (nNOS)-immunoreactive neurones in the cervical part of trigeminal nucleus caudalis. In the present experiments, we demonstrate that the 5-HT1B/D agonist sumatriptan (0.6 mg/kg s.c.) does not alter this phenomenon when given before NTG. By contrast, pretreatment with lysine acetylsalicylate (50 mg/kg i.m.) attenuates the NTG-induced nNOS expression in the superficial laminae of trigeminal nucleus caudalis. These findings suggest that effect of NTG on nNOS at a high dosage may involve the cycloxygenase pathway and that activation of the peripheral 5-HT1B/D receptors is not able to modify this effect. These data could help to better understand the role of NO in the pathogenesis of headaches and the action of antimigraine drugs.

Comment: This is an interesting study, because it may shed light on how aspirin aborts migraine in addition to its anti-inflammatory effects, that is by inhibiting NO synthesis. -Stewart J. Tepper A fascinating observation. I would be intrigued to know how selective the dose of aspirin chose is versus different prostanoid pathways and whether COX-2 inhibitors will interact in the same way? -David S. Millson

Galante M, Diana MA. Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci. 2004;24:4865-4874.

Actions of endocannabinoids in the cerebellum can be demonstrated following distinct stimulation protocols in Purkinje cells. First, depolarization-induced elevations of intracellular Ca(2+) lead to the suppression of neurotransmitter release from both inhibitory and excitatory afferents. In another case, postsynaptic group I metabotropic glutamate receptors (mGluRs) trigger a strong inhibition of the glutamatergic inputs from parallel and climbing fibers. Both pathways involve endocannabinoids retrogradely acting on type 1 cannabinoid receptors (CB1Rs) at presynaptic terminals. Here, we show that group I mGluR activation also depresses GABAergic transmission at the synapses between molecular layer interneurons and Purkinje cells. Using paired recordings, we found that application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine reduced the evoked IPSCs in Purkinje cells. This effect was independent of postsynaptic Ca(2+) increases and was completely blocked by a CB1R antagonist. Experiments performed with the GTP-analogues GDP-betaS and GTP-gammaS provided evidence that endocannabinoids released after G-protein activation can also inhibit GABAergic inputs onto nearby, unstimulated Purkinje cells. Block of the enzymes DAG lipase or phospholipase C reduced the group I mGluR-dependent inhibition, suggesting that 2-arachidonyl glycerol could act as retrograde messenger. Finally, group I mGluR activation by brief bursts of activity of the parallel fibers induced a short-lived depression of spontaneous IPSCs via presynaptic CB1Rs. Our results reveal a mechanism with potential physiological importance, by which glutamatergic synapses induce an endocannabinoid-mediated inhibition of the GABAergic inputs onto Purkinje cells.

Comment: Thus, glutamate (excitatory) also activates endocannabinoid inhibition of GABA (inhibitory), causing further excitatory tone. -Stewart J. Tepper

Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?Neuroendocrinol Lett. 2004;25:31-39.

Objectives: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis.

Methods: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources.

Results: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral, and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS, and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuroimaging.

Conclusion: Migraine, fibromyalgia, IBS, and its related conditions display common clinical, biochemical, and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

Comments: So, the theory, then is that endocannabinoids block 5-HT2A, that is, block excitatory serotonin receptors, have anti-inflammatory effects, and "modulate" (inhibit?) glutamatergic neurotransmission via NMDA receptors. However, as noted in the previous abstract, endocannabinoids can inhibit GABA, resulting in excitatory function, and they have been implicated in increased headache as well (Alvaro LC, Iriondo I, Villaverde FJ. Sexual headache and stroke in a heavy cannabis smoker. Headache. 2002;42:224-226). The story is by no means clear (Evans RW, Ramadan NM. Are cannabis-based chemicals helpful in headache? Headache. 2004;44:726-727).-Stewart J. Tepper.
I am cautiously optimistic about the therapeutic role of cannabinoids in pain control. However, I share Dr. Tepper's caution relating to the potential downsides of these agents. My own clinical experience in trying to unsuccessfully control the blood pressure of a young Afro-Caribbean patient was thwarted by his refusal to abandon his "joints," eventually leading to a hypertensive stroke. -David S. Millson.

Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B, Erhard P, Tolle TR. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain-an fMRI analysis. Pain. 2004;109:399-408.

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely, innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analog scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called "medial pain system." Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.

Comment: Dr. Richard Hargreaves has commented on the imaging studies that suggest attention and pain are related, thus distraction becomes a potentially useful tool, clinically.-Stewart J. Tepper. PMID: 15546280 [PubMed – as supplied by publisher]

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