Robin James Storer

Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat.

Calcitonin gene‐related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α‐CGRP‐(8–37) and BIBN4096BS. Cats were anaesthetised with α‐chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by microiontophoresis of L‐glutamate (n=43 cells). Microiontophoresis of α‐CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L‐glutamate, demonstrating a non‐presynaptic site of action for CGRP. α‐CGRP‐(8–37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose‐dependent inhibition of trigeminocervical SSS‐evoked activity (ED50 31 μg kg–1). The maximal effect observed within 30 min of administration. The data suggest that there are non‐presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.

Topiramate inhibits trigeminovascular neurons in the cat

To facilitate understanding the action of antimigraine preventives the effect of topiramate on trigeminocervical activation in the cat was examined. Animals (n = 7) were anaesthetized and physiologically monitored. The superior sagittal sinus (SSS) was stimulated to produce a model of trigeminovascular nociceptive activation. Cumulative dose-response curves were constructed for the effect of topiramate at doses of 3, 5, 10, 30 and 50 mg/kg on SSS-evoked firing of trigeminocervical neurons. Topiramate reduced SSS evoked firing in a dose-dependent fashion. The maximum effect was seen over 30 min for the cohort taken together. At 3 mg/kg firing was reduced by 36 ± 13% (mean ± SEM) after 15 min. At 5 and 50 mg/kg firing was reduced by 59 ± 6% and 65 ± 14%, respectively, after 30 min. Inhibition of the trigeminocervical complex directly, or neurons that modulate sensory input, are plausible mechanisms for the action of preventives in migraine.

Dopamine inhibits trigeminovascular transmission in the rat.

Clinical evidence, such as premonitory or postdromal symptoms, indicate involvement of dopamine in the pathophysiology of migraine.

Pathophysiology of medication overuse headache--an update.

The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5‐HT)‐, and perhaps endocannabinoid‐dependent or other, modulating systems. Increased expression of excitatory cortical 5‐HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5‐HT levels also increase the expression and release of calcitonin gene‐related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache.

GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by midazolam is antagonized by flumazenil

Studies of the pharmacology of trigeminocervical neurons with input from intracranial pain-producing structures have enhanced the understanding of the basic neurobiology of primary headache, such as migraine. Clinical observations of the treatment of migraine with medicines acting at the gamma-aminobutyric acid (GABA) GABAA receptor have lead to studies of their effects on models of trigeminovascular nociception. Extracellular recordings were made from neurons in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus (SSS) in the cat. Intravenous administration of the benzodiazepine receptor agonist midazolam, resulted in a dose-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity. The inhibition at 50 microg/kg midazolam was 65+/-11% compared to the baseline response (n=11). Intravenous administration of the benzodiazepine receptor antagonist flumazenil, resulted in a dose-dependent recovery of superior sagittal sinus evoked trigeminocervical nucleus activity. At a dose of 50 microg/kg, there was a 64+/-5% recovery (n=6). The data demonstrate a potent, reproducible effect of facilitation of GABA transmission at the GABAA receptor that results in inhibition of trigeminovascular nociceptive transmission. These data are consistent with the useful clinical effects reported with compounds that can augment GABAergic transmission in the central nervous system (CNS).

Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex

Opioid agonists have been used for many years to treat all forms of headache, including migraine. We sought to characterize opioid receptors involved in craniovascular nociceptive pathways by in vivo microiontophoresis of μ‐receptor agonists and antagonists onto neurons in the trigeminocervical complex of the cat. Cats were anaesthetized with α‐chloralose 60 mg kg−1, i.p. and 20 mg kg−1, i.v. supplements after induction and surgical preparation using halothane. Units were identified in the trigeminocervical complex responding to supramaximal electrical stimulation of the superior sagittal sinus, and extracellular recordings of activity made. Seven‐ or nine‐barrelled glass micropipettes incorporating tungsten recording electrodes in their centre barrels were used for microiontophoresis of test substances onto cell bodies. Superior sagittal sinus (SSS)‐linked cells whose firing was evoked by microiontophoretic application of L‐glutamate (n=8 cells) were reversibly inhibited by microiontophoresis of H2N‐Tyr‐D‐Ala‐Gly‐N‐Me‐Phe‐Gly‐ol (DAMGO) (n=12), a selective μ‐receptor agonist, in a dose dependent manner, but not by control ejection of sodium or chloride ions from a barrel containing saline. The inhibition by DAMGO of SSS‐linked neurons activated with L‐glutamate could be antagonized by microiontophoresis of selective μ‐receptor antagonists D‐Phe‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2 (CTOP) or D‐Phe‐Cys‐Tyr‐D‐Trp‐Arg‐Thr‐Pen‐Thr‐NH2 (CTAP), or both, in all cells tested (n=4 and 6, respectively). Local iontophoresis of DAMGO during stimulation of the superior sagittal sinus resulted in a reduction in SSS‐evoked activity. This effect was substantially reversed 10 min after cessation of iontophoresis. The effect of DAMGO was markedly inhibited by co‐iontophoresis of CTAP. Thus, we found that μ‐receptors modulate nociceptive input to the trigeminocervical complex. Characterizing the sub‐types of opioid receptors that influence trigeminovascular nociceptive transmission is an important component to understanding the pharmacology of this synapse, which is pivotal in primary neurovascular headache.

Polyamine oxidase activity in rheumatoid arthritis synovial fluid

Oxidation of polyamides by polyamine oxidases (PAO) leads to the generation of highly reactive aminoaldehydes which have been shown to have a variety of effects, including killing of pathogenic microorganisms and regulation of leucocyte functions. Data presented here show that PAO are present in synovial fluid from patients with rheumatoid arthritis. This finding may have important implications in the various properties attributed to synovial fluid which includes anti‐inflammatory activity

Animal models of chronic migraine.

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.

GABAA receptors in the nucleus raphe magnus modulate firing of neurons in the trigeminocervical complex.

Methods We used a model of trigeminovascular nociception in Sprague Dawley rats that measures transmission of craniovascular nociception in the trigeminocervical complex (TCC) by the firing of TCC neurons evoked in response to electrical stimulation of afferents from the middle meningeal artery, its branches, and periarterial meninges (MMA). To determine whether GABA receptors in the NRM modulate this nociceptive transmission, and to characterize the modulation, we microinjected GABA, and GABAAand GABAB-receptor agonists and antagonists into the NRM.

Identifying and quantifying methamphetamine in hair samples

In this issue of Asia Biomedicine, Junkuy and colleagues [1] describe a new, economical technique for quantifying levels of methamphetamine and itsmetabolite, amphetamine, in human hair samples. The method, using solid-phase microextraction with gas chromatography and mass spectrometry (SPME/GCMS), met international standards for analysis of methamphetamine (MA) in hair. A detection rate for MA of 35.5% from hair samples was derivedfrom young MA users who were participating in a randomized-controlled trial of community mobilization for behavior change in Chiang Mai, Thailand [2]. The highest percentage of positive samples was found among more intensive users, with 43.6% found among persons who reported having used more than 90 MA tablets in the previous 3 months. The article contributes to the literature in describing a simple, economically efficient technique for chemical validation of methamphetamine use. Hair-based assays have long been developed for a number of drugs, and have been used in both clinical, research, and forensic settings [3].