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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., (© 2013 American Headache Society.)

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 alpha-CGRP-(8-37) and BIBN4096BS. Cats were anaesthetised with alpha-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 alpha-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. alpha-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 microg 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., (Copyright 2004 Nature Publishing Group)

1. 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 micro -receptor agonists and antagonists onto neurons in the trigeminocervical complex of the cat. 2. Cats were anaesthetized with alpha-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. 3. Seven- or nine-barrelled glass micropipettes incorporating tungsten recording electrodes in their centre barrels were used for microiontophoresis of test substances onto cell bodies. 4. 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 H(2)N-Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (n=12), a selective micro -receptor agonist, in a dose dependent manner, but not by control ejection of sodium or chloride ions from a barrel containing saline. 5. The inhibition by DAMGO of SSS-linked neurons activated with L-glutamate could be antagonized by microiontophoresis of selective micro -receptor antagonists D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or both, in all cells tested (n=4 and 6, respectively). 6. 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. 7. Thus, we found that micro -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.

1. GABA (gamma-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2. Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3. Cell firing evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA(A) agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws. 4. The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA(A) antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA(B) antagonist 2-hydroxysaclofen (n=11). 5. R(-)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L-glutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofen-inhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6. GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA(A) receptors. GABA(A) receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders.