GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

Abstract

1 GABA (g-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 ®ring 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 speci®c input from cutaneous receptive ®elds 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(7)-baclofen, a GABA B agonist, inhibited the ®ring of three out of seven cells activated by Lglutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofeninhibited 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. British Journal of Pharmacology (2001) 134, 896 ± 904 Keywords: GABA; trigeminal nucleus caudalis; migraine; microiontophoresis Abbreviations: Baclofen, R(+)-baclofen hydrochloride; 2OH-saclofen, 2-hydroxysaclofen; GAD, glutamic acid dehydrogenase; LTM, low threshold mechanical; N-methylbicuculline, (7)-bicuculline metho-chloride/-bromide, 1(S),(9R); NS, nociceptive speci®c; PPE, plasma protein extravasation; SSS, superior sagittal sinus; TNC, trigeminal nucleus caudalis; WDR, wide dynamic range IntroductionThe pain in primary headache syndromes, such as migraine and cluster headache, is referred to the ophthalmic (®rst) division of the trigeminal nerve from pain-producing intracranial structures, such as the dura mater and large vessels, through the trigeminocervical complex (Goadsby, 2001). Modulation of trigeminal transmission in order to alleviate acute migraine requires an understanding of the pharmacology of the synapse onto second order trigeminal neurones. In recent years the pharmacology of this synapse has begun to be studied with most attention on serotonergic and glutamatergic transmission (Goadsby, 1999a). g-Aminobutyric acid (GABA) is well known as an inhibitory amino acid neurotransmitter in the central nervous system (CNS) (Roberts, 1976) and may modulate nociceptive response in spinal cord (Roberts et al., 1986). Its role in trigeminovascular nociceptive transmission within t...

Significant differences in gene expression of GABA receptors in peripheral blood leukocytes of migraineurs

“…Q-PCR gene expression analysis demonstrated that two of GABA receptor subunits examined (GABRA3 and GABBR2) were significantly down regulated in case subjects in comparison to control subjects. This is consistent with previous research that has suggested that individuals with migraine have a lower level of inhibition in the brain, and that this may be the result of decreased GABA A receptor activation (Storer et al, 2001;Storer et al, 2004;Schiene et al, 1996). As GABRA3 has a chromosomal location of Xq28, a region previously linked to migraine, this strengthens the implication of this genomic location in migraine etiology.…”

“…This theory is supported by a study in 2001, demonstrating that after Transcranial Magnetic Stimulation, MA patients were more susceptible to hyperexcibility in the visual cortex than controls, indicating that MA patients may have a lower level of inhibition in the cerebral cortex than control subjects (Mulleners et al, 2001). Other studies have suggested that this lack of inhibition may be due to defective gamma-aminobutyric acid (GABA) circuits (Palmer et al, 2000;Fierro et al, 2003) Decreased GABA A receptor activation and expression has been demonstrated in several studies to result in decreased inhibition within the brain (Storer et al, 2001(Storer et al, , 2004Schiene et al, 1996), suggesting that GABA receptor activation and expression may be decreased in individuals with migraine.…”

Convergence of cervical and trigeminal sensory afferents

“…Valproic acid, an inhibitor of γ aminobutyric acid (GABA) aminotransferase, when applied to the rat in the trigeminocervical nociceptive models, reduced the expression of c-fos-positive cells in the TNC [46] after trigeminal stimulation. Electrophysiologic studies, combined with microiontophoresis, also suggested that GABA receptors modulate trigeminovascular nociceptive transmission in the trigeminocervical complex [47].…”

“…However, it also receives other inputs that participate in head pain control. The parasympathetic system (vagus nerve), together with the TNC and LCN (trigeminocervical [46]; 5-HT 1 receptors for dihydroergotamine; opioids-receptor [47]; GABA-A-receptors [48,49]; trigeminocervical complex-trigeminal nucleus caudalis and lateral cervical nucleus [10,[15][16][17]23,44,45]; hypoglossal afferents [22]; simpato afferents [20,21]. structures), could increase or decrease the pain signals.…”

Prophylactic migraine therapy: Emerging treatment options

“…Recent clinical studies in migraine have indicated the efficacy of potentially GABAergic drugs. Storer et al [16] showed that GABA appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA A receptors. Therefore, GABA A receptors may …”