GABA and valproate modulate trigeminovascular nociceptive transmission in the thalamus.

OBJECTIVE: To study the role of GABA receptors in thalamic relay neurons in the ventroposteromedial (VPM) nucleus of the rat activated by a trigeminovascular nociceptive stimulus in relationship to migraine, and the potential modulation of nociceptive transmission by GABA acting anti-convulsants. METHODS: Trigeminovascular nociceptive afferents were identified in the VPM by electrical stimulation of the superior sagittal sinus (SSS), and cell bodies identified by activation with L-glutamate. The effect of GABA, valproate and gabapentin ejection during SSS stimulation and microiontophoresis of L-glutamate was studied. GABA responses were characterized with the selective GABA(A) and GABA(B) agonists muscimol and baclofen, respectively, and the antagonists bicuculline (GABA(A)) and hydroxysaclofen (GABA(B)). RESULTS: GABA inhibited the response to SSS stimulation and L-glutamate ejection. Both the selective GABA(A) receptor agonist muscimol, and the GABA(B) agonist baclofen strongly inhibited the post-synaptic response to L-glutamate. This inhibition could be antagonised by co-ejection of the appropriate antagonist. The post-synaptic inhibitory action of GABA on the cell bodies of third order neurons could be partially antagonised by co-ejection of bicuculline but not by hydroxysaclofen. Valproate inhibited the responses to SSS stimulation and L-glutamate ejection. Bicuculline, but not hydroxysaclofen, was able to antagonise the effect of valproate on both responses to L-glutamate and SSS stimulation. Gabapentin did not alter the responses to L-glutamate and SSS stimulation. INTERPRETATION: These results indicate that GABA(A) and GABA(B) receptors on thalamic neurons can modulate trigeminovascular nociceptive transmission in the VPM nucleus. Sodium valproate can inhibit trigeminovascular nociception at the level of VPM through GABA(A) receptor mechanisms, whereas gabapentin does not alter trigeminovascular nociception.

Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?

Migraine is a common, debilitating condition affecting up to 15% of the population. The ventroposteromedial nucleus of the thalamus relays trigeminal sensory input to the primary somatosensory cortex. In vivo electrophysiological recordings were made from the cell bodies of thalamocortical relay neurons in rats. We investigated whether microiontophoretic ejection of beta antagonists could inhibit thalamocortical activity in response to superior sagittal sinus (SSS) stimulation. We also studied 'postsynaptic' actions of these drugs through their modulatory actions on L-glutamate-evoked third order neuronal firing. Propranolol inhibited responses to SSS stimulation (P < 0.001) and L-glutamate ejection (P < 0.001). This was due to an action on beta receptors as it could be partially reversed by co-ejection of isoproterenol (SSS, P = 0.02; L-glutamate, P = 0.006). Serotonin (5-HT) receptor antagonism did not contribute to propranolol's action since the 5-HT1A receptor antagonist, (S)-WAY 100135 (P = 0.2), and the 5-HT1B/1D receptor antagonist, GR127935 (P = 0.6), did not affect L-glutamate-evoked neuronal firing. Atenolol inhibited both responses (SSS, P = 0.003; L-glutamate, P < 0.001). The beta2 antagonist ICI 118,551 had no effect (SSS, P = 0.9; L-glutamate, P = 0.4), nor did the beta2 agonist procaterol (SSS, P = 0.6; L-glutamate, P = 0.9). SR 59230A (beta3 antagonist) also produced no significant inhibition (SSS, P = 0.7; L-glutamate, P = 0.2), indicating an inhibitory role for beta1 antagonists only. beta Blockers therefore may exert some of their therapeutic effects in migraine through beta1 adrenoceptor antagonist actions in the thalamus. Thalamic involvement in migraine is attractive given the complex and widespread nature of the sensory disturbance.

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).

Extended phenotypic spectrum of KIF5A mutations: From spastic paraplegia to axonal neuropathy.

OBJECTIVE: To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2). METHODS: KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing. RESULTS: Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features. CONCLUSION: This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.

Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target?

Triptans, serotonin 5-HT(1B/1D), receptor agonists, which are so effective in acute migraine, are considered to act directly on the trigeminovascular system. Using an in vivo model of trigeminovascular nociception, we report a potentially novel action for the triptans within the somatosensory thalamus. Both microiontophoretically applied and intravenous naratriptans potently and reversibly modulate nociceptive neurotransmission by trigeminovascular thalamic neurons in the ventroposteromedial nucleus (VPM) driven by stimulation of the superior sagittal sinus. Naratriptan also suppresses l-glutamate activated trigeminovascular VPM neurons. Co-ejection of naratriptan with the 5-HT(1B/1D) receptor antagonist GR127935 antagonized this effect. (S)-WAY 100135 the 5-HT(1A) receptor antagonist also partially inhibited the effect of naratriptan in the VPM when co-ejected with it. Taken together, the new data suggest a potential effect of triptans in the VPM nucleus of the thalamus acting through 5-HT(1A/1B/1D) mechanisms, and offer an entirely new direction for the development of and understanding of the effects of anti-migraine medicines.