Stimulation of dural vessels excites the SI somatosensory cortex of the cat via a relay in the thalamus.

AIM: We carried out experiments in cats to determine the thalamo-cortical projection sites of trigeminovascular sensory neurons. METHODS: 1) We stimulated the middle meningeal artery (MMA) with C-fibre intensity electrical shocks and made field potential recordings over the somatosensory cortical surface. 2) We then recorded neurons in the ventroposteromedial (VPM) nucleus of the thalamus in search of neurons which could be activated from the skin, MMA and superior sagittal sinus. 3) Finally, we attempted to antidromically activate the neurons found in stage 2 by stimulating the responsive cortical areas revealed in stage 1. RESULTS: VPM neurons received trigeminovascular input, input from the V1 facial skin and could also be activated by electrical stimulation of the somatosensory cortex. VPM neurons activated from the cortex responded with short and invariant latencies (6.7 ± 7.7 msec mean and SD). They could follow high rates of stimulation and sometimes showed collision with orthodromic action potentials. CONCLUSIONS: We conclude that somatosensory (SI) cortical stimulation excites trigeminovascular VPM neurons antidromically. In consequence, these VPM neurons project to the somatosensory cortex. These findings may help to explain the ability of migraineurs with headache in the trigeminal distribution to localise their pain to a particular region in this distribution.

Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat.

Functional imaging studies and clinical evidence suggest that structures in the brainstem contribute to migraine pathophysiology with a strong association between the brainstem areas, such as periaqueductal gray (PAG), and the headache phase of migraine. Stimulation of the superior sagittal sinus (SSS) in humans evokes head pain. Second-order neurons in the trigeminal nucleus that are activated by SSS stimulation can be inhibited by PAG stimulation. The present study was undertaken to identify pontine and medullary structures that respond to noxious stimulation of the superior sagittal sinus or to ventrolateral PAG stimulation. The distribution of neurons expressing the protein product (fos) of the c-fos immediate early gene were examined in the rostral medulla and caudal pons of the cat after (i) sham, (ii) stimulation of the superior sagittal sinus, (iii) stimulation of the superior sagittal sinus with PAG stimulation, or (iv) stimulation of the PAG alone. The structures examined for fos were the trigeminal nucleus, infratrigeminal nucleus, reticular nuclei, nucleus raphe magnus, pontine blink premotor area, and superior salivatory nucleus. Compared with all other interventions, fos expression was significantly greater in the trigeminal nucleus and superior salivatory nucleus after SSS stimulation. After PAG with SSS stimulation, on the side ipsilateral to the site of PAG stimulation, fos was significantly greater in the nucleus raphe magnus. These structures are likely to be involved in the neurobiology of migraine.

Differential effects of low dose CP122,288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat.

CP122,288, a conformationally restricted analogue of sumatriptan, is a highly potent inhibitor of neurogenic plasma protein extravasation (PPE) in rat and guinea pig at low doses where it has no 5HT1B-mediated vascular actions. We have examined its effect on a model of trigeminovascular nociception to assess the relative importance of vasoconstrictor and serotonin (5HT)(1B/1D) agonist activity to the modulation trigeminal neuronal activation. For comparison to activate relevant 5HT receptors, the clinically effective relatively lipophilic 5HT(1B/1D) agonist eletriptan was studied in parallel. The superior sagittal sinus was isolated in the alpha-chloralose (60 mg/kg, i.p. and 15-20 mg/kg i.v. supplement every 2 h) anaesthetized cat. Animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus (250 micros, 100 V, 0.3 Hz) resulted in Fos expression in cells in the trigeminal nucleus caudalis and superficial laminae of the dorsal horns of C(1-2). Administration of low dose CP122,288 (100 ng/kg) had no effect on Fos expression after sinus stimulation either when administered alone or in combination with mannitol; the latter to ensure access to the trigeminocervical complex. The number of cells in the superficial laminae of the trigeminal nucleus caudalis with stimulation being a median of 50 (quartile range: 47-53) and 48 (35-48) after CP122,288, and after CP122,288 and mannitol 45 (41-53). In comparison, the clinically effective 5HT(1B/1D) agonist, eletriptan, reduced Fos expression in the trigeminocervical complex to a median of 24 (21-33). These data demonstrate that the potent inhibitor of neurogenic plasma protein extravasation (PPE) CP122,288 has no effect on Fos expression in central trigeminal neurons when administered at a dose which blocks PPE in rat and guinea pig, but has no vasoconstrictor 5HT(1B/1D) activity, and while ensuring its access to central trigeminal neurons. The data suggest that activation of the 5HT(1B/1D) receptor is important for the clinical action of this class of compounds and is consistent with the fact the CP122,288 is ineffective in the treatment of the acute attack of migraine.