Cortico-NRM influences on trigeminal neuronal sensation.

We tested the idea that migraine triggers cause cortical activation, which disinhibits craniovascular sensation through the nucleus raphe magnus (NRM) and thus produces the headache of migraine. Stimulation of the dura mater and facial skin activated neurons in the NRM and the trigeminal nucleus. Stimulation of the NRM caused suppression of responses of trigeminal neurons to electrical and mechanical stimulation of the dura mater, but not of the skin. This suppression was antagonized by the iontophoretic application of the 5-HT(1B/1D) receptor antagonist GR127935 to trigeminal neurons. Migraine trigger factors were simulated by cortical spreading depression (CSD) and light flash. Activity of neurons in the NRM was inhibited by these stimuli. Multiple waves of CSD antagonized the inhibitory effect of NRM stimulation on responses of trigeminal neurons to dural mechanical stimulation but not to skin mechanical stimulation. The cortico-NRM-trigeminal neuraxis might provide a target for a more universally effective migraine prophylactic treatment.

5-HT(1A) and 5-HT(1B/1D) receptors are involved in the modulation of the trigeminovascular system of the cat: a microiontophoretic study.

Electrical stimulation of the superior sagittal sinus in the cat activated neurones in the trigeminal nucleus caudalis. The mean latency of these responses (10.1 ms) was consistent with activation of Adelta-fibres. Microiontophoretic ejection of either the selective serotonin(1A) (5-HT(1A)) agonist (+)8-OH-DPAT or the 5-HT(1B/1D) agonist alniditan resulted in the reversible suppression of the response to superior sagittal sinus stimulation of 29/46 and 18/20 trigeminal neurones, respectively. The response to sagittal sinus stimulation was suppressed by 39+/-5% (n=46) by (+)8-OH-DPAT and 65+/-5% (n=20) by alniditan. Microiontophoretic ejection of the selective 5-HT(1A) receptor antagonist WAY-100635 significantly antagonised the effect of (+)8-OH-DPAT (effect reduced by 30%, P<0.05). The ejection of GR-127935, a selective 5-HT(1B/1D), antagonist, significantly antagonised the effect of alniditan (effect reduced by 52%, P<0.02). In eight neurones the response to convergent facial receptive field stimulation was also tested in the presence of alniditan. Only 4/8 receptive field responses were suppressed by alniditan (compared to 8/8 sagittal sinus responses) and alniditan had significantly less quantitative effect on the response to receptive field stimulation than on the response to sagittal sinus stimulation in the same neurones (mean reduction 36+/-14% and 66+/-8%, respectively, P<0.05). These results suggest that pharmacological modulation of the trigeminovascular system can occur at the first central synapse and that, in addition to 5-HT(1B/1D) receptors, 5-HT(1A) receptors may be involved in the modulation of sensory neurotransmission in the trigeminovascular system.

Interaction between yohimbine alkaloids and amphetamine in mice.

The toxicity (LD50) of the isomers yohimbine, beta-yohimbine, and corynanthine was determined in mice. The LD50 of amphetamine in the presence of a constant dose of a yohimbine isomer and that of the isomer in the presence of a constant dose of amphetamine were determined in aggregated mice. Isobolograms were constructed from these data and used to evaluate the interaction of the yohimbine alkaloids and amphetamine. Beta-yohimbine was found to be approximately twice as toxic as yohimbine and corynanthine about one fifth as toxic. There was a mutual potentiation between the toxicities of yohimbine and amphetamine. Potentiation of the toxicity of amphetamine occurred with beta-yohimbine but the effect was not as marked as with yohimbine. In contrast, corynanthine antagonized the toxicity of amphetamine. The interaction between yohimbine and amphetamine is unlikely to be due to noradrenergic mechanisms but could conceivably involve serotonergic or dopaminergic mechanisms.

Fabrication of a metal-cored multi-barrelled microiontophoresis assembly.

A method is described for fabrication of 7-barrelled microiontophoresis electrodes with a center barrel of platinum-coated tungsten. The electrodes require a minimum of expensive apparatus and can be fabricated in an hour or two. The electrodes have low recording impedance (typically 100 k omega and low resistance iontophoresis barrels (typically 20-50 M omega). Compared to electrodes with a micropipette recording barrel, these electrodes are practically noise-free and can pass ionotophoretic currents of up to 200 nA without an appreciable increase in recording noise.

Stimulation of the trigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey.

The trigeminal ganglion of 9 anesthetized paralysed artificially ventilated Macaca nemestrina monkeys was electrically stimulated with frequencies varying from 0.2 to 200 Hz. This stimulation led to a frequency-dependent decrease in external carotid resistance but no significant change in internal carotid resistance was recorded. The response is probably mediated as previously described in the cat, i.e. predominantly through the greater superficial petrosal branch of the facial nerve and a small proportion through antidromic activation of the trigeminal system. Elucidation of the physiological and pharmacological mechanisms underlying such a response may aid in a better understanding of the pathophysiology of vascular headache.

The mechanism of cerebrovascular vasoconstriction in response to locus coeruleus stimulation.

Stimulation of the locus coeruleus in 11 Macaca nemestrina monkeys resulted in a frequency-dependent increase in internal carotid resistance (vasoconstriction) and a frequency-dependent decrease in external carotid resistance (vasodilation). The internal carotid constrictor response is maximal at low frequency stimulation (5 s-1), and decreases as frequency of stimulation is increased or decreased. It is blocked by the non-specific alpha-adrenoceptor blocker phentolamine and the alpha-2 adrenoceptor blocker yohimbine, but is unaffected by the alpha-1 adrenoceptor blocker prazosin. It is concluded that the cerebral vasoconstrictor response to locus coeruleus stimulation is mediated by alpha-2 adrenoceptors.

Activation of trigeminovascular neurons by glyceryl trinitrate.

The effect of intra-carotid arterial infusions of glyceryl trinitrate (GTN), a substance known to precipitate headache, including migraine, upon the spontaneous activity of trigeminal neurons with craniovascular input was studied in cats. Second-order craniovascular neurons which received sensory input from the superior sagittal sinus were recorded in the trigeminal nucleus caudalis. Infusions of GTN were administered via a catheter inserted retrogradely into the common carotid artery through the lingual artery. Infusions of GTN (100 microg kg(-1) min(-1) in a volume of 2 ml min(-1)) increased the mean basal discharge rate of all second-order neurons to 239+/-47% of control. GTN produced a fall in mean blood pressure, but there was no correlation between this fall and the changes in discharge rate. GTN infusions sensitised neurons to the effects of electrical stimulation of the superior sagittal sinus, but not to subsequent GTN infusions. Infusions of similar volumes of vehicle did not alter the discharge rate of neurons. We conclude that GTN activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron and that such an action may account for at least the acute-onset headache induced by GTN.

Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation.

Electrical stimulation at 1-200/s of the locus coeruleus in 12 Macaca nemestrina monkeys caused a frequency-dependent drop in vascular resistance in the extracerebral circulation which was twice as great on the side stimulated. Accompanying this dilatation of the extracerebral vasculature was a frequency-dependent rise in internal carotid vascular resistance, usually seen only on the side ipsilateral to stimulation. This constrictor response was maximal at low frequencies of stimulation and minimal at higher frequencies. Neither the dilator nor constrictor responses were affected by sectioning of the vagus nerve or sympathetic trunk in the neck. The simultaneous occurrence of intracranial vasoconstriction and extracranial vasodilatation has not been demonstrated previously, and bears a remarkable resemblance to the vascular changes of migraine.

Effects of locus coeruleus stimulation on carotid vascular resistance in the cat.

The locus coeruleus was stimulated in 62 cats in order to investigate the effect on cephalic blood flow and cephalic vascular resistance. Flow was measured by electromagnetic flow probes applied to the common carotid artery. Stimulation over a range of frequencies (0.2-200 s-1) produced a frequency-dependent fall in carotid vascular resistance, greater on the ipsilateral side. This response was not affected by either cervical sympathectomy or spinal cord section. The response was blocked by bilateral section of the facial nerve but was not abolished by classical cholinergic, histaminergic or adrenergic blocking agents. Stimulation of the locus coeruleus also resulted in a pressor response through spinal mechanisms in which coeruleo-hypothalamic projections were not involved. A post-stimulation constriction in the carotid vasculature followed the dilator response and was attributed to release of catecholamines from the adrenal medulla.

The spinal cord processing of input from the superior sagittal sinus: pathway and modulation by ergot alkaloids.

The effects of ergot alkaloids on field potentials and unit responses produced in the upper cervical spinal cord by stimulation of the superior sagittal sinus (SSS) were examined in 57 anesthetized cats. Electrical stimulation of the SSS produced field potentials and single-unit responses at latencies of 5-20 ms. Field potentials were abolished by section of the first division of the trigeminal nerve but were unaffected or increased by section of the upper cervical nerves. Field potentials were reduced or abolished by intravenous injection of ergotamine or dihydroergotamine (DHE). The evoked response of 41 units (34.4%) were suppressed by either i.v. or iontophoretic administration of ergotamine, DHE or ergometrine. The results suggest that ergot alkaloids exert an effect at a spinal cord relay centre which receives trigeminally mediated input from cranial blood vessels.

Suppression by eletriptan of the activation of trigeminovascular sensory neurons by glyceryl trinitrate.

The effect of intracarotid arterial infusions of glyceryl trinitrate (GTN), a substance known to precipitate vascular headache, on the spontaneous activity of trigeminal neurons with craniovascular input was studied in cats. Cats were anaesthetised with alpha-chloralose, immobilised and artificially ventilated. The superior sagittal sinus (SSS) was isolated and stimulated electrically. Facial receptive fields (RF) were also stimulated. Single neurons were recorded from the trigeminal nucleus caudalis with a metal microelectrode equipped with six glass barrels for microiontophoresis. Infusions of GTN were administered via a catheter inserted retrogradely into the common carotid artery through the lingual artery. Infusions of GTN (mean rate 19+/-7, range 5-100 microg kg(-1) min(-1), in a volume of 2 ml min(-1)) increased the spontaneous discharge rate of second-order neurons which received dural and facial sensory input to 429+/-80% of control. Iontophoretic application of the 5-HT(1B/1D) receptor agonist eletriptan (50 nA) at the peak of the response decreased the discharge rate of neurons towards pre-GTN control levels. In the presence of continuous iontophoretic application of the 5-HT(1B/1D) receptor antagonist GR127935, the decrease in discharge rate caused by eletriptan was antagonised. We conclude (1) that GTN activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron and that such an action may account for at least the acute-onset headache induced by GTN and (2) that the antimigraine agent eletriptan is able to selectively suppress noxious sensory information from the dura, induced by GTN, via an action at 5-HT(1B/1D) receptors.

Comparative effects of stimulation of the trigeminal ganglion and the superior sagittal sinus on cerebral blood flow and evoked potentials in the cat.

The superior sagittal sinus (SSS) and the trigeminal ganglion (Vg) of anesthetized cats were stimulated electrically and field potentials in the upper cervical spinal cord and regional cerebral blood flow were recorded. Stimulation of the entire ganglion produced smaller field potential changes in two regions (medioventral area (MVA); dorsolateral area (DLA] of the upper spinal cord than did stimulation of the sagittal sinus (Vg/SSS response ratio = 17% for the MVA and 48% for the DLA). Stimulation of the trigeminal ganglion increased blood flow in only the frontal and parietal cortices (+93% and +33%), whereas stimulation of the sinus produced both larger changes in these areas (+137% and +139%) and also produced changes in regional cerebral blood flow in the thalamus (+122%).

2,5-Dimethoxy-4-methylamphetamine (DOM)- a central component of its cardiovascular effects in rats; involvement of serotonin.

The hallucinogen DOM produces a rise in blood pressure and heart rate when injected into the cerebral ventricles of anesthetized rats. These effects are abolished in rats with transected spinal cords but are unaffected by prior treatment with hexamethonium. Central but not peripheral administration of the serotonin antagonist BOL reduces the response. Tachyphylaxis to the response develops rapidly and is accompanied by a decrease in the ability of 5-HT to induce a centrally mediated cardiovascular change. It is concluded that the response is mediated by direct stimulation of central 5HT receptors. Tachyphylaxis may be the result of irreversible binding of DOM to 5-HT receptors or to 5-HT receptor densensitization.

Low pharmacological responsiveness of the vertebro-basilar circulation in Macaca nemestrina monkeys.

We have examined the responsiveness of the vertebro-basilar circulation of the anesthetized Macaca nemestrina monkey to vasoactive agents infused directly into the artery. Infusion of noradrenaline caused a slight increase in vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or external carotid arteries. In the presence of vasodilatation caused by inhalation of a CO2-rich gas mixture, this constriction became a dilatation. Serotonin was without significant effect on the vertebral arterial bed. Bradykinin, histamine and prostaglandin E1 all produced slight dilatation, with bradykinin being the most potent. In all cases the concentration required to produce an effect on the vasculature was much greater in the vertebral circulation than it is in the internal carotid and extracerebral circulations. We conclude that the intact vertebro-basilar circulation is much less sensitive to vasoactive agents than experiments with isolated segments of these arteries would indicate and that therefore these agents are unlikely to play a significant part in the pathogenesis of vertebro-basilar migraine.

Pharmacological and biochemical properties of isomeric yohimbine alkaloids.

The stereochemical and pharmacological properties of yohimbine and some of its isomers are briefly reviewed. Several pharmacological and physical properties of a selection of the isomers have been determined with a view to elucidating which might be important in the elaboration of the known behavioral effects produced by them. Activity is not dependent upon lipid solubility or on the ease of access to the central nervous system. The isomers are weak inhibitors of rat-brain acetylcholinesterase and weak antagonists at muscarinic cholinergic receptors. In the rat brain in vitro they do not possess significant monoamine oxidase-inhibiting properties nor do they inhibit the uptake of serotonin. They are relatively potent antagonists of 5HT on the rat isolated fundus preparation and their potency in this preparation may be related to their ability to produce behavioral and cardiovascular effects in man and dogs.

Craniovascular application of capsaicin activates nociceptive thalamic neurones in the cat.

In cats anaesthetized with alpha-chloralose and urethane, extracellular recordings were made in ventrobasal thalamus from cells responding to electrical stimulation of the superior sagittal sinus and middle meningeal artery. Capsaicin, but not vehicle, evoked an increase in the firing rate of nociceptive cells (5 of 6 wide dynamic range and the only nociceptive specific cell). Non-nociceptive cells did not respond to either capsaicin or vehicle. Cells with long latencies to electrical stimulation were excited by capsaicin but cells with short latencies were not. Capsaicin-responsive cells were found in the ventroposteromedial nucleus and the medial nucleus of the posterior complex and mostly had receptive fields involving the first trigeminal division.

Electrical stimulation of the fastigial nucleus increases total cerebral blood flow in the monkey.

Internal and external carotid blood flows were monitored continuously in the barbiturate-anesthetized monkey with appropriately-sized electromagnetic flow probes. Electrical stimulation of the fastigial nucleus increased blood flow in both the internal and external carotid circulations in a frequency-dependent manner. This response was entirely intracerebral and independent of infra-bulbar mechanisms since it was present following high cervical spinal cord section. These data re-affirm the presence of the fastigial nucleus cerebral vasodilator response and add the observations that the response is present in the primate and markedly frequency-dependent.

Convergence of afferents from superior sagittal sinus and tooth pulp on cells in the upper cervical spinal cord of the cat.

Units in the dorsolateral area of the upper cervical cord respond to craniovascular stimulation. This study examined tooth pulp responses in this area in cats. Eleven of 21 units tested in the dorsolateral area had convergent inputs from superior sagittal sinus and tooth pulp; while 10 units had sagittal sinus, but not tooth pulp, input. Mean response latency to tooth pulp stimulation (25.8 ms) was significantly longer than to superior sagittal sinus stimulation (9.8 ms). Half of the units had cutaneous receptive fields; and in five units, action potentials could be evoked by electrical stimulation in the posterior complex of the thalamus.

Craniovascular nociceptive pathways relay in the upper cervical spinal cord in the cat.

Units in the dorsolateral area of the upper cervical cord and the ventroposteromedial nucleus of the thalamus respond to stimulation of cranial vessels. To study the physiological role of the upper cervical cord in craniovascular transmission, we used a cryoprobe to interrupt reversibly neural transmission through the cord while recording in the thalamus. Twenty-one of 47 thalamic units tested showed reversible diminution in their response to superior sagittal sinus stimulation during cervical cord cooling. In contrast, receptive field responses and spontaneous thalamic activity were unaffected. These data suggest offt the cervical cord relays craniovascular nociceptive afferents.