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K Messlinger

Publications and source records attributed to K Messlinger.

At least 19 recordsLinked to original sources
PubMed2005

The TRPV1/2/3 activator 2-aminoethoxydiphenyl borate sensitizes native nociceptive neurons to heat in wildtype but not TRPV1 deficient mice.

TRPV1 gene disruption results in a loss of capsaicin and proton responsiveness, but has minimal effects on heat-induced nocifensive behavior, suggesting that sensory transduction of heat is independent of TRPV1. TRPV3, another heat-activated ion channel but insensitive to capsaicin, was shown to be expressed in keratinocytes as well as in sensory neurons projecting to the skin. Recently, 2-aminoethoxydiphenyl borate was introduced as a TRPV3 agonist, but its selectivity was questioned by showing that it activated recombinant TRPV1 and TRPV2 as well. We used the isolated mouse skin-saphenous nerve preparation and whole-cell patch-clamping of cultured dorsal root ganglia neurons from TRPV1-/- and wildtype mice. We found no phenotypic differences between the heat responses of polymodal C-fibers, whereas cultured dorsal root ganglia neurons of TRPV1-/- hardly showed any heat-activated currents. Only C-fibers of wildtype but not TRPV1-/- mice were clearly sensitized to heat by 2-aminoethoxydiphenyl borate 10 and 100 microM; heat-activated current in wildtype neurons was only facilitated at 100 microM. Noxious heat-induced calcitonin gene-related peptide release showed clear deficits (<50%) in TRPV1 deficient skin, but the stimulated calcitonin gene-related peptide release from the isolated skull dura was unaffected. In both models, 2-aminoethoxydiphenyl borate was able to potentiate the heat response (46 degrees C, 5 min) in a concentration-dependent manner, again, only in wildtype but not TRPV1-/- mice, suggesting that TRPV2/3 are not involved in this sensitization to heat. The results further suggest that TRPV1 is not responsible for the normal heat response of native nociceptors but plays the essential role in thermal sensitization and a prominent one in controlling dermal calcitonin gene-related peptide release, i.e. neurogenic inflammation.

Animals↗
PubMed2004

Noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino-parasympathetic reflex--an experimental model for vascular dysfunctions in cluster headache.

Cluster headache is characterized by typical autonomic dysfunctions including facial and intracranial vascular disturbances. Both the trigeminal and the cranial parasympathetic systems may be involved in mediating these dysfunctions. An experimental model was developed in the rat to measure changes in lacrimation and intracranial blood flow following noxious chemical stimulation of facial mucosa. Blood flow was monitored in arteries of the exposed cranial dura mater and the parietal cortex using laser Doppler flowmetry. Capsaicin (0.01-1 mm) applied to oral or nasal mucosa induced increases in dural and cortical blood flow and provoked lacrimation. These responses were blocked by systemic pre-administration of hexamethonium chloride (20 mg/kg). The evoked increases in dural blood flow were also abolished by topical pre-administration of atropine (1 mm) and [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP (0.1 mm), a vasoactive intestinal polypeptide (VIP) antagonist, onto the exposed dura mater. We conclude that noxious stimulation of facial mucosa increases intracranial blood flow and lacrimation via a trigemino-parasympathetic reflex. The blood flow responses seem to be mediated by the release of acetylcholine and VIP within the meninges. Similar mechanisms may be involved in the pathogenesis of cluster headache.

Animals↗
PubMed2003

[Neuropeptide release in the dura mater encephali in response to nitric oxide--relevance for the development of vascular headaches?].

Nitric oxide (NO) and calcitonin gene-related peptide (CGRP), potent vasodilators in the meninges,may be involved in the pathophysiology of vascular headaches such as migraine pain. NO donators can provoke headache attacks in migraineurs and increased levels of CGRP have been found in the venous outflow from the head during migraine attacks. We therefore examined the effect of both NO and CGRP on dural blood, a process which may parallel nociceptive processes in the meninges. 1. Arterial blood flow was measured in the exposed dura mater encephali of the rat using laser Doppler flowmetry. Local application of different NO donors (SNAP,NONOate, and NOC-12) caused dose-dependent increases in meningeal blood flow. CGRP(8-37) at 10(-4) M did not significantly change the basal flow but attenuated increases in blood flow caused by the NO donors at concentrations of 10(-5)-10(-3) M.2. In another series of experiments, the hemisected skulls of adult Wistar rats, complete with intact dura mater, were filled with oxygenated synthetic interstitial fluid (SIF) and the CGRP content of this fluid was assessed every 5 min. When the NO donator NONOate, at concentrations of 10(-5)-10(-3) M, was added to the SIF, or when the SIF was bubbled with NO gas (1000 ppm in N(2) atmosphere) instead of carbogen, CGRP release increased in a concentration-dependent manner. We conclude that the vasodilatory effect of NO that causes increased meningeal blood flow is in part the result of both stimulating the release of CGRP and promoting the vasodilatory action of CGRP. Since NO donors such as nitroglycerin are known to provoke headache and CGRP is released during migraine pain, the NO-stimulated CGRP release may be relevant for the development of vascular headaches that are accompanied by meningeal hyperaemia.

Animals↗
PubMed2002

Increase in meningeal blood flow by nitric oxide--interaction with calcitonin gene-related peptide receptor and prostaglandin synthesis inhibition.

This study addresses possible interactions of the vasodilators nitric oxide (NO), calcitonin gene-related peptide (CGRP) and prostaglandins, which may be implicated in the generation of vascular headaches. Local application of the NO donator diethylamine-NONOate (NONOate) to the exposed dura mater encephali of the rat caused dose-dependent increases in meningeal blood flow recorded by laser Doppler flowmetry. Pre-application of the CGRP receptor antagonist CGRP8-37 significantly attenuated the evoked blood flow increases, while the cyclooxygenase inhibitors acetylsalicylic acid and metamizol were only marginally effective. Stimulation of rat dura mater with NONOate in vitro caused increases in CGRP release. NADPH-diaphorase activity indicating NO production was restricted to the endothelium of dural arterial vessels. We conclude that increases in meningeal blood flow caused by NO depend partly on the release and vasodilatory action of CGRP from dural afferents, while prostaglandins are not significantly involved.

Animals↗
PubMed2001

Histological demonstration of increased vascular permeability in the dura mater of the rat.

Neurogenic inflammation of the dura mater encephali has been suggested to play an important role in the pathophysiology of headaches. Although functional studies using extravasation techniques indicate an enhanced permeability of blood vessels after chemical or electrical stimulation of C-fibres supplying the dura mater, histological demonstration of leaky blood vessels is still a problem. We used the vascular labelling method combined with i.v. injection of colloidal silver solution to test the permeability increasing effect of intravenous administration of substance P, topical application of mustard oil or acidic phosphate buffer and local electrical stimulation of the exposed dura mater. Histological characteristics of increased vascular permeability were observed exclusively after mustard oil and acidic phosphate buffer. This observation may indicate different mechanisms of increased vascular permeability involving pinocytosis and formation of interendothelial gaps selectively visualized by the vascular labelling method.

Administration, Topical↗
PubMed2001

Meningeal nociception: electrophysiological studies related to headache and referred pain.

Headaches, which are usually referred to characteristic sites of the skull, are believed to involve meningeal nociceptors located in the dura mater encephali. Animal experiments show that these meningeal nociceptors are polymodal and usually highly sensitive to mechanical stimulation. These properties are also characteristic for the second order neurons in the spinal trigeminal nucleus, most of which receive convergent input from facial receptive sites. Sensitization of primary and secondary neurons by chemical irritants to mechanical stimuli may be an important mechanism in the generation of headaches. The convergent input from extracranial structures, which seems to be differentially organized in rodents and man, may explain the typical features of referred headache. Targets for analgesics used in the therapy of headaches (non-steroidal antiinflammatory drugs, 5-HT(1) receptor agonists) are probably meningeal nociceptors and different sites of the central trigeminal nociceptive and antinociceptive pathways.

Afferent Pathways↗
PubMed2000

Involvement of nitric oxide in the modulation of dural arterial blood flow in the rat.

1. Nitric oxide (NO) has been proposed to be a key molecule in the pathogenesis of migraine pain and other headaches that are linked to vascular disorders. Several lines of evidence indicate that the meningeal vascularization is crucially involved in the generation of these headaches. In an experimental model in the rat a dominating role of calcitonin gene-related peptide (CGRP) in causing neurogenic vasodilatation and increased blood flow has been shown. The aim of the present study was to clarify the role of NO in this model with regard to the meningeal blood flow. 2. The blood flow in and around the medial meningeal artery (dural arterial flow) was recorded in the exposed parietal dura mater encephali of barbiturate anaesthetized rats using laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses of 0.5 ms delivered at 7.5 - 17.5 V and 5 or 10 Hz for 30 s) caused temporary increases in dural arterial flow for about 1 min that reached peaks of 1.6 - 2.6 times the basal flow. The effects of NO synthase (NOS) inhibitors on the basal flow and the electrically evoked increases in flow were examined. 3. Systemic (i. v.) administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) at cumulative doses of 10 and 50 mg kg(-1) lowered the basal flow to 87 and 72%, respectively, of the control and reduced the evoked increases in blood flow to 82 and 44% on an average. Both these effects could partly be reversed by 300 mg kg(-1) L-arginine. The systemic arterial pressure was increased by L-NAME at both doses. Injection of the stereoisomer D-NAME at same doses did not change basal flow and evoked increases in flow. 4. 4. Topical application of L-NAME (10(-4) - 10(-2) M) was effective only at the highest concentration, which caused lowering of the basal blood flow to 78% of the control; the evoked increases in flow were not changed. Topical application of 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of the inducible NOS, at concentrations of 10(-4) - 10(-2) M lowered the basal flow to 89, 87.5 and 85%, respectively, but did not significantly change the evoked flow increases. Same concentrations of 7-nitroindazole monosodium salt (7-NINA), a specific inhibitor of the neuronal NOS, had no significant effects on basal flow and evoked increases in flow. 5. It is concluded that NO is involved in the maintenance of the basal level of dural arterial blood flow as well as in the electrically evoked flow increases, which have been shown to be mainly mediated by CGRP released from dural afferent fibres. The most important source of NO is probably the endothelium of dural arterial vessels. The synergistic effect of NO and CGRP on the stimulated blood flow may be in part due to a NO mediated facilitation of the CGRP release.

Animals↗
PubMed1999

Somatostatin reduces the meningeal arterial blood flow in the rat.

The effect of somatostatin (SOM) on neurogenic increases in meningeal blood flow was examined in barbiturate anaesthetized rats. The parietal skull was trepanized and the blood flow in the medial meningeal artery was monitored using a laser Doppler flowmeter with needle probes. Electrical stimulation (pulses of 8-10 V at 5-10 Hz for 30 s) close to the superior sagittal sinus evoked reproducible increases in blood flow. These increases were reduced by topical applications of SOM at concentrations of 10(-5)-10(-3) M in a dose-dependent manner. The effect was most pronounced within 10 min after application of SOM followed by a recovery of the flow responses. We conclude that stimulus-evoked increases in dural arterial flow, which are most likely caused by afferent activation and can be regarded as an element of neurogenic inflammation, are reduced by anti-inflammatory peptides such as SOM.

Animals↗
PubMed1999

Afferent input to the medullary dorsal horn from the contralateral face in rat.

Sensory deficits on the contralateral face in Wallenberg's lateral medullary syndrome (WS) may be due to an involvement of the crossing contralateral trigeminothalamic tract. Alternatively, neurons within the medullary dorsal horn (MDH) get input from the contralateral face. MDH neurons supplying the supraorbital nerve area in rat were recorded by electrophysiological techniques. In this first study on contralateral projections, about 60% of the neurons received excitatory afferent input from the contralateral face as well as the ipsilateral supraorbital area. Thus, contralateral sensory deficits in WS may be due to an involvement of these neurons.

Animals↗
PubMed1999

Acetylsalicylic acid inhibits meningeal nociception in rat.

Although acetylsalicylic acid (ASA) is one of the most commonly administered drugs in the treatment of acute headaches, the sites of its action and the mechanisms of its therapeutic efficacy are still unclear. In this study using extracellular recording we examined the effects of ASA on spontaneous and mechanically evoked activities of neurons within the medullary dorsal horn with input from the parietal dura mater in rat. Their dural receptive fields were identified by von Frey filaments and found to be mainly located at the medial meningeal artery. All units showed spontaneous activity and had convergent input from the face. Neuronal activities were recorded before and after intravenously applied ASA (30 mg/kg) in 13 and saline in four units. Systemic application of ASA inhibited spontaneous and mechanically evoked activity within 15 min after application. Additionally, neuronal activities were recorded before, during and after topical application of ASA (1 mg/ml) onto the parietal dura mater in 5 units. Topically applied ASA inhibited the mechanically evoked activity, whereas the spontaneous activity remained unchanged. It is concluded, that there are different effects of systemic and topical ASA on trigeminal neuronal activity, which may be due to both central and peripheral mechanisms.

Administration, Topical↗
PubMed1999

Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro.

Neurogenic inflammation of the dura, expressed in plasma extravasation and vasodilatation, putatively contributes to different types of headache. A novel in vitro preparation of the fluid-filled skull cavities was developed to measure mediator release from dura mater encephali upon antidromic electrical stimulation of the trigeminal ganglion and after application of a mixture of inflammatory mediators (serotonin, histamine and bradykinin, 10(-5) M each, pH 6.1) to the arachnoid side of rat dura. The release of calcitonin gene-related peptide, substance P and prostaglandin E2 from dura mater was measured in 5-min samples of superfusates using enzyme immunoassays. Orthodromic chemical and antidromic electrical stimulation of dural afferents caused significant release of calcitonin gene-related peptide (2.8- and 4.5-fold of baseline). The neuropeptide was found to be increased during the 5-min stimulation period and returned to baseline (20.9 +/- 12 pg/ml) in the sampling period after stimulation. In contrast, release of substance P remained at baseline levels (19.3 +/- 11 pg/ml) throughout the experiment. Prostaglandin E2 release was elevated during chemical and significantly also after antidromic electrical stimulation (6- and 4.2-fold of baseline, which was 305 +/- 250 pg/ml). Prostaglandin E2 release outlasted the stimulation period for at least another 5 min. The data support the hypothesis of neurogenic inflammation being involved in headaches and provide new evidence for prostaglandin E2 possibly facilitating meningeal nociceptor excitation and, hence, pain.

Afferent Pathways↗
PubMed1999

Response properties of trigeminal brain stem neurons with input from dura mater encephali in the rat.

The responsiveness of trigeminal brain stem neurons to selective local mechanical and chemical stimulation of the cranial dura mater was examined in a preparation in the rat. The dura mater encephali was exposed and its surface stimulated with electrical pulses through bipolar electrodes. Extracellular recordings were made from neurons in the subnucleus caudalis of the spinal trigeminal nucleus. Single neurons driven by meningeal input were identified by their responses to electrical stimulation and to probing their receptive fields on the dura. Facial receptive fields were defined mechanically. Chemical stimuli (a combination of inflammatory mediators, bradykinin, prostaglandin E2, serotonin, capsaicin and acidic Tyrode's solution) were applied topically to the dura and by injection through a catheter into the superior sagittal sinus. All neurons with input from the parietal dura mater had convergent input from the facial skin, with preponderance of the periorbital region. Proportions of units were activated by the combination of inflammatory mediators (55%), bradykinin (64.5%), acidic Tyrode's solution (64.1%) and capsaicin (78.6%). We conclude that, among the chemical mediators of inflammation, bradykinin and low pH are the most effective chemical stimuli in activating meningeal nociceptors. These stimuli may be important during meningeal inflammatory processes that lead to the generation of headaches.

Animals↗
PubMed1998

Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH - inhibition by the serotonin (5-HT1) receptor agonist CP 93,129.

1. The therapeutical benefit of serotonin (5-HT1) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory effect on the release of pro-inflammatory neuropeptides from trigeminal afferents within the cranial meninges. The effect of 5-HT1 receptor agonists on the release of neuropeptides from central afferent terminals has not been examined so far. In the present study in the rat we therefore measured the effect of the 5-HT1B receptor agonist CP 93,129 on the stimulation-evoked release of immunoreactive substance P (ir-SP) in the spinal trigeminal nucleus. 2. To measure release of ir-SP, microprobes coated with antibody to substance P were inserted into the medulla oblongata at the level of the obex. The ipsilateral parietal dura mater encephali was exposed and stimulated with acid phosphate buffered Tyrode solution (pH 5.8). This chemical stimulus increased the release of ir-SP in the medullary dorsal horn. 3. Systemic (i.v.) administration of CP 93,129 (460 nmol kg(-1)) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 microM) to the dorsal surface of the medulla had no significant inhibitory effect on the release. 4. It is concluded that systemically applied 5-HT1 receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal afferents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory effect may contribute to the antinociceptive effect of 5-HT1 receptor agonists in migraine.

Animals↗
PubMed1997

[Activation of trigeminal brain stem neurons by chemical stimulation of the dura mater encephali--preparation for studying meningeal nociception in the rat].

INTRODUCTION: Headache is thought to be generated by nociceptive processes within the meninges, followed by activation of trigeminal neurons within the brainstem. The noxious stimuli initially involved in these nociceptive processes are unknown. A preparation was developed in the barbiturate-anesthetized rat, in which the activation of trigeminal brain stem neurons by selective local stimulation of the dura mater could be observed. METHODS: The dura mater encephali was exposed by trepanizing the parietal bone up to the sagittal superior sinus. The surface of the dura was stimulated with electrical pulses using bipolar electrodes. Extracellular recordings were made from neurons in the subnucleus interpolaris and caudalis of the spinal trigeminal nucleus. Neurons driven by meningeal afferents were identified by electrical stimulation and by probing their receptive fields on the dura mater. For chemical stimulation a combination of several inflammatory mediators (bradykinin, serotonin, histamine and prostaglandin E(2), each 10(-4)M, 6.1) was topically applied to the dura mater or injected through a catheter into the sagittal sinus. RESULTS: Most of the trigeminal brain stem neurons with input from the parietal dura mater had convergent input from the facial skin with preponderance of the periorbital region. A high proportion of neurons (69%) could be activated by the combination of inflammatory mediators administered to the dura mater. CONCLUSION: We conclude that chemical stimuli activating the meningeal nociceptive system may play a decisive role in the generation of headache. This is particularly relevant for the nociceptive processes during neurogenic inflammation, which is believed to be an important step in the pathophysiology and development of migraine pain. The preparation presented here may be a valuable model for further studying the neurophysiological changes that are involved in the generation of headache.

English Abstract↗
PubMed1997

Effects of the 5-HT1 receptor agonists, sumatriptan and CP 93,129, on dural arterial flow in the rat.

The blood flow in and around the medial meningeal artery (dural arterial flow) was recorded in the exposed parietal dura mater encephali of the anesthetized rat using laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses of 0.5 ms delivered at 7.5-17.5 V and 5 or 10 Hz for 30 s) caused temporary increases in dural arterial flow. The effects of the 5-HT1 receptor agonists sumatriptan and CP 93,129 on the basal flow and the electrically evoked increases in flow were examined. Topical administration of undiluted sumatriptan (12 mg/ml) lowered the basal and the evoked flow by 20% on average. Systemic (i.v.) administration of sumatriptan (0.24, 0.72 and 3.6 mumol/kg) caused a short-lasting reduction of the evoked flow increases only at the higher doses while the basal flow was not significantly altered. Systemic administration of CP 93, 129 (0.46 and 4.6 mumol/kg) caused no significant changes of the basal and the evoked flow. At a dose of 23 mumol/kg CP 93,129 lowered the basal flow by 20% and the evoked flow by 30% for 20 min. The systemic arterial pressure was not significantly altered by sumatriptan and CP 93,129 within the whole range of doses. It is suggested that sumatriptan and CP 93,129 at high doses exert inhibitory effects on those fine afferent nerve fibers which release the calcitonin gene-related peptide, since this neuropeptide mediates the evoked increases in dural arterial flow.

Animals↗
PubMed1997

[What is a nociceptor?].

INTRODUCTION: Nociceptors can be defined as sensory receptors that are activated by noxious stimuli that damage or threaten the body's integrity. Nociceptors belong to the slowly conducting afferent A delta and C fibres. They are classified according to their responses to mechanical, thermal, and chemical stimuli. SKIN NOCICEPTORS: In the skin, high-threshold mechano-nociceptors (HTMs) and mechano-heat nociceptors of A and C fibres (AMHs and CMHs) are frequently found. CMHs are usually called polymodal C fibres (CPMs) if they also show chemosensitive properties. Sensations of sharp pain are evoked by intraneural microstimulation of nociceptive A delta fibres, whereas stimulation of C fibres causes dull pain sensations. NOCICEPTORS OF DEEP TISSUES AND VISCERA: Slowly conducting afferents of deep tissues (muscles, joints) are primarily classified according to their mechanosensitivity. High-threshold afferents in somatic and visceral tissues are specifically activated by noxious mechanical stimuli. Many visceral afferents, however, are already activated by peristaltic contractions encoding the stimulus intensity over a wide range. High proportions of somatic and visceral nociceptors can be excited or sensitised by various irritants and inflammatory mediators such as capsaicin, bradykinin, prostaglandins, leukotrienes, serotonin, histamine, and free radicals. As a special class of nociceptors, mechano-insensitive or "silent" afferents have been found in nearly all tissues. Silent afferents become mechanosensitive only after long noxious stimulation, e.g., during an inflammation. FREE NERVE ENDINGS: "Free nerve endings", which are regarded as the morphological correlatives of nociceptors, usually consist of bundles of unmyelinated fibres. With electron microscopy varicose segments of the sensory axon are visible that are characterised by free areas of axolemma, accumulations of mitochondria and vesicles, and a modified axoplasm. These presumptive receptive sites are periodically arranged along the whole course of the sensory endings at a length of up to several hundred microns. Additionally, the fine sensory endings are branched, forming tree-like structures, and frequently innervate different types of tissues. Studies correlating structure and function of articular afferents provide evidence for a close relationship between topographical and functional properties of sensory endings. High-threshold afferents (nociceptors) seem to terminate in structures of dense connective tissue. Proportions of nociceptors contain neuropeptides such as substance P and calcitonin gene-related peptide, which are released from the activated nociceptive terminals and cause neurogenic inflammation, including precapillary vasodilatation and postcapillary plasma extravasation. PAIN TREATMENT: Experimental and clinical progress has been achieved in using the nociceptor as a target for chemical anti-nociception and treatment of pain. Substances that act directly or indirectly on the nociceptor are steroidal and non-steroidal analgesics, capsaicin analogs, bradykinin antagonists, opioids, and (in the trigeminal system) 5-hydroxytryptamine agonists.

Animals↗
PubMed1997

Release of immunoreactive substance P in the trigeminal brain stem nuclear complex evoked by chemical stimulation of the nasal mucosa and the dura mater encephali--a study with antibody microprobes.

In order to study a possible involvement of substance P in the processing of chemonociceptive input from the nasal mucosa and the dura mater encephali in the spinal trigeminal, the release of immunoreactive substance P was measured in the trigeminal brain stem nuclear complex in anaesthetized rats. Microprobes coated with antibody to substance P were inserted into the lateral area of the brain stem up to 1 mm posterior to the obex corresponding to the trigeminal subnucleus caudalis. When the nasal mucosa was stimulated by topical administration of mustard oil (1% and 5%) into the nostrils, immunoreactive substance P was mainly detected in the dorsal region of the trigeminal brain stem nuclear complex with a maximum in the superficial gray matter. When the dura mater encephali was stimulated by topical administration of Tyrode's solution (pH 6.2), immunoreactive substance P was mainly released in the ventral region of the trigeminal brain stem nuclear complex; with pH 5.5 the release was more diffuse extending from the ventral to the dorsal part of the spinal trigeminal nucleus. Release was maximal rather after than during the administration of the stimuli, and it considerably outlasted the stimulation periods. These data suggest that substance P plays an important role in the processing of chemonociceptive inputs from the nasal mucosa and the dura mater encephali in the trigeminal brain stem nuclear complex. Substance P may be important, therefore, in the generation of those headaches that are caused by affections of the nasal mucosa and the dura mater encephali. Since enhanced levels of immunoreactive substance P were present for considerable time periods beyond the administration of the stimuli, substance P and neurokinin-1 receptors may be involved in long-lasting neuronal events following noxious stimulation.

Animals↗