Trigeminal Endings Research Articles

The Frontotemporal Region Plays a Role in the Genesis of Migraine Without Aura

We have compared the migraine-inducing effect of nitroglycerin ointment applied to the frontotemporal region of the head, which is innervated by the ophthalmic and maxillary divisions of the trigeminal nerve, with that of nitroglycerin applied to the chin (innervated by the mandibular division), the posterolateral region of the neck (innervated by the second and third cervical roots), the lateral surface of the proximal third of the forearm (innervated by the sixth cervical root), and the medial surface of the upper-arm region (second dorsal root). One hundred patients suffering from migraine without aura were randomly divided into five equal groups. Each group received an application of 5 mg nitroglycerin in 2% ointment on a preselected body area for 2 hours. Frontotemporal nitroglycerin induced a significantly greater number of early onset migraine attacks with respect to the arm and forearm regions. In all cases, nitroglycerin applied to the frontotemporal region resulted in subsequent migraine, whereas there was a significant number of negative trials with nitroglycerin applied to the neck, arm, and forearm vs the frontotemporal area. It, therefore, appears that the trigeminal nerve endings in the affected frontotemporal region are particularly sensitive to the migraine-inducing effect of the nitrate. This suggests a peripheral neurogenic hypothesis of migraine genesis.

Responses recorded from the frog olfactory epithelium after stimulation with R(+)- and S(-)-nicotine.

The aim of this study was to determine whether the olfactory system is responsible for the discriminability of the stereoisomers of nicotine. The EOG was recorded after stimulation with different concentrations of undistilled S(-)-, distilled S(-)- and distilled R(-)-nicotine separately in three groups of frogs (Xenopus laevis). The responses to all types of nicotine used in the experiments increased with increasing stimulus concentration. The responses to undistilled S(-)-nicotine were significantly lower compared to responses to distilled S(-)- and R(+)-nicotine, whereas no significant differences could be found when the purified stereoisomers of nicotine [distilled S(-)-nicotine, distilled R(+)-nicotine] were compared. Control measurements of time course and peak concentration employing a UV-detection method demonstrated that the differences between distilled and undistilled S(-)-nicotine could not be explained by different nicotine concentrations. The fact that no differences between the pure nicotine stereoisomers could be found for all concentrations used in our experiments and that experiments in humans revealed similar detection thresholds for both stereoisomers points to a similar receptor affinity of R(+)- and S(-)-nicotine within the olfactory system. At this point, it cannot be determined whether the observed differences in the perception of nicotine enantiomers in humans are due to differences in quality coding by stereospecific receptors on the olfactory sensory cells or by specific receptors on the trigeminal nerve endings.

Factors affecting the sensitivity of the lingual trigeminal nerve to acids

Oral sensitivity to acids mediates a range of irritation, from desirable sensations of pungency in various foods and beverages to the pain associated with harmful levels of acidity and inflammation. To characterize the role of the epithelial and vascular processes in neural sensitivity to acid applied to the lingual mucosa, we measured lingual trigeminal nerve responses in rats to acidic stimuli of varying physicochemical properties. Stimulatory efficacy was strongly correlated with lipophilicity (octanol-H2O partition coefficient) for the series of straight-chain fatty acids from one to six carbons. Neither acid dissociation constant nor the pH of stimulus solutions correlated with stimulatory efficacy for the fatty acids and six other organic acids. The hypothesis that weakly acidic stimuli gain access to trigeminal nerve endings primarily through the lipid phase of the epithelium was supported by these findings. Further support for this hypothesis is the result that LaCl3, an inhibitor of epithelial tight junctions, had no effect on the neural response to n-pentanoic acid. The potential relevance of buffering-clearance in modulating responses to acid was indicated by the finding that the application of 1 mM capsaicin to the tongue reversibly inhibited the neural response to acid, as well as causing plasma extravasation in lingual epithelium.

Ruthenium red antagonism of capsaicin-induced vascular changes in the rat nasal mucosa.

Mechanisms of capsaicin-induced vascular changes were examined in the nasal mucosa of anesthetized adult rats. Intra-arterial infusions of capsaicin at doses of 20-100 pmol/min into the external carotid artery resulted in a dose-dependent increase in nasal blood flow as assessed by laser-Doppler flowmetry. Intra-arterial infusion of ruthenium red (RR, 2.5-10 mumol) prior to the administration of capsaicin significantly inhibited the capsaicin-evoked response. The technique of vascular labelling was used to examine nasal mucosal vascular permeability. Intravenous administration of colloidal silver solution prior to capsaicin infusion resulted in accumulation of colloid in the walls of small blood vessels, indicative of enhanced vascular permeability. Vascular labelling was largely abolished after RR pretreatment. These findings suggest that neuropeptides released from trigeminal sensory nerve endings play a significant role in the local vascular and inflammatory reactions of the nasal mucosa. The experimental approach utilized in this study provides a promising model for defining the roles of capsaicin-sensitive afferent nerves in the mechanisms of allergic and/or inflammatory diseases affecting the nasal mucosa.

Neural responses of thermal-sensitive lingual fibers to brief menthol stimulation

The addition of the coolant menthol to several oral and facial products is to increase their attractiveness and commercial value. Little is, however, known about the physiological basis of menthol's sensory effects. We studied the electrophysiological responses of 45 thermal-sensitive lingual fibers to anterior tongue stimulation (10 s) with menthol in male Sprague-Dawley rats. Menthol responses were unlike the responses to cold water. Cold water (6°C, 15°C) elicited an immediate sustained increase in impulse frequencies of thermal-sensitive fibers adapted to room temperature water (22–24°C). Inhibitory off-responses followed cold water stimulation. Depending on the concentration and time of measurement, menthol stimulation either excited, inhibited, or had no effect on impulse frequencies of thermal-sensitive fibers. Strong menthol (0.64 mM, 1.28 mM) unequivocally excited thermal-sensitive fibers with a response latency of 4–6 s. In most cases after menthol stimulation, the impulse frequencies returned to baseline; there were no off-responses. Weak menthol (0.0128 mM, 0.064 mM, 0.128 mM) inhibited impulse frequencies of 14 thermal-sensitive fibers and excited impulse frequencies of 6 fibers primarily during the first 2 s of stimulation. Menthol responses were also unlike responses to stimulation with taste solutions. Most taste solutions (30 and 100 mM NaCl, 0.3 and 1 mM quinine-HCl, 0.3 mM citric acid) significantly inhibited impulse frequencies but only during the first 2–5 s of stimulation. The effect of NaCl was biphasic with the initial inhibitory phase followed by an excitatory phase during the second 5 s of stimulation. An excitatory off-response followed quinine stimulation. While considered principally a coolant, menthol elicits a unique pattern of responses from trigeminal and taste nerve endings quite unlike those of conventional thermal and taste stimuli.

Sensory irritation and pulmonary irritation of n-methyl ketones: receptor activation mechanisms and relationships with threshold limit values.

Activation of the trigeminal nerve endings in eyes and nose, termed sensory irritation, was determined from the reflexively induced decrease in respiratory rate in mice for methyl propyl ketone, methyl butyl ketone, methyl amyl ketone and methyl hexyl ketone. The relationship between exposure concentration and the decrease in respiratory rate followed Michaelis-Menten equations. Two estimates of each agonist-receptor dissociation constant were obtained, one from the Michaelis-Menten equation and one from the threshold (RD-0) of the log concentration-effect curve. The values were equal and thus one receptor type could account for the activation process. The hydrophobic properties of the receptor biophase were found to approach that of the internal part of the bilayer membrane. It therefore follows that the receptor-air partition coefficients increase with the size of the ketones, thus accounting for the observed increase in potency. Estimates of Threshold Limit Values (TLV) were obtained and compared with established values. Close agreements were found for methyl propyl ketone and methyl amyl ketone, but not for methyl butyl ketone, where the neurotoxic effect constituted a more sensitive endpoint than sensory irritation.

Trigeminal nerve endings of lingual mucosa and musculature of the rat

Horseradish peroxidase conjugated with wheat germ agglutinin (HRP-WGA) was injected into the trigeminal ganglion of adult rats to label the peripheral sensory receptors of the tongue. The conjugate was transported anterogradely to all the ipsilateral fungiform papillae and filiform papillae. Some labeled fibers crossed over to the contralateral papillae. In the intrinsic tongue muscle undulating nerve fibers along or across muscle fibers were often observed, and formed simple spiral endings.

Neuropathology of Bovine β-Mannosidosis

beta-Mannosidosis, an inherited defect of glycoprotein catabolism previously identified in goats and humans, has been recently diagnosed in Salers cattle. This disorder is associated with deficiency of lysosomal beta-mannosidase and accumulation of oligosaccharides. Analysis of bovine beta-mannosidosis neuropathology was initiated to determine whether independently arising gene defects in cattle and goats result in expression of similar lesions. Brain, spinal cord, and selected peripheral nerves from seven affected newborn Salers calves and three normal newborn calves were available for gross, light microscopic, and electron microscopic analysis. Gross examination revealed hydrocephalus of variable severity and myelin deficiency in the cerebral hemispheres, cerebellum, and brainstem. Microscopic examination revealed cytoplasmic vacuolation, myelin deficiency, and axonal spheroids of similar type and distribution to that reported in affected goats. Cytoplasmic vacuolation resulting from lysosomal storage showed consistent variation among cell types. Myelin deficits were more severe in the cerebral hemispheres and cerebellum than in the spinal cord. Axonal spheroids occurred in the cerebrum, brainstem, cerebellum, and trigeminal nerve endings. The presence of similar lesions in bovine and caprine beta-mannosidosis supports a direct relationship with the gene defect.

A pharmacological approach to the analgesizing mechanism of somatostatin in cluster headache

Vasodilation, conjunctival and nasal edema as well as miosis are symptoms associated with cluster headache (CH) attacks. Similar symptomatology is caused by substance P (SP) release from peripheral trigeminal nerve endings. The symptomatic effect of somatostatin (SRIF) during CH attacks was attributed to the inhibition of SP release from trigeminal neurons. This study was designed to evaluate both the vascular effect of SRIF on the dorsal hand vein and SRIF plasma levels prior to and after subcutaneous and intranasal administration in CH patients. A powerful venoconstriction and tachyphylaxis were demonstrated when SRIF was administered both as bolus and infusion. Plasma levels of SRIF in CH sufferers were lower than in control subjects. Subcutaneous and intranasal SRIF administrations induced maximal plasma levels after 5 and 10 min, respectively. These data suggest that SRIF plays an important role during CH attacks; however, its exact mechanism of action is still to be defined.

Nasal trigeminal chemoreception: Responses to n-aliphatic alcohols

Odorant molecules can stimulate nasal trigeminal receptors, but the properties of such molecules which make them effective stimuli are largely unknown. In the present study, we obtained integrated multiunit responses from the ethmoid branch of the rat trigeminal nerve to a homologous series of alipathic alcohols. Our aim was to determine whether lipid solubility might correlate with stimulus efficacy. Response thresholds (ranging from 3000 ppm for methanol to 3 ppm for octanol) decreased with increasing carbon chain length, suggesting that lipid solubility is important for stimulus effectiveness. One plausible explanation for the importance of lipophilicity is that the more lipid soluble a substance, the more easily it can penetrate epithelial layers to reach chemoreceptive trigeminal nerve endings. Since all stimuli at vapor saturation elicited responses within 0.5 s, and because diffusion of stimulus molecules through epithelium is slow, we speculate that trigeminal nerve endings lie closer to the epithelial surface than previously thought.

Substance P Mechanism in Cluster Headache: Evaluation in Plasma and Cerebrospinal Fluid

Substance P (SP), present in sensory afferent neurons, seems to process nociceptive information in the trigeminal system. SP, released from peripheral trigeminal endings, causes typical cluster headache (CH) signs, e.g. vasodilatation, conjunctival and nasal edema and miosis. Opiates and somatostatin (SRIF), both active in relieving CH attack, inhibit SP release from the central and peripheral trigeminal system. In the present study, plasma and cerebrospinal fluid (CSF), SP-like immunoreactivity (SPLI) and enkephalinase activity (EKA), and plasma SRIF-like immunoreactivity (SRIFLI) have been evaluated during spontaneous and histamine induced attacks in the cluster phase. During the histamine provoked attacks, CSF SPLI and plasma SRIFLI and EKA were unchanged, while plasma SPLI decreased significantly. During spontaneously occurring attacks, plasma SRIFLI was found to be unmodified and a significant lowering of SPLI was detected when compared with controls. Moreover, both during and between attacks in the cluster phase, plasma EKA was increased in comparison with the values in controls. It remains to be seen whether variations of plasma SPLI and EKA levels play a role in the CH mechanism.

Pupillary supersensitivity to substance P following prolonged treatment with tetrodotoxin or substance P antagonists

Pilocarpine contracts the sphincter pupillae muscle via an effect on muscarinic receptors and phenylephrine contracts the dilator pupillae muscle via an effect on α-adrenergic receptors. These effects are thought to mimic the action of the parasympathetic and sympathetic nervous systems, respectively. Intracellular injection of substance P (SP) produces an atropine-resistant constriction of the pupil. This response is thought to mimic the effect of local sensory reflexes on the sphincter pupillae muscle, involving SP-containing trigeminal nerve endings. Repeated intraocular injections of tetrodotoxin, a general blocker of nervous conduction, over a period of 3 weeks produced supersensitivity to pilocarpine, phenylephrine and SP in the rabbit iris. These findings support the view that, like acetylcholine and noradrenaline, SP or an SP-like compound acts as a neurotransmitter in the iris. Also, long-term topical application of an SP antagonist, (D-Pro 2, D-Trp 7,9)-SP or (Arg 5, D-Trp 7,9)-SP 5–11, to the rabbit eye produced supersensitivity to SP but not to pilocarpine, thus supporting the view that the SP antagonists interact specifically with the SP receptors. The isolated rabbit iris sphincter muscle responds to electrical stimulation with a cholinergic twitch followed by a slow non-cholinergic contraction that can be blocked by antagonists to SP. Analysis of the motor activity of the iris sphincter muscle after long-term topical treatment of the eye with an SP antagonist followed by an interval of 2 days after termination of treatment revealed a greatly enhanced non-cholinergic contraction compared with the cholinergic twitch, a finding that seems to be consistent with the idea that supersensitivity to SP had developed.

Sensory irritation tolerance and cross-tolerance in F-344 rats exposed to chlorine or formaldehyde gas

Inhalation of chlorine (Cl 2) or formaldehyde (HCHO) stimulates the trigeminal nerve endings in the nasal mucosa and results in respiratory rate depression in a concentration-dependent manner. To determine tolerance and cross-tolerance, the concentration-response curves of respiratory depression were compared between naive rats and rats pre-exposed to Cl 2 or HCHO. Chlorine tolerance development was time and concentration dependent, being significant following a 1-day (6 hr/day), 10 ppm exposure, and reaching the maximum in 4 days. At 2.5 ppm of Cl 2, tolerance was significant only after 10 days of exposure. Rats tolerant to Cl 2 also showed cross-tolerance to HCHO. Tolerance to HCHO was observed in rats exposed to 28 ppm for 4 days, but not in groups exposed to 15 ppm for 1, 4, or 10 days. However, significant cross-tolerance to Cl 2 was evident following a 1-day exposure to 15 ppm HCHO, with greatest effect seen in the group exposed for 10 days. Tolerance was reduced after a 7-day recovery following a 4-day exposure. Cross-tolerance was reduced also, but to a much lesser extent. These results suggest a common mechanism for tolerance and cross-tolerance development, but different reactive sites may exist for Cl 2 and HCHO at the trigeminal nerve endings.

Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice

The sensory irritation potential of a series of saturated and unsaturated aliphatic and cyclic aldehydes was investigated in B6C3F1 and Swiss-Webster mice. With the reflex decrease in respiratory rate as the endpoint response, α,β-unsaturated aliphatic aldehydes yielded RD50 values (concentration which elicits a 50% decrease in respiratory rate) ranging from 1 to 5 ppm while saturated aliphatic aldehydes with two or more carbons produced RD50 values from 750 to 4200 ppm. Cyclic aldehydes produced intermediate RD50 values which ranged from 60 to 400 ppm. No statistically significant differences were found between concentration-response curves of B6C3F1 and Swiss-Webster mice. Saturated aliphatic aldehydes with two or more carbons were nearly 1000 times less potent than formaldehyde. Although the mechanisms responsible for stimulation of trigeminal nerve endings by airborne chemicals are poorly understood, several hypotheses may help to explain the differences seen in this study. For example, the sensory irritation potency of the saturated aliphatic aldehydes diminished with their reported dehydration constants which may determine the degree to which these aldehydes crosslink with receptor proteins. The sensory irritation potency of acrolein and crotonaldehyde was probably due to 1,2 or 1,4 addition reactions. Additionally, molecular conformation and a recently published physical mechanism may contribute to sensory irritation responses, particularly for the less reactive aldehydes. Tentative threshold limit values (TLVs), based upon prevention of sensory irritation, were extrapolated from the RD50 values of Swiss-Webster mice. With the exception of crotonaldehyde, good agreement was found with currently published TLVs.

Fine structure of subepithelial "free" and corpuscular trigeminal nerve endings in anterior hard palate of the rat.

Axonally transported protein labeled many trigeminal nerve endings in subepithelial regions of the anterior hard palate of the rat. Sensory endings were most numerous in the lamina propria near the tips of the palatal rugae where large connective tissue and epithelial papillae interdigitated. Two kinds of sensory ending were found there: "free" endings, and a variety of corpuscular endings. The "free" sensory endings consisted of bundles of unmyelinated axons separated from the connective tissue by relatively unspecialized Schwann cells covering part or all of their surface and a completely continuous basal lamina; they were commonly found running parallel to the epithelium or near corpuscular endings. The corpuscular sensory endings all had a specialized nerve form, specialized Schwann cells, and axonal fingers projecting into the corpuscular basal lamina or connective tissue. There were at least four distinct types of corpuscular ending: Ruffini-like endings were found among dense collagen bundles, and they had a flattened nerve ending with a flattened Schwann lamella on either side. Meissner endings had an ordered stack of flattened nerve terminals with flattened Schwann cells and much basal lamina within and around the corpuscle. Simple corpuscles were single nerve endings surrounded by several layers of concentric lamellar Schwann processes. Glomerular endings were found in lamina propria papillae or encircling epithelial papillae; they were a tangle of varied neural forms each of which had apposed flattened Schwann cells, and a layer of basal lamina of varied thickness. Fibroblasts often formed incomplete partitions around Meissner and simple corpuscles. The axoplasm of all kinds of subepithelial sensory endings contained numerous mitochondria and vesicles, as well as occasional multivesicular bodies and lysosomes; the axoplasm of all endings was pale with few microtubules and neurofilaments. The specialized lamellar Schwann cells had much pinocytotic activity. Four kinds of junctions were found between the corpuscular sensory endings and the lamellar Schwann cells: (1) symmetric densities that resemble desmosomes; (2) asymmetric densities with either the neuronal or glial membrane more dense; (3) neural membrane densities adjacent to Schwann parallel inner and outer membrane densities; and (4) sites of apparent Schwann endocytosis associated with neural blebs. The "free" sensory endings only made occasional desmosome-like junctions with their Schwann cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Substance P in trigeminal nerve endings: occurrence and release.

Substance P in trigeminal nerve endings: occurrence and release.

NEUROTRANSMITTERS AND THE FIFTH CRANIAL NERVE: IS THERE A RELATION TO THE HEADACHE PHASE OF MIGRAINE?

The headache phase of migraine may develop as the result of an abnormal interaction (and perhaps an abnormal release) of vasoactive neurotransmitters from terminals of the trigeminal nerve with large intracranial and extracranial blood-vessels. These blood-vessels, which dilate during the headache phase of migraine, are thought to receive axonal projections from all three divisions of the trigeminal nerve. Substance P, a potent vasodilating peptide, seems to be released from trigeminal nerve endings in response to nervous stimulation and is involved in the transmission of painful stimuli within the periphery. The vasoactive molecule serotonin, implicated in the pathogenesis of migraine, coexists with substance P in some terminals of the central nervous system and is present within the trigeminal ganglia. Within this nerve serotonin may modulate the function of primary sensory neurons. The abnormal release of substance P or as yet unidentified peptides or other transmitters from the fifth cranial nerve may explain both the hemicranial pain and the vasodilation which are characteristic of the headache of migraine.

Trigeminal nerve endings in gingiva, junctional epithelium and periodontal ligament of rat molars as demonstrated by autoradiography.

Tritiated-L-proline was injected into the right Gasserian ganglion of mature rats for incorporation into proteins being carried by rapid axonal transport to nerve endings. The distribution of the nerve endings in molar gingivae and periodontium was subsequently mapped in serial sections by autoradiography. We found that sensory nerve terminals are most prominent in two regions of the free gingiva: (1) In the junctional epithelium there is a rich innervation of the basal epithelial layer with many endings penetrating several cell layers. (2) In the crestal epithelium arborized endings are present, especially on the marginal side of the crest. In the attached gingiva a few terminals are found in the epithelium with more in the lamina propria; the latter appear to be encapsulated. The periodontal ligament is only moderately labeled with silver grains located over nerve bundles, over nerves associated with blood vessels, and over a few apparent endings in the apical region. In the cementum no labeled endings are seen. Labeling of Gasserian cell bodies primarily reveals specific intra-epithelial nerve endings in gingiva crest and junctional epithelium. The absence of major labeling of the periodontal ligament supports the view that many nerves in that region are derived from cell bodies in the mesencephalic nucleus.

Comparison of the sensory irritation response in mice to chlorine and hydrogen chloride.

Groups of male Swiss-Webster mice were exposed to concentrations of chlorine varying from 0.7 to 38.4 ppm and to concentrations of hydrogen chloride varying from 40 to 943 ppm. The total exposure time to both gases was 10 minutes. Dose-response curves were plotted for both chlorine and hydrogen chloride, using the percentage decrease in respiratory rate during each exposure as the response reflecting sensory irritation of the upper respiratory tract. The results showed chlorine to be 33.0 times more irritating than hydrogen chloride, with 95% confidence limits of 18.6 and 57.1. Guidelines for obtaining a range of acceptable threshold limit values (TLV) based on sensory irritation of the upper respiratory tract are discussed. It was concluded that the current TLV of 1 ppm for chlorine is the upper acceptable limit, and that the established TLV of 5 ppm for hydrogen chloride lies at the lower limit of the predicted range. The mechanism of chlorine's and hydrogen chloride's sensory irritation may be explained by their reaction with various functional groups in the membranes of the trigeminal nerve endings lining the nasal mucosa.

Central relationships of trigeminal and cervical primary afferents in the spinal cord and medulla

The structural relationships between primary trigeminal and cervical dorsal root afferents in the spinal cord and the medulla were investigated in 13 cats. In 5 cats rhizotomies of one upper cervical dorsal root and of the contralateral trigeminal dorsal root were done at one operative session. In the remaining 8 cats rhizotomies of from 1 to 3 cervical roots were performed. The resultant degeneration was studied by the Nauta-Gygax and Fink-Heimer methods. The degree of anatomical overlap between afferents of the first 3 upper cervical roots and trigeminal terminals in the dorsal horn at identical levels is maximal in the lower half of C1 and upper third of C2. Minimal overlap of C4 with trigeminal endings occurs, while no afferents from the C5 to C8 roots reach the caudalmost endings of the trigeminal. Convergence of cervical with trigeminal afferents is also seen in the spinal nucleus of V in the low medulla in two discrete loci.