Trigeminal Innervation Research Articles

Pregnancy increases perivascular trigeminal innervation of cerebral arteries without changing reactivity to calcitonin gene‐related peptide (CGRP)

This study investigated the influence of pregnancy and postpartum on trigeminal innervation of posterior cerebral arteries (PCA) and reactivity to CGRP. Third-order PCAs were dissected from nonpregnant (NP, n=35), late-pregnant (LP, day 19–20, n=32), or postpartum (PP, day 3–4, n=32) Sprague Dawley rats and either fixed for immunohistochemical staining of CGRP-reactive nerve fibers or mounted in an arteriograph chamber for concentration-response curves to CGRP (0.1–300nM). Nerve density was determined by Metamorph analysis as intersect points on a grid per area after confocal imaging. Pregnancy had a trophic influence on perivascular CGRP-containing nerve fibers, increasing nerve density from 0.6 ± 0.2 counts/μm2 in NP to 1.3 ± 0.3 counts/μm2 in LP (p<0.01). Nerve density significantly decreased in PP animals to 0.2 ± 0.1 counts/μm2 (p<0.01 vs. LP). The gestation-induced increase in CGRP innervation was not accompanied by a change in reactivity. Percent dilation from spontaneous tone at 300nM CGRP for NP, LP and PP animals was: 70±7%, 69±12% and 74±10% (p>0.05). These results demonstrate that trigeminal innervation of PCAs is increased during gestation that is not accompanied by changes in reactivity. It is possible that increased CGRP nerve density during pregnancy relates more to nociception and a predisposition to the neurologic symptoms of eclampsia than to changes in blood flow. Supported by RO1 NS045940 and AHA 0540081N.

Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat

Migraine pathophysiology is thought to involve the trigeminal innervation of the dura mater and intracranial blood vessels. Electrical stimulation of dural blood vessels is painful in humans and causes activation of neurons in the caudal-most portion of the trigeminal nucleus in experimental animals. The hypothalamic neuropeptides orexin A and B are selectively synthesized in the lateral and posterior hypothalamus, and recent findings have implicated their involvement in nociceptive processing. To evaluate the potential for orexin receptor modulation of trigeminovascular nociceptive afferents, we examined the effects of intravenous orexin A and B on responses of neurons in the trigeminal nucleus caudalis. To dissect the receptor pharmacology of responses to stimulation we utilized the novel orexin 1 receptor (OX(1)R) antagonist N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl urea (SB-334867). Orexin A 30 microg/kg (F(1.9,9.8) = 21.93, P < 0.001) and 50 microg/kg (F(3.2,16.4) = 3.28, P < 0.045) inhibited the A-fibre responses to dural electrical stimulation over 60 min. Maximum inhibition was achieved at 25 min for both 30 microg/kg (t(5) = 19.83, n = 6, P < 0.001) and 50 microg/kg (t(5) = 7.74, n = 6, P < 0.001). The response with orexin A 30 microg/kg was reversed by pretreatment with the OX(1)R antagonist SB-334867 (F(3.5,17.5) = 0.49, P = 0.73), which had no effect when given alone. Orexin B and control vehicle administration had no significant effect on trigeminal neuronal firing. The current study demonstrates that orexin A is able to inhibit A-fibre responses to dural electrical stimulation via activation of the OX(1)R.

Delta (δ) opioid receptors in small and medium-sized trigeminal neurons supporting the dental pulp of rats

The control of pain perception is a challenge in clinical dentistry, most prominent during tooth pulp inflammation. The tooth pulp is a well-defined target, and is densely supplied by a sensory trigeminal innervation. Opioids are signaling molecules that are suggested to participate in pain perception. Here we analysed the presence of delta opioid receptor (DOR) in trigeminal neurons innervating the tooth pulp of rat molars. Immunohistochemical and ultrastructural analysis revealed that DOR was identified in peripheral nerves in the molar dental pulp, both in the root and the coronal pulpal parts, with branching in the highly innervated subodontoblast layer. DOR was localised in about one third of all the trigeminal dental neurons, identified by means of retrograde neuronal transport of fluorogold (FG) from the dental pulp. Of the DOR-labeled neurons, nearly all were small and medium-sized (147.5-1,810.2 microm(2), mean 749.1 +/- 327.3 microm(2)). Confocal microscopy confirmed that DOR-immunoreactivity was distributed as granules in the neuronal cytoplasm. Approximately 70% of the DOR-immunoreactive neurons were also immunopositive for vanilloid receptor 1 (TRPV1). Ultrastructural analysis demonstrated DOR-immunoreactivity in the unmyelinated and in some of the myelinated nerve fibers in the dental pulp. These results indicate that DOR may influence the function in a subset of small and medium-sized trigeminal sensory neurons supporting the tooth, which are mainly known for their ability to mediate nociceptive stimuli. Agonists, acting on DOR, may thus have an influence on a subpopulation of nociceptive neurons supporting the rat tooth.

Tissue interactions in the regulation of axon pathfinding during tooth morphogenesis

Like many other organs, the tooth develops as a result of the epithelial-mesenchymal interactions. In addition, the tooth is a well-defined peripheral target organ for sensory trigeminal nerves, which are required for the function and protection of the teeth. Dental trigeminal axon growth and patterning are tightly linked with advancing tooth morphogenesis and cell differentiation. This review summarizes recent findings on the regulation of dental axon pathfinding, which have provided evidence that the development of tooth trigeminal innervation is controlled by epithelial-mesenchymal interactions. The early dental epithelium possesses the information to instruct tooth nerve supply, and signals mediating these interactions are part of the signaling networks regulating tooth morphogenesis. Tissue interactions, thus, appear to provide a central mechanism of spatiotemporally orchestrating tooth formation and dental axon navigation and patterning.

Greater Occipital Nerve Block is Ineffective in Chronic Tension Type Headache

Patients with primary headache syndromes often describe a pain distribution, that does not respect the trigeminal innervation of the head. In addition to pain in frontal areas, innervated by the first (ophthalmic) division of the trigeminal nerve, the pain often occurs in occipital parts of the head, innervated by the greater occipital nerve, a branch of the C2 spinal nerve root. Anatomical and neurophysiological studies in animals suggest a convergence of cervical and trigeminal input in the trigeminal nucleus caudalis. Modulation of this pathway has been discussed to be of potential benefit in headache disorders. We investigated in an open pilot study the effect of bilateral block of the greater occipital nerve with 50 mg prilocaine and 4 mg dexamethasone in patients with chronic tension type headache. From 15 patients, only one patient described a headache relief after initial exacerbation of headache for 2 days. Headache intensity was unchanged in 11 patients. In further three patients, the headache worsened in the first hours or days after injection. No serious adverse events were observed. One patient showed a bradycardia (36/min) after the first injection during palpation of the muscles of the neck. Three patients suffered pain on the injection site for a few days. Our results indicate that block of the greater occipital nerve is not effective in the treatment of chronic tension type headache. If at all, rather a 'pro-nociceptive' effect was observed.

Trigeminal autonomic cephalalgias. Pathophysiology and classification

Trigeminal Autonomic Cephalalgias (TACs) is a grouping of headache syndromes that includes cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). They are recognized clinically by their episodic, stereotypic attack profile and very often prominent cranial autonomic symptoms, such as lacrimation, conjunctival injection or rhinorrhea. They involve afferent activation of the trigeminal innervation of intracranial pain-producing structures, or the perception of that activation, and reflex activation of the facial, seventh cranial, nerve outflow pathway. This excess reflex trigeminal-autonomic activation seems to be permitted by dysfunction in the brain, specifically in the posterior hypothalamic gray matter. Understanding the anatomy and physiology of these disorders has greatly facilitated their management and the development of exciting new strategies such as neuromodulatory approaches to the management of the more intractable cases.

Migraine and the neck: New insights from basic data

The clinical presentation of pain in patients with migraine showing spread and referral of pain throughout the trigeminal and cervical innervation territories accompanied by hyperalgesia and allodynia indicates a dynamic trigemino-cervical interaction. The physiologic mechanisms may be convergence of trigemino-cervical afferents and central sensitization of trigemino-cervical neurons leading to dynamic neuroplastic changes during migraine. This review highlights the clinical phenotype and mechanisms of how nociceptive input from neck structures of the upper cervical spine are integrated into the trigemino-cervical system. The nociceptive input into the spinal cord also is subject to a modulation by segmental mechanisms in the spinal cord and by inhibitory projections from brain stem structures such as the periaqueductal gray. The functional relevance of these basic mechanisms is discussed with reference to recent studies using neurostimulation of afferent nerves aiming at pain modulation in patients with migraine.

Anatomy and Physiology of Pain Referral Patterns in Primary and Cervicogenic Headache Disorders

The clinical presentation of pain in primary headache disorders, such as migraine and cervicogenic headache, shows that the trigeminal and cervical innervation territories frequently are not respected during an attack. Here we review evidence that trigeminal afferents innervating the meninges, and cervical afferents in the greater occipital nerve (GON), have synaptic convergent input onto the same second‐order neurons in the trigeminocervical complex. Furthermore, dynamic changes of excitability in terms of a sensitization to noxious input may occur on the central neuron level. The possible role of segmental mechanisms in the spinal cord and of inhibitory projections from brainstem structures such as the periaqueductal gray (PAG) in pain processing is discussed in view of data using neurostimulation of peripheral nerves in pain modulation. Recent experimental animal and human studies have facilitated our understanding of the role of these basic mechanisms in the spread, referral, and maintenance of pain in headache.

TrkC kinase expression in distinct subsets of cutaneous trigeminal innervation and nonneuronal cells.

Neurotrophin-activated receptor tyrosine kinases (Trks) regulate sensory neuron survival, differentiation, and function. To permanently mark cells that ever express TrkC-kinase, mice with lacZ and GFP reporters of Cre recombinase activity were crossed with mice having IRES-cre inserted into the kinase-containing exon of the TrkC gene. Prenatal reporter expression matched published locations of TrkC-expression. Postnatally, more trigeminal neurons and types of mystacial pad innervation expressed reporter than immunodetectable TrkC, indicating that some innervation transiently expresses TrkC-kinase. Reporter-tagged neurons include all those that immunolabel for TrkC, a majority for TrkB, and a small proportion for TrkA. TrkA neurons expressing TrkC-reporter range from small to large size and supply well-defined types of mystacial pad innervation. Virtually all small neurons and C-fiber innervation requires TrkA to develop, but TrkC-reporter is present in only a small proportion that uniquely innervates piloneural complexes of guard hairs and inner conical bodies of vibrissa follicle-sinus complexes. TrkC-reporter is expressed in nearly all presumptive Adelta innervation, which is all eliminated in TrkA knockouts and partially eliminated in TrkC knockouts. Many types of Abeta-fiber innervation express TrkC-reporter including all Merkel, spiny, and circumferentially oriented lanceolate endings, and some reticular and longitudinally oriented lanceolate endings. Only Merkel endings require TrkC to develop and survive, whereas the other endings require TrkA and/or TrkB. Thus, TrkC is required for the existence of some types of innervation that express TrkC, but may have different functions in others. Many types of nonneuronal cells affiliated with hair follicles and blood vessels also express TrkC-reporter but lack immunodetectable TrkC.

What is needed to develop a headache? Anatomical and pathophysiological implications

The shared anatomical and physiological substrate for headache syndromes is the neural innervation of the cranial circulation. Evidence suggests, that the observed dilatation of vessels in trigeminal pain is not inherent to a specific headache syndrome but rather a feature of the physiology of the trigeminal neural innervation of the cranial circulation. Moreover, the impact of vascular changes for the generation of headaches remains elusive. The trigeminal nerve innervates blood vessels within ipsilateral meninges. Upon activation neuropeptides such as CGRP are released. Blockade of both the trigeminal nerve system and neuropeptides are crucial targets for headache alleviating drugs. While these mechanisms are well known the events within and outside the CNS which initiate headaches are poorly understood. This article will review the anatomy and physiology of the trigeminovascular system which demand renewed consideration of the neural influences in many primary headaches.

CLUSTER

The trigeminal innervation of the dura and its vessels has a prominent role in the mechanism of cluster headache. Nociceptin, an opioid neuropeptide, is the endogenous ligand of the OP‐4 receptor, with both algesic and analgesic properties depending on the site of action. Nociceptin and its receptor are expressed by trigeminal ganglion cells where they colocalize with calcitonin gene‐related peptide (CGRP), a marker peptide of the trigeminovascular neurones. Nociceptin inhibits neurogenic dural vasodilatation, a phenomenon related to trigeminovascular activation. To explore its possible involvement in cluster headache, we studied circulating levels of nociceptin when attack‐free during the cluster period, and also after the termination of the cluster period, using radioimmunoassay. In 14 cluster headache patients nociceptin levels during the cluster period were significantly lower than in age‐, and sex‐matched controls (4.91 ± 1.96 vs. 9.58 ± 2.57 pg/ml; P &lt; .01). After the termination of the cluster period nociceptin levels (8.60 ± 1.47 pg/ml) were not statistically different from controls. Nociceptin levels did not correlate with age, length of disease, or episode length. Lower nociceptin levels during the cluster period may result in a defective regulation of trigeminal activity that might not protect sufficiently against the attacks.

A rat model of radiofrequency ablation of trigeminal innervation via a ventral approach with stereotaxic surgery

Neurotrophic keratopathy (NK), a consequence of sensory denervation of the cornea, must be better understood in order to develop new approaches to therapy. The purpose of this study was to create a rat model for neurotrophic keratopathy by denervating the trigeminal nerve through a ventral approach with stereotaxic surgery. Stereotaxic coordinates were measured in 46 male Sprague Dawley rat cadavers for localization of V1. After further refining the coordinates in nine live animals, radiofrequency ablation was chosen as an effective method of disrupting the innervation to the cornea. Fifty-two live rats were treated with radiofrequency ablation to define the anatomical localization of the lesion by utilizing gross and histopathological studies. A gross lesion of the trigeminal nerve and/or ganglion was observed in 47 (90%) of the 52 animals. Histopathological studies revealed that all 52 animals had anatomical damage of the trigeminal innervation to the eye. Low mortality and little morbidity were observed in these animals. We have developed a rat model for neurotrophic keratopathy that is simple to produce, accurate in creating a lesion by utilizing stereotaxic techniques combined with radiofrequency ablation, and successful in decreasing morbidity and mortality.

Glial cell line-derived neurotrophic factor (GDNF) from adult rat tooth serves a distinct population of large-sized trigeminal neurons.

Glial cell line-derived neurotrophic factor (GDNF) mediates trophic effects for specific classes of sensory neurons. The adult tooth pulp is a well-defined target of sensory trigeminal innervation. Here we investigated potential roles of GDNF in the regulation of adult trigeminal neurons and the dental pulp nerve supply of the rat maxillary first molar. Western blot analysis and radioactive 35S-UTP in situ hybridization revealed that GDNF in the dental pulp and its mRNAs were localized with Ngf in the coronal pulp periphery, in particular in the highly innervated subodontoblast layer. Retrograde neuronal transport of iodinated GDNF and Fluorogold (FG) from the dental pulp indicated that GDNF was transported in about one third of all the trigeminal dental neurons. Of the GDNF-labelled neurons, nearly all (97%) were large-sized (> or =35 microm in diameter). Analysis of FG-labelled neurons revealed that, of the trigeminal neurons supporting the adult dental pulp, approximately 20% were small-sized, lacked isolectin B4 binding and did not transport GDNF. Of the large-sized dental trigeminal neurons approximately 40% transported GDNF. About 90% of the GDNF-accumulating neurons were negative for the high-temperature nociceptive marker VRL-1. Our results show that a subclass of large adult trigeminal neurons are potentially dependent on dental pulp-derived GDNF while small dental trigeminal neurons seems not to require GDNF. This suggests that GDNF may function as a neurotrophic factor for subsets of nerves in the tooth, which apparently mediate mechanosensitive stimuli. As in dorsal root ganglia both small- and large-sized neurons are known to be GDNF-dependent; these data provide molecular evidence that the sensory supply in the adult tooth differs, in some aspects, from the cutaneous sensory system.

Circulating nociceptin levels during the cluster headache period.

The trigeminal innervation of the dura and its vessels has a prominent role in the mechanism of cluster headache. Nociceptin, an opioid neuropeptide, is the endogenous ligand of the OP-4 receptor, with both algesic and analgesic properties depending on the site of action. Nociceptin and its receptor are expressed by trigeminal ganglion cells where they co-localize with calcitonin gene-related peptide, a marker peptide of the trigeminovascular neurones. Nociceptin inhibits neurogenic dural vasodilatation, a phenomenon related to trigeminovascular activation. To explore its possible involvement in cluster headache, we studied circulating levels of nociceptin when attack-free during the cluster period, and also after the termination of the cluster period, using radioimmunoassay. In 14 cluster headache patients nociceptin levels during the cluster period were significantly lower than in age-, and sex-matched controls (4.91 +/- 1.96 vs. 9.58 +/- 2.57 pg/ml, P < 0.01). After the termination of the cluster period nociceptin levels (8.60 +/- 1.47 pg/ml) were not statistically different from controls. Nociceptin levels did not correlate with age, length of disease or episode length. Lower nociceptin levels during the cluster period may result in a defective regulation of trigeminal activity that might not protect sufficiently against the attacks.

Trigeminal somatosensory innervation of the head of a teleost fish with particular reference to nociception

Trigeminal somatosensory receptors have not been characterised in teleost fish and studies in elasmobranchs have failed to identify nociceptors. The present study examined the trigeminal nerve of a teleost fish, the rainbow trout ( Oncorhynchus mykiss) to determine what types of somatosensory receptors were present on the head of the trout specifically searching for nociceptors. Single unit recordings were made from receptive fields on the head of the fish innervated by the trigeminal nerve. Each receptive field was tested for sensitivity to mechanical, thermal and chemical stimulation. Five different receptor types were found: fast adapting receptors responding to mechanical stimulation; slowly adapting receptors responding to mechanical stimuli; polymodal nociceptors responding to mechanical, noxious thermal and chemical stimulation; mechanothermal nociceptors responding to mechanical stimulation and noxious heat; and mechanochemical receptors responsive to mechanical and chemical stimulation. Mechanical thresholds, receptive field diameter, conduction velocities and thermal thresholds of the receptors were determined and there was no significant difference between the receptor types in terms of these properties. Three shapes of action potential (AP) were recorded from these receptors: type 1 with no inflexion; type 2 with an inflexion on depolarisation; and type 3 with an inflexion on repolarisation. Conduction velocity, amplitude and duration of the APs, afterhypolarisation amplitude and duration, as well as the maximum rate of depolarisation were measured for each action potential type. No major differences were found when making comparisons within receptor type and between receptor types. The fish nociceptors had similar physiological properties to nociceptors found in higher vertebrates.

Mouse rudimentary diastema tooth primordia are devoid of peripheral nerve fibers.

The tooth is a well-defined peripheral target organ for trigeminal nerve fibers. However, only limited information is available regarding pioneer axon guidance to the developing tooth target field. In rodents there is a toothless diastema region between incisors and molars that in the mouse maxilla contains three rudimentary tooth anlagen. Their development stop at the early bud stage when the primary nerve axons grow towards the developing first molar tooth germs. In order to provide background information for studies of regulatory mechanisms of pioneer axon guidance to the developing tooth germs, we investigated the distribution of nerve fibers in the mouse diastema tooth buds, and compared it to the axon growth to the maxillary and mandibular first molar tooth germs by immunohistochemical localization of peripherin and PGP9.5. Analysis of serial sections showed that trigeminal nerve fibers emerging from the trigeminal maxillary and mandibular nerve trunks started to grow towards the developing molar tooth germ at the early bud stage, and subsequently they diverged into buccal and lingual branches next to the condensed dental mesenchyme. During the cap stage, nerve fibers were observed around the tooth germ in the dental follicle region. In contrast, no nerve fibers were located in the vicinity of the diastema tooth primordia at any stage studied, nor did any nerve fibers appear to grow towards this region. Our results show that the development and subsequent disappearance of the diastema tooth primordia takes place without peripheral trigeminal innervation. The diastema tooth primordia may therefore be a useful model system for future studies on molecular regulatory mechanisms of pioneer axon guidance to the tooth germs, and possibly also for evolutionary studies of peripheral axon guidance mechanisms.

Trigeminal neuropathy in dogs: a retrospective study of 29 cases (1991-2000).

The medical records of 29 dogs unable to close their mouths due to flaccid paralysis or paresis of the muscles innervated by the mandibular branch of the trigeminal nerve, were reviewed. Idiopathic trigeminal neuropathy was diagnosed in 26 dogs based on complete resolution of clinical signs and lack of any long-term neurological disease. Of these dogs, golden retrievers were overrepresented. No age, sex, or seasonal predispositions were identified. Trigeminal sensory innervation deficits were observed in 35% (9/26), facial nerve deficits were observed in 8% (2/26), and Horner's syndrome was observed in 8% (2/26) of dogs. Electromyographic examination of the muscles of mastication revealed abnormalities in seven of nine dogs. Results of cerebrospinal fluid analysis were abnormal in seven of eight dogs. Corticosteroid therapy did not affect the clinical course of the disease. Mean time to recovery was 22 days. Lymphosarcoma, Neospora caninum infection, and severe polyneuritis of unknown origin were diagnosed in three of 29 dogs at necropsy.

Magnetic resonance angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation.

For much of the twentieth century migraine and cluster headache have been considered as vascular headaches whose pathophysiology was determined by changes in cranial vascular diameter. To examine nociceptive neural influences on the cranial circulation, the authors studied healthy volunteers' responses to injection of the pain-producing compound capsaicin in terms of the caliber of the internal carotid artery. The study was conducted using magnetic resonance angiographic techniques. Injection of capsaicin into the skin innervated by the ophthalmic (first) division of the trigeminal nerve elicited 40% +/- 27% (mean +/- SD) increase in vascular cross-sectional area in the right (ipsilateral) internal carotid artery when compared with the mean baseline ( P < 0.001). Injection of capsaicin into the skin of the chin to stimulate the mandibular (third) division of the trigeminal nerve and into the leg led to a similar pain perception and failed to produce any significant change in vessel caliber. The data suggest that there is a highly functionally organized, somatotopically congruent trigeminal innervation of the cranial vessels, with a potent vasodilator effect of the ophthalmic division on the large intracranial vessels. The data are consistent with the notion that pain drives changes in vessel caliber in migraine and cluster headache, not vice versa. These conditions therefore should be regarded as primary neurovascular headaches not as vascular headaches.

Relation between PROP taster status and fat perception, touch, and olfaction

We tested the hypothesis that fat perception (sensitivity to and preferences for fat) may be linked to 6- n-propylthiouracil (PROP) taster status as a result of differences in trigeminal innervation of the oral cavity. In addition, we examined the relationship between taster status and sensitivity to other taste attributes, as well as tactile and olfactory sensitivities. Subjects (40 nontasters, 67 medium tasters, and 40 supertasters of PROP) rated samples (potato chips, chocolate drink, mashed potatoes, and vanilla pudding) varying in fat and flavor concentrations for the intensity of fattiness, saltiness, and sweetness, first without and then with nose clips, and for liking. Tactile sensitivity of the tongue was assessed according to responses to stimulation with Von Frey filaments (2.36, 2.44). Olfactory thresholds were determined for two odors (diacetyl and phenylethyl methyl ethyl carbinol). In general, taster status was not related to the perceptions of fat, saltiness, and sweetness. Subjects were able to accurately assess the fat content of the samples. Increasing the flavor levels in the potato chips and mashed potatoes enhanced the perception of fattiness for these systems. Supertasters were more sensitive to stimulation on the median of the tongue with the no. 2.36 Von Frey filament, and the olfactory thresholds for diacetyl were lower for PROP tasters and supertasters than for nontasters.

Presence of PACAP-immunoreactive neurons in the trigeminal ganglion of the sheep. Indications for a trigeminal innervation of the pineal gland.

Presence of PACAP-immunoreactive neurons in the trigeminal ganglion of the sheep. Indications for a trigeminal innervation of the pineal gland.