BACKGROUND: The study was designed to explore the correlation of the asymmetric regulation between periaqueductal gray (PAG) and bilateral trigeminal nucleus caudalis (TNC) in migraine rats through studying the changes of metabolites in pain regulatory pathway of acute migraine attack.
METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups: blank, control, model groups. Then, blank group was intraperitoneally injected with ultrapure water, while control group injected with saline and model group injected with Glyceryl Trinitrate (GTN). Two hours later, PAG and bilateral TNC were removed respectively, and metabolite concentrations of PAG, Left-TNC, Right-TNC were obtained. Lastly, the differences of metabolite among three brain tissues were compared.
RESULTS: The relative concentrations of rNAA, rGlu, rGln, rTau, rMI in PAG or bilateral TNC had interaction effects between groups and sites. The concentration of rLac of three brain tissues increased in migraine rats, however, the rLac of LTNC and RTNC increased more than that of PAG. Besides, the concentrations of rNAA and rGln increased in RTNC, while rGABA decreased in RTNC.
CONCLUSIONS: There is correlation between PAG, LTNC and RTNC in regulation of pain during acute migraine attack, and the regulation of LTNC and RTNC on pain is asymmetric.

Objective: To determine the opening and closing action of the external muscle, the projection pathway of the axon terminal of trigeminal motor nucleus (Vmo) neuron to the lateral pterygoid muscle was revealed. Methods: In this study, 10 SD rats of 8 weeks old were included. The left lateral pterygoid muscle of SD rats was surgically exposed, and the wound was closed after intramuscular injection of hydroxystilbamidine/fluorogold (FG) 3-5 μl. Seven days after the operation, the experimental animals were perfused, samples collected and sectioned for immunofluorescence staining. After FG injection into the lateral pterygoid muscle, the FG reversed in the Vmo neurons. Results: In the Vmo neurons on the FG injection side (left side), a large number of FG reversed neurons were found in the corpus luteum and dendrites. These neurons were not only distributed in the dorsolateral part of the trigeminal motor nucleus that innervated the closed muscle, but also in the ventral medial portion of the trigeminal nucleus of the open muscle. Conclusions: The neuronal conduction pathway between the Vmo and the lateral pterygoid muscle innervates the lateral pterygoid muscle. The neurons are distributed both in the dorsolateral and in the nucleus of the ventral ventricle. It is concluded that the lateral pterygoid muscle involve in the jaw closing and opening movement.
目的： 通过对SD大鼠三叉神经运动核（trigeminal motor nucleus，Vmo）-翼外肌神经元投射通路的定性研究分析，揭示Vmo神经元轴突终末向翼外肌的投射通路，以确定翼外肌的开闭口作用。 方法： 纳入8周龄SD大鼠10只，手术暴露SD大鼠左侧翼外肌，肌内注射荧光金3~5 μl后，关闭并缝合伤口。术后7 d，实验动物灌注、取材、切片后免疫荧光染色，荧光显微镜下观察荧光金注入翼外肌后，在三叉神经运动核内荧光金的逆行标记情况。 结果： 在荧光金注射侧的Vmo神经元内可见大量的荧光金逆标神经元的胞体和树突，这些神经元不仅分布于支配闭口肌的三叉神经运动核的背外侧部，也分布于支配开口肌的三叉神经运动核的腹内侧部。 结论： Vmo与翼外肌之间的神经元传导通路支配翼外肌，神经元既分布在背外侧部也分布在腹内侧部的核团内，推断翼外肌既在开口运动中发挥作用，又在闭口运动中发挥作用。.

Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during some primary headache disorders. The goal of this study was to compare the effects of two KYNA analogs, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1) and N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2), in the orofacial formalin test of trigeminal pain. Following pretreatment with KA-1 or KA-2, rats were injected with subcutaneous formalin solution in the right whisker pad. Thereafter, the rubbing activity and c-Fos immunoreactivity changes in the spinal trigeminal nucleus pars caudalis (TNC) were investigated. To obtain pharmacokinetic data, KA-1, KA-2 and KYNA concentrations were measured following KA-1 or KA-2 injection. Behavioral tests demonstrated that KA-2 induced larger amelioration of formalin-evoked alterations as compared with KA-1 and the assessment of c-Fos immunoreactivity in the TNC yielded similar results. Although KA-1 treatment resulted in approximately four times larger area under the curve values in the serum relative to KA-2, the latter resulted in a higher KYNA elevation than in the case of KA-1. With regard to TNC, the concentration of KA-1 was under the limit of detection, while that of KA-2 was quite small and there was no major difference in the approximately tenfold KYNA elevations. These findings indicate that the differences between the beneficial effects of KA-1 and KA-2 may be explained by the markedly higher peripheral KYNA levels following KA-2 pretreatment. Targeting the peripheral component of trigeminal pain processing would provide an option for drug design which might prove beneficial in headache conditions.

OBJECTIVE: To investigate signs of central sensitization in a cohort of patients with chronic whiplash associated headache (CWAH).
BACKGROUND: Central sensitization is one of the mechanisms leading to chronicity of primary headache, and thus might contribute to CWAH. However, the pathophysiological mechanism of CWAH is poorly understood and whether it is simply an expression of the primary headache or has a distinct pathogenesis remains unclear. Thus, the factors involved in the genesis of CWAH require further investigation.
METHODS: Twenty-two patients with CWAH (20 females, 2 males; age 25-50 years, mean age 36.3 years) and 25 asymptomatic participants (13 females, 12 males; age 18-50 years, mean age 35.6 years) rated glare and light-induced discomfort in response to light from an ophthalmoscope. Hyperalgesia evoked by a pressure algometer was assessed bilaterally on the forehead, temples, occipital base, and the middle phalanx of the third finger. The number, latency, area under the curve, and recovery cycle of nociceptive blink reflexes elicited by a supraorbital electrical stimulus were also recorded.
RESULTS: Eight and 6 CWAH patients had migrainous and tension-type headache (TTH) profiles, respectively; the remainder had features attributable to both migraine and TTH. Patients in the whiplash group reported significantly greater light-induced pain than controls (8.48 ± .35 vs 6.66 ± .43 on a 0-10 scale; P = .001). The CWAH patients reported significantly lower pressure pain thresholds at all sites. For stimuli delivered at 20 second intervals, whiplash patients were more responsive than controls (4.8 ± .6 blinks vs 3.0 ± .6 blinks in a block of 10 stimuli; P = .036). While R2 latencies and the area under the curve for the 20 second interval trials were comparable in both groups, there was a significant reduction of the area under the curve from the first to the second of the 2-second interval trials only in controls (99 ± 8% of baseline in whiplash patients vs 68 ± 7% in controls; P = .009). The recovery cycle was comparable for both groups.
CONCLUSIONS: Our results corroborate previous findings of mechanical hypersensitivity and photophobia in CWAH patients. The neurophysiological data provide further evidence for hyperexcitability in central nociceptive pathways, and endorse the hypothesis that CWAH may be driven by central sensitization.

The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology.

BACKGROUND: This cases report confirms the hypothesis that embryonic and maxillofacial growth are influenced by the peripheral nervous system, including the trigeminal nerve (V). So, it\'s interesting to use the stigma of the trigeminal nerve as landmarks to analyze the maxillofacial volume and understand its growth. The aim of this study is to evaluate the validity of the three-dimensional cephalometric analysis of Treil based on trigeminal landmarks.
METHODS: The first case is a caucasian female child with Goldenhar syndrome. The second case is a caucasian male adult affected by the same syndrome. In both cases, brain MRI showed an unilateral trigeminal nerve lesion, ipsilateral to the facial dysmorphia.
CONCLUSIONS: The results of this radiological study tend to prove the primary role of the trigeminal nerve in craniofacial growth. These cases demonstrate the validity of the theory of Moss. They are one of anatomo-functional justifications of the three-dimensional cephalometric biometry of Treil based on trigeminal nerve landmarks.

Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.

Jaw muscle spindle afferents (JMSA) in the mesencephalic trigeminal nucleus (Vme) project to the parvocellular reticular nucleus (PCRt) and dorsomedial spinal trigeminal nucleus (dm-Vsp). A number of premotor neurons that project to the trigeminal motor nucleus (Vmo), facial nucleus (VII) and hypoglossal nucleus (XII) are also located in the PCRt and dm-Vsp. In this study, we examined whether these premotor neurons serve as common relay pool for relaying JMSA to multiple orofacial motoneurons. JMSA inputs to the PCRt and dm-Vsp neurons were verified by recording extracellular responses to electrical stimulation of the caudal Vme or masseter nerve, mechanical stimulation of jaw muscles and jaw opening. After recording, biocytin in recording electrode was inotophorized into recording sites. Biocytin-Iabeled fibers traveled to the Vmo, VII, XII, and the nucleus ambiguus (Amb). Labeled boutons were seen in close apposition with Nissl-stained motoneurons in the Vmo, VII, XII and Amb. In addition, an anterograde tracer (biotinylated dextran amine) was iontophorized into the caudal Vme, and a retrograde tracer (Cholera toxin B subunit) was delivered into either the VII or Xll to identify VII and XII premotor neurons that receive JMSA input. Contacts between labeled Vme neuronal boutons and premotor neurons were observed in the PCRt and adjacent dm-Vsp. Confocal microscopic observations confirmed close contacts between Vme boutons and VII and XII premotor neurons. This study provides evidence that JMSA may coordinate activities of multiple orofacial motor nuclei, including Vmo, VII, XII and Amb in the brainstem via a common premotor neuron pool.

It has been established that a postsynaptic scaffolding protein, gephyrin, is essential for anchoring two main groups of inhibitory receptors, GABA(A) receptors (GABA(A) Rs) and glycine receptors (GlyRs), to the postsynaptic sites of neurons. The present study was primarily attempted to examine if expression patterns of gephyrin might be different between jaw-closing (JC) and jaw-opening (JO) motoneurons. The JC- and JO-motoneurons in the rat trigeminal motor nucleus (Vm) were located in the dorsolateral (Vm.dl) and ventromedial (Vm.vm) divisions, respectively (Mizuno et al.,1975). Thus, immunoreactivity (IR) for gephyrin was investigated in the Vm: immunofluorescence histochemistry for gephyrin was combined with retrograde tract-tracing of fluorogold (FG), which was injected into nerves innervating JC-muscles or nerves innervating JO-muscles; neuronal cells were counterstained with propidium iodide (PI). The Vm.dl was discriminated from the Vm.vm by the presence of vesicular glutamate transporter 1 (VGLUT1)-immunopositive axon terminals, which were distributed in the Vm.dl but not in the Vm.vm (Pang et al., J Comp Neurol 2009;512:595-612). Gephyrin-IR showed a punctate pattern of fluorescence, and motoneuronal profiles were coated with small clusters of gephyrin-immunopositive puncta throughout the Vm. The distribution density of such clusters was apparently higher in the Vm.dl than in the Vm.vm; this was confirmed quantitatively by a method similar to that described by Lorenzo et al. (Eur J Neurosci 2006;23:3161-3170). On the basis of the present results, possible correlation between the distribution density of gephyrin clusters in the submembrane region of Vm motoneurons and that of axon terminals making inhibitory synapses on Vm motoneurons was discussed.

It is well known that most odorants stimulate the trigeminal system but the time course of the brain regions activated by these chemical stimulations remains poorly documented, especially regarding the trigeminal system. This functional magnetic resonance imaging (fMRI) study compares brain activations resulting from the contrast between two odorant conditions (one bimodal odor and one relatively pure olfactory stimulant) according to the duration of the stimulation (i.e. one inhalation, or three or six successive inhalations). The results show striking differences in the main brain regions activated according to these durations. The caudate nucleus and the orbitofrontal cortex are only involved in short-duration stimulations, and the posterior insular cortex and post-central gyrus (SI) are only activated by long duration stimulations. Different regions of the frontal, temporal and occipital lobe are activated depending on the duration but mainly during medium-duration stimulations. These results expand on the findings of previous studies and contribute to the description of temporal networks in trigeminal perception.