In healthy subjects nasal nitric oxide does not correlate with olfactory sensitivity, trigeminal sensitivity, and nasal airflow.

OBJECTIVE: The aim of the study was to determine the relationship between nasal nitric oxide (nNO) and olfactory sensitivity, trigeminal sensitivity and nasal airflow in healthy subjects. STUDY DESIGN: This is a correlational study. SETTING: This study was carried out in a tertiary referral centre. PARTICIPANTS: Forty healthy participants were recruited. MAIN OUTCOME MEASURES: nNO was measured using a chemiluminescence analyser (Niox Vero® , Circassia AB, Uppsala, Sweden), olfactory sensitivity was determined using phenyl ethyl alcohol odour thresholds using the 'Sniffin' Sticks', trigeminal sensitivity was assessed with carbon dioxide delivered by an automated device, and nasal airflow was measured using the peak nasal inspiratory flow (PNIF). RESULTS: The median nNO was 518 ppb (IQR =333) in the right nostril, and it was 567 ppb (IQR = 314) in the left nostril. The median odour threshold was 7.1 (IQR = 4.4), the median CO2 threshold was 919 ms (IQR = 1297) and the mean PNIF was 108 L/min (SEM = 4.9). nNO did not correlate significantly with odour threshold, CO2 threshold or PNIF (Spearman's |ρ|  <0.15, p > .18). CONCLUSION: In healthy subjects, nNO does not appear to be associated with olfactory sensitivity, trigeminal sensitivity and PNIF.

Greater occipital nerve block modulates nociceptive signals within the trigeminocervical complex.

INTRODUCTION: The pharmacological block of the greater occipital nerve has been proven effective in numerous headache and facial pain syndromes. This clinical effect supports the hypothesis of a strong functional interaction between the occipital and trigeminal nerves which has been proposed in neurophysiological in vivo experiments in rodents. Although it is likely that the interaction has to occur in the central nervous system, the exact site and the mechanisms of the interaction remain largely unknown. METHODS: Focusing on these questions we investigated in a double-blind, placebo-controlled, randomised study the influence of an occipital nerve block with lidocaine 1% on neuronal activation in the trigeminocervical complex using high-resolution functional magnetic resonance on a 3T scanner. In order to investigate potential clinical effects on the trigeminal nerve, we further performed quantitative sensory testing and analysed a potential shift in thermal detection and pain thresholds. RESULTS: The pharmacological block of the greater occipital nerve induced an occipital anaesthesia ipsilateral to the block. Functional imaging revealed that the occipital injection of lidocaine but not placebo significantly reduced nociceptive trigeminal activation. CONCLUSIONS: These data suggest that the functional inhibition of the occipital nerve block on trigeminal nociceptive activity is likely to occur at the C2 level where the occipital nerve enters the trigeminocervical complex and converges on the same central nuclei before the signal crosses the midline at that level and is then transmitted to higher processing centres.

Vinaxanthone inhibits Semaphorin3A induced axonal growth cone collapse in embryonic neurons but fails to block its growth promoting effects on adult neurons.

Semaphorin3A is considered a classical repellent molecule for developing neurons and a potent inhibitor of regeneration after nervous system trauma. Vinaxanthone and other Sema3A inhibitors are currently being tested as possible therapeutics to promote nervous system regeneration from injury. Our previous study on Sema3A demonstrated a switch in Sema3A's function toward induction of nerve regeneration in adult murine corneas and in culture of adult peripheral neurons. The aim of the current study is to determine the direct effects of Vinaxanthone on the Sema3A induced adult neuronal growth. We first demonstrate that Vinaxanthone maintains its anti-Sema3A activity in embryonic dorsal root ganglia neurons by inhibiting Sema3A-induced growth cone collapse. However, at concentrations approximating its IC50 Vinaxanthone treatment does not significantly inhibit neurite formation of adult peripheral neurons induced by Sema3A treatment. Furthermore, Vinaxanthone has off target effects when used at concentrations above its IC50, and inhibits neurite growth of adult neurons treated with either Sema3A or NGF. Our results suggest that Vinaxanthone's pro-regenerative effects seen in multiple in vivo models of neuronal injury in adult animals need further investigation due to the pleiotropic effect of Sema3A on various non-neuronal cell types and the possible effect of Vinaxanthone on other neuroregenerative signals.

Screen of anti-migraine active compounds from Duijinsan by spectrum-effect relationship analysis and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Duijinsan (DJS) is a famous Chinese medicine prescription composed of Radix scutellariae (RS) and Rhei Radix (RRR), which has been mainly used for treating migraine. AIM OF THE STUDY: This study aimed to uncover the anti-migraine active compounds from DJS and preliminary predicted the pharmacological mechanism by evaluating the spectrum-effect relationship between high-performance liquid chromatography (HPLC) fingerprints and anti-migraine effects of Duijinsan (DJS) extract combined with molecular docking. MATERIALS AND METHODS: HPLC and LC-MS were applied for chemical analyses of DJS extracts in different proportions. Inhibition of DJS extracts on trigeminal nerve cell releasing calcitonin gene related peptide (CGRP) experiment was performed. The active compounds were screened by spectrum-effect relationship analysis and confirmed by molecular docking and the activities of major predicted compounds were validated in vitro. RESULTS: Twenty-six common peaks were assigned and identified from the fingerprints of different proportions DJS extracts. In vitro experimental results showed that DJS extracts inhibited inflammation and release of CGRP from trigeminal nerve cells. Five predicted active compounds, Chrysin 6-C-arabinoside 8-C-glucoside, Chrysin 6-C-glucoside 8-C-arabinoside, baicalin, Chrysin-7-O-Beta-D-glucoronide and Oroxylin A 7-O-glucuronide were sorted out according to spectrum-effect relationship analysis and molecular docking comprehensively. In vitro validation experiments showed that all the predicted compounds inhibited the CGRP releasing and the activation of TRPV1 channel. Baicalin, chrysin-7-O-ß-D-glucuronide and Oroxylin A-7-glucoronide significantly inhibited the activation of TRPV1 channel. CONCLUSION: Chrysin 6-C-arabinoside 8-C-glucoside, Chrysin 6-C-glucoside 8-C-arabinoside, baicalin, Chrysin-7-O-Beta-D-glucoronide and Oroxylin A 7-O-glucuronide which can inhibit the CGRP releasing and the activation of TRPV1 channel were screened as the anti-migraine active compounds by spectrum-effect relationship analysis and molecular docking.

Local administration of genistein as a local anesthetic agent inhibits the trigeminal nociceptive neuronal activity in rats.

A modulatory role has been reported for the isoflavone, genistein, on voltage-gated Na+ channels in the trigeminal ganglion in vitro. However, the acute effects of genistein in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The aim of the present study was to examine whether acute local genistein administration to rats attenuates the excitability of wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from SpVc WDR neurons in response to orofacial non-noxious and noxious mechanical stimulation of pentobarbital-anesthetized rats. The effects of local administration of genistein, lidocaine, and lidocaine with genistein to the receptive field on the discharge frequency of SpVc neurons were evaluated. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was significantly and dose-dependently (0.1-10 mM) inhibited by genistein, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of genistein lasted for 20 min and was reversible. No significant difference was seen between the relative magnitude of inhibition by genistein on the SpVc WDR neuronal discharge frequency for noxious and non-noxious stimulation. The mean magnitude of inhibition by genistein (10 mM) on SpVc neuronal discharge frequency was almost equal to that of the local anesthetic, 1 % lidocaine (37 mM). Local injection of half-dose of lidocaine replaced the half-dose of genistein. These results suggest that local injection of genistein into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of voltage-gated Na+ channels in the nociceptive nerve terminals of trigeminal ganglion. Therefore, administration of genistein as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects, thus contributing to the area of complementary and alternative medicines.

Intranasal administration of the chemotherapeutic perillyl alcohol results in selective delivery to the cerebrospinal fluid in rats.

Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood-brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.

A new era for migraine: The role of calcitonin gene-related peptide in the trigeminovascular system.

There is a huge improvement in our understanding of migraine pathophysiology in the past decades. The activation of the trigeminovascular system has been proved to play a key role in migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are widely distributed in the trigeminovascular system. The CGRP is expressed on the C-fibers, and the CGRP receptors are distributed on the A-δ fibers of the trigeminal ganglion and nerves. Further studies found elevated serum CGRP level during migraine attacks, and infusion of CGRP can trigger migraine-like attacks, provide more direct evidence of the link between CGRP and migraine attack. Based on these findings, several treatment options have been designed for migraine treatment, including CGRP receptor antagonists (gepants) and monoclonal antibodies targeting CGRP or CGRP receptors. The clinical trials show both gepants and monoclonal antibodies are effective for migraine treatment. In this section, we describe the roles of the trigeminovascular system in migraine, the discovery of CGRP, and the CGRP signaling pathway.

Triptan efficacy does not predict onabotulinumtoxinA efficacy but improves with onabotulinumtoxinA response in chronic migraine patients.

Chronic migraine (CM) is a highly disabling primary headache. Botulinum toxin (onabotulinumtoxinA) is effective for treatment of CM, with ~ 50% of patients responding after 24 weeks. A response predictor would prevent unnecessary treatments. Inhibiting calcitonin gene related peptide (CGRP) release from trigeminal nociceptive fibres is one of the modes of acting discussed for onabotulinumtoxinA in CM. Therefore, we hypothesized that the response to triptans might predict response to onabotulinumtoxinA. Contrariwise, onabotulinumtoxinA treatment might affect triptan efficacy. 49 CM patients scheduled for their first onabotulinumtoxinA treatment were included. Before (T0) and three months after (T1) onabotulinumtoxinA treatment, patients rated triptan efficacy and indicated number of headache days/month. At T1, patients additionally rated onabotulinumtoxinA efficacy. Headache days/month were on average reduced by 7.1 ± 7.0 days from T0 to T1 (p < 0.001). Triptan efficacy ratings at T0 did not predict onabotulinumtoxinA efficacy ratings at T1 (p = 0.19) or reduction of headache days (p = 0.37). However, triptan efficacy significantly improved from T0 to T1 in onabotulinumtoxinA responders (p < 0.001) but not in non-responders (p = 1.00). Triptan efficacy did not predict response to onabotulinumtoxinA in CM. However, triptan efficacy increased after successful onabotulinumtoxinA treatment. This supports the hypothesis that efficacy of acute migraine treatment with triptans improves with effective migraine prophylaxis.

Diffusion tensor imaging reveals microstructural alteration of the trigeminal nerve root in classical trigeminal neuralgia without neurovascular compression and correlation with outcome after internal neurolysis.

OBJECTIVES: Diffusion tensor imaging (DTI) has been used to detect microstructural alteration and effect of surgical treatment of the trigeminal nerve root (TR) in patients with classical trigeminal neuralgia (CTN) underwent microvascular decompression (MVD). Patients with CTN without neurovascular compression (woNVC) is a special population of TN, however, the pathogenesy of CTN woNVC and the mechanism of internal neurolysis (IN) remain unknown. MATERIALS AND METHODS: 21 patients with CTN woNVC who underwent IN and 20 healthy controls were included in this study. The differences in the means, kurtosis and skewness of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between the affected and unaffected nerves in patients and both nerves in controls were investigated by independent t-test and paired t-test respectively. Longitudinal changes of FA and ADC were correlated with outcome of IN via Spearman correlation coefficient. RESULTS: Significant differences were found in preoperative mean and kurtosis values for both FA and ADC of the affected side TR, compared to the unaffected side and control group respectively. However, these differences remarkably reduced postoperatively. Further, the Spearman correlation coefficient showed a strong negative correlation between decrease of ADC in the affected side and the surgical outcome in BNI total score. CONCLUSION: The changes of diffusive property of TR, especially the FA and ADC, provide alternative radiological evidence for evaluating the mechanism of CTN woNVC. The modification of DTI metrics could be an effective factor for providing potential noninvasive biomarkers for determining the prognosis of patients with CTN woNVC underwent IN.

Gomez-López-Hernández syndrome: A case report with clinical and molecular evaluation and literature review.

Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

Multiple Cranial Nerve Blocks as an Alternative Preventative Therapy for Chronic Migraine.

OBJECTIVE: The objective of this prospective cohort study is to evaluate the efficacy of multiple cranial nerve blocks (MCNBs) as a preventative therapy for chronic migraine. BACKGROUND: MCNBs, namely greater occipital nerve (GON) blocks, are frequently used for the acute and transitional treatment of migraine. There is little evidence on the efficacy of repeated MCNBs as a preventative treatment for chronic migraine. DESIGN: This single-center, prospective cohort study collected demographic and outcome data on chronic migraine patients who had MCNBs in the headache service between June 2017 and March 2019. Outcome measures included reduction in headache days, Headache Impact Test 6 (HIT6) scores and patient-reported effectiveness of the blocks. RESULTS: Outcomes for 64 patients with a diagnosis of chronic migraine or chronic migraine with aura (MWA) were collected. Average age at first block procedure was 41 years (range 21-72) with a female predominance of 54/64 patients (84%). About 37/64 patients (58%) had repetitive occipital nerve blocks only, and 27/64 patients (42%) had occipital and trigeminal nerve blocks. Mean (±SD) reduction in headache days post-MCNBs was 5.4 (±5.0) days and mean (±SD) reduction in HIT6 scores was 5.3 (±10.3). About 42/64 patients (66%) responded to the MCNBs with at least a 30% reduction in headache days. Mean (±SD) duration of effect was 5.7 (±5.4) weeks. About 13/64 of the patients transformed to low-frequency episodic migraine on follow-up. About 22/64 patients (34%) showed no reduction in headache days or HIT6 scores. About 9/112 (8%) instances of minor post block complications were documented with a total of 501 injections. CONCLUSION: This study demonstrates that repetitive MCNBs could provide effective prevention in patients with chronic migraine.

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature.

The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. We have previously demonstrated that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) promotes corneal nerve regeneration; here, we report the mechanism involved and the discovery of a stereospecific Resolvin D6-isomer (RvD6si) that drives the process. RvD6si promotes corneal wound healing and functional recovery by restoring corneal innervation after injury. RvD6si applied to the eye surface elicits a specific transcriptome signature in the trigeminal ganglion (TG) that includes Rictor, the rapamycin-insensitive complex-2 of mTOR (mTORC2), and genes involved in axon growth, whereas genes related to neuropathic pain are decreased. As a result, attenuation of ocular neuropathic pain and dry eye will take place. Thus, RvD6si opens up new therapeutic avenues for pathologies that affect corneal innervation.

Resolvin D1 suppresses inflammation-induced hyperexcitability of nociceptive trigeminal neurons associated with mechanical hyperalgesia.

7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (resolvin D1 [RvD1]) is biosynthesized from docosahexaenoic acid (DHA), and belongs to a novel family of lipid mediators showing remarkable anti-inflammatory effects; however, the effect of RvD1 on inflammation-induced hyperexcitability of nociceptive neurons under in vivo conditions remains to be determined. The present study, therefore, investigated whether under in vivo conditions, systemic administration of RvD1 could attenuate the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis (SpVc) wide-dynamic range (WDR) neurons associated with hyperalgesia in rats. The threshold of escape from mechanical stimulation applied to the orofacial area in rats with complete Freund's adjuvant-induced inflammation was significantly lower than in naïve rats. The lowered mechanical threshold in rats with inflammation was returned to control levels following administration of RvD1 (3 ng/kg, i.p.) for 3 days. The mean discharge frequency of SpVc WDR neurons in rats with inflammation was significantly decreased after RvD1 administration for both non-noxious and noxious mechanical stimuli. Increased spontaneous discharge of SpVc WDR neurons in rats with inflammation was also significantly decreased after RvD1 administration. Noxious pinch-evoked afterdischarge frequency and occurrence in rats with inflammation was significantly diminished after RvD1 administration. Expansion of the receptive field in rats with inflammation also returned to control levels after RvD1 administration. These results suggest that administration of RvD1 attenuates inflammation-induced hyperexcitability of SpVc WDR neurons associated with inflammatory hyperalgesia. These findings support the idea that RvD1, derived from DHA, as well as DHA itself, are potential complementary or alternative therapeutic agents for the alleviation of inflammatory hyperalgesia.

Quantification of Trigeminovascular Hypersensitivity Using Laser Speckle Contrast Analysis in a Patient With Chronic Migraine.

BACKGROUND: Activation of peripheral and/or central trigeminovascular pain pathways are implicated in the pathogenesis of migraine. Small fibers mediate pain, thermal sensation, and autonomic functions. Axon flare response is correlated with local C-fiber activation and calcitonin gene-related peptide release. Laser speckle contrast analysis (LASCA) detects very subtle microcirculatory changes that are not visible to the naked eye. CASE: Axon flare response was elicited by 0.01 mL intradermal (i.d.) histamine introduced to the left forehead, trigeminal nerve ophthalmic branch (V1) skin area. Skin microvascular blood flow data were recorded using a LASCA real-time microcirculation imaging system. In the healthy control, prick stimulus slightly elevated focal skin microcirculation only at the stimulated focal area. However, in our patient with chronic migraine, the unilateral prick stimulation transiently (over 10 to 12 seconds) increased ipsilateral skin microcirculation at all 3 branches of the trigeminal nerve, with a slight expansion across the midline. Left V1 stimulation by i.d. histamine induced not only prominent but also long-lasting (10 to 15 minutes of recording time) axon flare response at the ipsilateral V1, V2, and V3 areas, with an expansion to the contralateral V1 area and without any report of allodynia or hyperalgesia. The treatment decreased axon flare characteristics probably by inhibiting neurogenic inflammation. DISCUSSION: The clinical characteristics and individual response to treatment vary widely across patients with pain. Here, we demonstrated the presence of transient spread of increased microcirculation at the ipsilateral trigeminal nerve, and also across the midline after prick stimulus, whereas a more prominent, widespread, and long-lasting histamine-induced axon flare response occurred in a rare subclass of patient who had chronic migraine with autonomic symptoms. The modulatory effect of the pharmacological intervention has also been objectively quantified by LASCA.

The Influence of Metoclopramide on Trigeminovascular Nociception: Possible Anti-migraine Mechanism of Action.

Metoclopramide is widely used as an abortive migraine therapy due to the advantage of having not only antiemetic, but also analgesic properties. Despite the proven clinical efficacy of metoclopramide in acute migraine, the mechanism of its anti-cephalalgic action has not been entirely elucidated. Taking into account the key role of the trigeminovascular system activation in migraine pathophysiology, we aimed to investigate metoclopramide effects on the excitability of central trigeminovascular neurons and neurogenic dural vasodilation using valid electrophysiological and neurovascular models of trigeminovascular nociception. Extracellular recordings of the activity of second-order dura-sensitive neurons were made in the trigeminocervical complex (TCC) of 16 anaesthetised rats. Cumulative metoclopramide infusion (three steps in 30 min intervals, 5 mg/kg i.v. per step, n = 8) significantly and dose-dependently suppressed both ongoing firing of the TCC neurons and their responses to dural electrical stimulation, maximally to 30%[0-49%] (median[Q1-Q3]) and 4%[0-30%] of the initial level, respectively (both p = 0.001, compared to saline (n = 8)). By contrast, the neurogenic dural vasodilation studied in a separate group of 12 rats was not significantly affected by cumulative infusion of metoclopramide (5 mg/kg i.v. per step, n = 6) compared to both baseline values and the vehicle group (n = 6) (all p > 0.05). These results provide evidence that metoclopramide is unable to affect the peripheral response to trigeminovascular activation, but it does suppress the central response, which is highly predictive of anti-migraine action. Thus, here we show the neurophysiological mechanism underlying the therapeutic efficacy of metoclopramide in migraine.

Trigeminal-Targeted Treatments in Migraine: Is 60% the Magic Number?

Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery.

Photoactivation of olfactory sensory neurons does not affect action potential conduction in individual trigeminal sensory axons innervating the rodent nasal cavity.

Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we explored the influence of olfactory and trigeminal signaling in the nasal cavity. A forced choice water consumption paradigm was used to ascertain whether trigeminal and olfactory stimuli could influence behaviour in mice. Mice avoided water sources surrounded by both volatile TRPV1 (cyclohexanone) and TRPA1 (allyl isothiocyanate) irritants and the aversion to cyclohexanone was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioural effect we recorded from single trigeminal sensory axons innervating the nasal respiratory and olfactory epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in mice expressing channel-rhodopsin (ChR2) under the olfactory marker protein (OMP) promoter. Photoactivation of olfactory sensory neurons produced no modulation of axonal action potential conduction in individual trigeminal axons. Similarly, no evidence was found for collateral branching of trigeminal axon that might serve as a conduit for cross-talk between the olfactory and respiratory epithelium and olfactory dura mater. Using direct assessment of action potential activity in trigeminal axons we observed neither paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the rodent nasal cavity. Our current results suggest that olfactory sensory neurons exert minimal influence on trigeminal signals within the nasal cavity.

(-)-α-Bisabolol reduces nociception and trigeminal central sensitisation in acute orofacial neuropathic pain induced by infraorbital nerve injury.

Neuropathic orofacial pain conditions represent a challenge to diagnose and treat. Natural substances are promising therapeutic options for the control of pain. AIMS: This study aimed to examine whether (-)-α-bisabolol (BISA), a natural terpene, can attenuate nociceptive behaviour and central sensitisation in a rodent model of trigeminal neuropathic pain. MATERIALS AND METHODS: Infraorbital nerve transection (IONX) or sham operation was performed in adult male rats. Head withdrawal thresholds as a measure of facial mechanical sensitivity were tested with von Frey monofilaments applied bilaterally to the facial vibrissal pad pre-operatively (baseline) and then post-operatively before and at 60, 120, 240 and 360 min after administration of vehicle control per oris (p.o.) or BISA (200 mg/kg p.o.) (n = 8/group). Effects of BISA or vehicle on the activity of nociceptive neurons recorded in the medullary dorsal horn (MDH) were tested on post - operative day 8-10. ANOVA followed by post-hoc Bonferroni tested for statistically significant differences (p < 0.05) across study groups and time points. KEY FINDINGS: IONX animals (but not sham or naïve animals) showed post-operative facial mechanical hypersensitivity that was unaffected by vehicle. However, administration of BISA at post-operative day 7 significantly reversed the mechanical hypersensitivity in IONX rats; this effect lasted for at least 6 h. BISA also attenuated IONX-induced central sensitisation of MDH nociceptive neurons, as reflected in reversal of their reduced activation thresholds, increased responses to graded mechanical stimuli and enhanced spontaneous activity. SIGNIFICANCE: BISA may attenuate nociceptive behaviour and central sensitisation in a rat model of acute trigeminal neuropathic pain.

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

PREMISE: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. PROBLEM: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. CONCLUSION: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.