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Allergic rhinitis (AR) is a chronic, non-infectious condition affecting the nasal mucosa, primarily mediated mainly by IgE. Recent studies reveal that AR is intricately associated not only with type 2 immunity but also with neuroimmunity. Nociceptive neurons, a subset of primary sensory neurons, are pivotal in detecting external nociceptive stimuli and modulating immune responses. This review examines nociceptive neuron receptors and elucidates how neuropeptides released by these neurons impact the immune system. Additionally, we summarize the role of immune cells and inflammatory mediators on nociceptive neurons. A comprehensive understanding of the dynamic interplay between nociceptive neurons and the immune system augments our understanding of the neuroimmune mechanisms underlying AR, thereby opening novel avenues for AR treatment modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cong, Lv and Xu.)

Blood-Brain Barrier (BBB) acts as a highly impermeable barrier, presenting an impediment to the crossing of most classical drugs targeted for neurodegenerative diseases including Parkinson's disease (PD). About the nature of drugs and other potential molecules, they impose unavoidable doserestricted limitations eventually leading to the failure of therapy. However, many advancements in formulation technology and modification of delivery approaches have been successful in delivering the drug to the brain in the therapeutic window. The nose to the brain (N2B) drug delivery employing the nanoformulation, is one such emerging delivery approach, overcoming both classical drug formulation and delivery-associated limitations. This latter approach offers increased bioavailability, greater patient acceptance, lesser metabolic degradation of drugs, circumvention of BBB, ample drug loading along with the controlled release of the drugs. In N2B delivery, the intranasal (IN) route carries therapeutics firstly into the nasal cavity followed by the brain through olfactory and trigeminal nerve connections linked with nasal mucosa. The N2B delivery approach is being explored for delivering other biologicals like neuropeptides and mitochondria. Meanwhile, this N2B delivery system is associated with critical challenges consisting of mucociliary clearance, degradation by enzymes, and drug translocations by efflux mechanisms. These challenges finally culminated in the development of suitable surfacemodified nano-carriers and Focused- Ultrasound-Assisted IN as FUS-IN technique which has expanded the horizons of N2B drug delivery. Hence, nanotechnology, in collaboration with advances in the IN route of drug administration, has a diversified approach for treating PD. The present review discusses the physiology and limitation of IN delivery along with current advances in nanocarrier and technical development assisting N2B drug delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives/hypothesis: To assess the long-term (12-24 months) safety and effectiveness of cryoablation of the posterior nasal nerve as treatment for chronic rhinitis., Study Design: A multicenter, prospective, single-arm clinical study., Methods: The study was conducted from February 2017 to April 2020. Study endpoints included change from baseline in the reflective Total Nasal Symptom Score (rTNSS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), physician assessment of improvement using the Clinical Global Impression-Improvement (CGI-I), and the incidence of treatment-related adverse events., Results: Ninety-one participants completed the study through the initial 12-month study period. Sixty-two participants consented to the long-term follow-up with 57 completing the 24-month follow-up. Significant improvements in the total rTNSS were reflected in a median change from baseline of -3.0 or -4.0 at all timepoints (P < .001). Greater than 80.0% of participants achieved the minimum clinically important difference (MCID) of improvement by ≥1 point on the rTNSS at all follow-ups. Total RQLQ scores indicated significant improvement (P < .0001) in quality of life. Over 77% of participants achieved the MCID (≥0.5 points) for the total RQLQ score. According to the CGI-I, ≥83.0% experienced improvement at all but the 12-month visit (61.9%). One participant experienced two treatment-related serious adverse events (epistaxis and retained pledget). A total of 29 nonserious treatment-related AEs were reported in 23 participants; most events were transient and resolved with little to no intervention., Conclusions: Cryotherapy significantly and clinically improves rhinitis symptoms and quality of life with outcomes that are durable through 24 months after treatment., Level of Evidence: 4 Laryngoscope, 131:1952-1957, 2021., (© 2021 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Solitary chemosensory cells and chemosensory cell clusters are distributed in the pharynx and larynx. In the present study, the morphology and reflexogenic function of solitary chemosensory cells and chemosensory cell clusters in the nasal cavity and pharynx were examined using immunofluorescence for GNAT3 and electrophysiology. In the nasal cavity, GNAT3-immunoreactive solitary chemosensory cells were widely distributed in the nasal mucosa, particularly in the cranial region near the nostrils. Solitary chemosensory cells were also observed in the nasopharynx. Solitary chemosensory cells in the nasopharyngeal cavity were barrel like or slender in shape with long lateral processes within the epithelial layer to attach surrounding ciliated epithelial cells. Chemosensory cell clusters containing GNAT3-immunoreactive cells were also detected in the pharynx. GNAT3-immunoreactive cells gathered with SNAP25-immunoreactive cells in chemosensory clusters. GNAT3-immunoreactive chemosensory cells were in close contact with a few SP- or CGRP-immunoreactive nerve endings. In the pharynx, GNAT3-immunoreactive chemosensory cells were also attached to P2X3-immunoreactive nerve endings. Physiologically, the perfusion of 10 mM quinine hydrochloride (QHCl) solution induced ventilatory depression. The QHCl-induced reflex was diminished by bilateral section of the glossopharyngeal nerve, suggesting autonomic reflex were evoked by chemosensory cells in pharynx but not in nasal mucosa. The present results indicate that complex shape of nasopharyngeal solitary chemosensory cells may contribute to intercellular communication, and pharyngeal chemosensory cells may play a role in respiratory depression., (© 2021 Anatomical Society.)

Purpose: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain., Methods: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation. Outcome measures included objective change in tear volume measured via phenol red test, and subjective change in sensations of dryness and ocular pain measured on a 0-10 Numerical Rating Scale., Results: The mean age of the 75 individuals was 59±13 years, and the majority were male (73%). Intranasal neurostimulation increased tear volume (mean 13.40±8.00 mm, p<0.0005) and reduced intensities of dryness (mean -2.85±2.79, p<0.0005) and ocular pain (mean -1.48±2.41, p<0.0005 for both). However, these effects were independent of one another as change in symptom report did not correlate with change in tear volume (r=-0.13, p=0.25 for dryness; r=0.07, p=0.56 for pain). In a multivariable model, the strongest predictors for increased tear volume were lower baseline tear volume (standardised beta (β)=-0.50, p<0.0005) and absence of an autoimmune disease (β=-0.36, p=0.001) (R 2 =0.30). The strongest predictors for reduced dryness and pain scores were lower baseline dryness and ocular pain scores. No complications related to neurostimulation were noted., Conclusion: Intranasal neurostimulation increased tear volume and reduced intensities of dryness and ocular pain, independently of one another., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Posterior nasal nerve (PNN) surgery, Radiofrequency (RF), and cryoablation have been described as alternative treatments for allergic and vasomotor rhinitis. We hypothesize that endoscopic (diode) laser ablation (ELA) is effective and less invasive than previously described methods., Methods: An IRB approved prospective study was performed. Thirty-two patients with chronic rhinitis and nasal congestion resistant to medical management were recruited. Total Nasal Symptom Score (TNSS) measurements were used to assess symptom severity and treatment outcomes. ELA was performed bilaterally in the clinic with a 940 nm diode laser with CW 5 W output, under topical/local anesthesia in 21 patients, while the remaining 11 were treated under sedation in the operating room. The 400-micron uninitiated diode laser fiber tip with a malleable protective shaft was specially designed for PNN ablation. The fiber was pre-shaped according to the intranasal anatomy and endoscopically advanced toward the posterior middle meatus. Patients were followed up for the first 90 days after treatment., Results: ELA was successfully completed in 97% of patients. No crusting, epistaxis, or other complications were observed. One patient could not be treated in the office due to limited endoscopic access. TNSS was reduced significantly after30 and 90 days (mean ± SD: 6.0 ± 0.7 prior to ablation, 2.3 ± 0.4 at 90 days, p < .001). Rhinitis and congestion scores decreased at 30 and 90 days after treatment compared to the baseline (p < .001)., Conclusion: ELA of the PNN region is safe and well tolerated both in the office and ambulatory settings. Symptom scores were significantly decreased after 30 and 90 days. This new minimally invasive method appears to be a promising treatment method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Recent guidelines have revealed that allergic rhinitis (AR) impairs quality of life. Neuropeptides play a central role in AR. The aim of this study was to determine the efficacy of posterior nasal neurectomy (PNN) for the treatment of AR and for the suppression of neuropeptides and type 2 cytokine expression., Methods: In total, 77 patients undergoing PNN were recruited. Subjective symptoms, including sneezing and rhinorrhea, were elicited with a questionnaire using a 10 cm visual analogue scale (VAS). Nasal lavage fluid taken from a random sample of 17 patients both preoperatively and 1 year postoperatively was screened with enzyme-linked immunosorbent assays., Results: Postoperative rhinorrhea (6.03 ± 1.31vs 2.12 ± 1.40, P < 0.001) and sneezing (5.53 ± 1.25vs 2.04 ± 1.29, P < 0.001) were significantly improved relative to the preoperative levels; the mean SP and NPY concentrations in the nasal lavage fluid were 91.6 ± 20.9 pg/ml and 71.5 ± 10.5 pg/ml, which decreased significantly to 52.9 ± 16.7 pg/ml and 31.8 ± 8.2 pg/ml, respectively, and the mean periostin and IL-5 concentrations were 215.2 ± 87.7 pg/ml and 984.5 ± 181.8 pg/ml, which decreased significantly to 146.1 ± 70.1 pg/ml and 281.6 ± 74.0 pg/ml, respectively., Conclusions: PNN was safe and well tolerated, and the symptom (sneezing and rhinorrhea) scores were significantly decreased by 1 year postoperatively., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background: Posterior nasal nerve (PNN) cryoablation is a novel surgical technique to address allergic and nonallergic rhinitis. Periprocedural pain has been reported after PNN cryoablation and there are no standardized protocols for optimal in-office local anesthesia. This study sought to evaluate the effect of gabapentin on patient discomfort following in-office PNN cryoablation., Methods: Multi-institutional prospective analysis of patients undergoing in-office PNN cryoablation for allergic or nonallergic rhinitis between March 2018 and April 2019. Patients received local anesthesia with or without 600 mg oral gabapentin 1 hour preprocedure. Rhinitis diagnosis, demographics, and baseline disease-specific quality of life (mini-Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ] and Total Nasal Symptom Score [TNSS]) were recorded. Patient discomfort was measured by the pain visual analogue scale (VAS) posttreatment and rated 0 to 10 on an ordinal scale. Fisher's exact and Wilcoxon 2-sample tests were used to evaluate differences between the 2 groups., Results: A total of 26 patients were enrolled (gabapentin n = 15, control = 11). Baseline TNSS scores in the gabapentin vs control group were median [25th percentile to 75th percentile]) 10 (7.5 to 11.0) and 9 (6.0 to 10.0) (p = 0.35). Baseline Mini-RQLQ scores in gabapentin vs control groups were 3.21 (2.0 to 4.0) and 2.92 (2.78 to 4.35) (p = 0.51). The median VAS pain scores at 5, 20, and 30 minutes in the gabapentin vs control group were 0.0 (0.0 to 2.0) vs 3.0 (1.0 to 4.0), 2.0 (0.0 to 3.0) vs 8.0 (6.0 to 10.0), and 1.0 (0.0 to 1.0) vs 5.0 (4.0 to 6.0) (p = 0.02, p = 0.0043, and p = 0.003, respectively)., Conclusion: Preprocedure gabapentin significantly reduces immediate and delayed postprocedural patient discomfort following PNN cryoablation., (© 2019 ARS-AAOA, LLC.)

Purpose: We assess the safety and effectiveness of intranasal neurostimulation to promote tear production via the nasolacrimal pathway in subjects with dry eye disease., Methods: A multicenter, randomized, controlled, double-masked pilot study was conducted in adults with dry eye diagnosis and at least one eye with corneal fluorescein staining ≥2 in at least one region or a sum of all regions ≥5 (National Eye Institute grading), basal Schirmer test score ≤10 mm, a cotton-swab stimulated Schirmer score ≥7 mm higher, and an Ocular Surface Disease Index score ≥23. Subjects were randomized to receive active intranasal neurostimulation or sham control intranasal stimulation 4 to 8 times per day. Assessments were scheduled before (unstimulated) and during (stimulated) device application at days 0, 7, 14, 30, and 90. The primary effectiveness endpoint was stimulation-induced change in Schirmer test (with anesthesia) score. Primary safety measure was incidence of device-related adverse events (AEs)., Results: Fifty-eight subjects were randomized at nine sites in Australia and New Zealand; 56 completed the 90-day study. Stimulation-induced change in Schirmer score was significantly greater with active intranasal (mean ± SEM, 9.0 ± 2.0) than sham control intranasal stimulation (0.4 ± 0.6; P < 0.001) at day 90. Similar results were observed at days 0, 7, 14, and 30 (P < 0.001). No serious device-related AEs were observed. Mild nosebleed, the most common device-related AE, was reported in five (16.7%) subjects., Conclusions: Intranasal neurostimulation was effective in inducing acute tear production after 90 days of use and generally was well tolerated in subjects with dry eye disease.

Purpose: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED)., Methods: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) ≤10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index ® ≥13 and ≥ 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for ≤3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs)., Results: Study 1: Schirmer scores (mean ± SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 ± 1.5 mm) vs extranasal (9.5 ± 1.2 mm) and sham (9.2 ± 1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 ± 1.3 mm vs 7.9 ± 0.7 mm). No serious device-related AEs were reported in either study., Conclusion: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS., Gov Identifier: NCT02680158 and NCT02526290., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuromodulation is a novel approach that utilizes electrical signals, pharmaceutical agents, or other forms of energy to modulate abnormal neural function through neurostimulation. Neurostimulation is a novel technique that uses electrical currents to stimulate the nervous system. During the recent few decades, neuromodulation has gained significant attention, in particular for the treatment of chronic neurological diseases, due to its success in treating patients unresponsive to conventional pharmacological therapies. Dry eye disease (DED) is a chronic, multifactorial disease that affects millions of people worldwide. Recent data have demonstrated that neurosensory abnormalities contribute to the pathogenesis of DED. Current mainstays of dry eye therapy include lubrication, tear retention, and anti-inflammatory therapies, among others. The recent development of intranasal neurostimulation therapy for DED utilizes the nasolacrimal reflex as an alternative pathway, not only to increase tear production via increased lacrimation, but also to target other tear film components, such as mucin and meibum secretion, promoting tear film homeostasis. This review aims to describe the different types of neuromodulation devices available and their application for non-ocular diseases, as well as to review recent advances and literature on ocular neurostimulation., (Copyright © 2018. Published by Elsevier Inc.)

In response to stimulation of the nasal passages with volatile ammonia vapors, the nasopharyngeal reflex produces parasympathetically mediated bradycardia, sympathetically mediated increased peripheral vascular tone, and apnea. The anterior ethmoidal nerve (AEN), which innervates the anterior nasal mucosa, is thought to be primarily responsible for providing the sensory afferent signals that initiate these protective reflexes, as bilateral sectioning causes an attenuation of this response. However, recent evidence has shown cardiovascular responses to nasal stimulation with ammonia vapors are fully intact 9 days after bilateral AEN sectioning, and are similar to control animals without bilaterally sectioned AENs. To investigate this restoration of the nasopharyngeal response, we recorded the cardiorespiratory responses to nasal stimulation with ammonia vapors immediately after, and 3 and 9 days after, bilateral AEN sectioning. We also processed brainstem tissue for Fos to determine how the restoration of the nasopharyngeal response would affect the activity of neurons in the medullary dorsal horn (MDH), the part of the ventral spinal trigeminal nucleus caudalis region that receives primary afferent signals from the nose and nasal passages. We found 3 days after bilateral AEN sectioning the cardiorespiratory responses to nasal stimulation are partially restored. The bradycardic response to nasal stimulation is significantly more intense 3 days after AEN sectioning compared to Acute AEN sectioning. Surprisingly, 3 days after AEN sectioning the number of Fos-positive neurons within MDH decreased, even though the cardiorespiratory responses to nasal stimulation intensified. Collectively these findings indicate that, besides the AEN, there are alternate sensory pathways that can activate neurons within the trigeminal nucleus in response to nasal stimulation. The findings further suggest trigeminal neuronal plasticity involving these alternate sensory pathways occurs in as few as 3 days after bilateral AEN sectioning. Finally, activation of even a significantly reduced number of MDH neurons is sufficient to initiate the nasopharyngeal response., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Neuropeptides, such as substance P (SP), have long been seen as mediators of widespread continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules., Objectives: We sought to examine the role of SP in nasal infection by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, with the latter reflected in changes in local Toll-like receptor (TLR) expression., Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy., Results: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation., Conclusions: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Interessenkonflikt: Erstautorin Haneen Sadick erklärt, innerhalb der letzten 3 Jahre Forschungsunterstützung von der Firma Spirox Inc., Menlo Park, CA, USA erhalten zu haben.Letztautor Holger G. Gassner erklärt, dass innerhalb der letzten 3 Jahre keine Interessenkonflikte bestehen.

Background: The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) induces denervation of the nasal mucosa and relieves the nasal symptoms of intractable rhinitis. PNN depletes nerve fibers, choline acetyltransferase, and neuropeptides in nasal respiratory mucosa, and reduces nasal secretion. However, the histological and symptomatic changes over an extended period after PNN remain unknown., Methods: Using a rat model of PNN via the transorbital approach, we investigated chronological changes of nasal morphology, innervation, and secretion over a 48-week postoperative period after PNN., Results: The respiratory nasal mucosa exhibited squamous metaplasia, lymphocyte and plasma cell infiltration, basement membrane thickening, loss of cilia, and hyperplasia of the mucus gland in thickened epithelium with increased connective tissue from 24 weeks after PNN. These changes resemble the characteristics of remodeling in chronic rhinosinusitis. DNA microarray and quantitative polymerase chain reaction analysis revealed that mucin 5ac, interleukin 13, and brain-derived neurotrophic factor messenger RNA (mRNA) were upregulated in PNN-treated mucosa compared to untreated mucosa. During this period, nerve fibers including sensory, sympathetic, and parasympathetic fibers gradually reinnervated the mucosa from 12 weeks after PNN. However, nasal secretion was decreased even at 48 weeks after PNN probably due to the prolonged absence of choline acetyltransferase., Conclusion: Prolonged denervation induces remodeling of the nasal mucosa. Although the depleted nerves were partially reinnervated a few months after PNN, nasal secretion was still suppressed, partly due to a sustained deficiency of acetylcholine synthesis., (© 2017 ARS-AAOA, LLC.)

Background: The convoluted pathophysiology of brain disorders along with penetration issue of drugs to brain represents major hurdle that requires some novel therapies. The blood-brain barrier (BBB) denotes a rigid barrier for delivery of therapeutics in vivo; to overcome this barrier, intranasal delivery is an excellent strategy to deliver the drug directly to brain via olfactory and trigeminal nerve pathways that originate as olfactory neuro-epithelium in the nasal cavity and terminate in brain., Method: Kind of therapeutics like low molecular weight drugs can be delivered to the CNS via this route. In this review, we have outlined the anatomy and physiological aspect of nasal mucosa, certain hurdles, various strategies including importance of muco-adhesive polymers to increase the drug delivery and possible clinical prospects that partly contribute in intranasal drug delivery., Results: Exhaustive literature survey related to intranasal drug delivery system revealed the new strategy that circumvents the BBB, based on non-invasive concept for treating various CNS disorders. Numerous advantages like prompt effects, self-medication through wide-ranging devices, and the frequent as well protracted dosing are associated with this novel route., Conclusion: Recently few reports have proven that nasal to brain drug delivery system bypasses the BBB. This novel route is associated with targeting efficiency and less exposure of therapeutic substances to non-target site. Nevertheless, this route desires much more research into the safe transferring of therapeutics to the brain. Role of muco-adhesive polymer and surface modification with specific ligands are area of interest of researcher to explore more about this., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) is thought to induce denervation of the nasal mucosa and relieve the nasal symptoms of allergic rhinitis. However, the underlying mechanisms and therapeutic action of PNN remain unknown. To investigate the impact of PNN-induced denervation of the nasal mucosa on allergic rhinitis, we developed a rat model of PNN and examined the effects of PNN on allergic rhinitis in ovalbumin-sensitized rats. This rat model of PNN was characterized by the depletion of nerve fibers, choline acetyltransferase, and neuropeptides (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y) in the nasal respiratory mucosa. These animals exhibited nasal gland and goblet cell hypertrophy in the septal mucosa and atrophy of the submucosal gland in the lateral nasal wall, as well as reduced nasal secretion due to deficient acetylcholine synthesis. In an ovalbumin-sensitized model of allergic rhinitis, PNN also induced the depletion of nerve fibers, choline acetyltransferase, and neuropeptides in the nasal mucosa and suppressed nasal secretion. However, PNN did not affect mucosal thickening, eosinophil and mast cell infiltration, interleukin-4 and interferon-γ mRNA expression, and allergic symptoms (ie, sneezing and nasal scratching). These results suggest that the peripheral nerves and corresponding neuropeptides regulate nasal secretion, but not hypersensitivity, in allergic rhinitis, and that allergic rhinitis-related mucosal reactions occur in a highly denervated mucosa after PNN. Posterior nasal neurectomy may be a therapeutic option for the treatment of hyperrhinorrhea, but not allergic rhinitis hypersensitivity.

Objectives: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR., Methods: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR., Results: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs., Conclusions: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR., (© 2016 S. Karger AG, Basel.)

Background: The transient receptor potential channel melastatin 8 (TRPM8) has been proposed to be a cold receptor. However, its distribution and physiologic role in the nose is not yet fully explored., Objective: We investigated the expression of TRPM8 in human nasal mucosa and its function when using the TRPM8 agonist., Methods: Immunohistochemistry was used to study TRPM8 receptors in the nasal mucosa from patients with and those without allergic rhinitis (AR). By using isometric contraction studies, we also tested the effectiveness of the TRPM8 agonist menthol on nasal mucosa. Changes in nasal mucosal contractility in response to the application of the adrenergic agent methoxamine were also measured. We explored the effect of menthol on electrical field stimulation (EFS) induced nasal mucosal contractions., Results: TRPM8 immunoreactivity was present principally in the nasal cilia, epithelium, and subepithelium around the glands. Except for nerve fibers, no obvious TRPM8-immunoreactive cells were detected in connective tissues. The immunoreactivity revealed no significant difference between patients with AR and those without AR. Adding menthol had a negligible effect on the basal tension of the nasal mucosa, but higher doses of menthol had a significant spasmolytic effect on nasal mucosa precontracted with methoxamine. Menthol inhibited the spike contraction induced by EFS, even at low doses., Conclusions: The finding of the TRPM8 immunoreactivity underlines the important physiologic role of the nose in temperature regulation, both in patients with allergy and those without allergy. Isometric contraction studies demonstrate the role of TRPM8 in regulating nasal patency and airway resistance. The antiadrenergic effect of menthol showed an effect apparently opposite that of clinical observations, that we usually feel decongested after menthol inhalation. The underlying mechanisms deserve further investigation, and the TRPM8 antagonists deserve consideration for treatment of rhinitis in a therapeutic trial.

Objectives/hypothesis: To review current knowledge on nasal airflow sensation in relation to empty nose syndrome (ENS)., Study Design: PubMed searches., Methods: Current literature pertaining to measurement of nasal patency, mechanism of sensory perception of nasal airflow, and ENS., Results: A reliance on pure anatomical analysis of the anatomy in ENS falls short of explaining the disorder. Our understanding of subjective nasal sensation has advanced, as has our understanding of the flow of air through the nose. Neural healing following a surgical insult may not result in a return to a normal physiologic state. Aberrations in neurosensory systems from improper healing may play a major role in the abnormal sensations ENS patients experience., Conclusions: An evidence-based hypothesis for the development and symptoms of ENS is offered., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

We analyzed the expression of G protein α subunits and the axonal projection into the brain in the olfactory system of the semiaquatic newt Cynops pyrrhogaster by immunostaining with antibodies against Gαolf and Gαo , by in situ hybridization using probes for Gαolf , Gαo , and Gαi2 , and by neuronal tracing with DiI and DiA. The main olfactory epithelium (OE) consists of two parts, the ventral OE and dorsal OE. In the ventral OE, the Gαolf - and Gαo -expressing neurons are located in the apical and basal zone of the OE, respectively. This zonal expression was similar to that of the OE in the middle cavity of the fully aquatic toad Xenopus laevis. However, the Gαolf - and Gαo -expressing neurons in the newt ventral OE project their axons toward the main olfactory bulb (MOB) and the accessory olfactory bulb (AOB), respectively, whereas in Xenopus, the axons of both neurons project solely toward the MOB. In the dorsal OE of the newt, as in the principal cavity of Xenopus, the majority of the neurons express Gαolf and extend their axons into the MOB. In the vomeronasal organ (VNO), the neurons mostly express Gαo . These neurons and quite a few Gαolf -expressing neurons project their axons toward the AOB. This feature is similar to that in the terrestrial toad Bufo japonicus and is different from that in Xenopus, in which VNO neurons express solely Gαo , although their axons invariably project toward the AOB. We discuss the findings in the light of diversification and evolution of the vertebrate olfactory system., (© 2014 Wiley Periodicals, Inc.)

The intricate pathophysiology of brain disorders, difficult access to the brain, and the complexity and high risks and costs of drug development represent major hurdles for improving therapies. Nose-to-brain drug transport offers an attractive alternative or addition to formulation-only strategies attempting to enhance drug penetration into the CNS. Although still a matter of controversy, many studies in animals claim direct nose-to-brain transport along the olfactory and trigeminal nerves, circumventing the traditional barriers to CNS entry. Some clinical trials in man also suggest nose-to-brain drug delivery, although definitive proof in man is lacking. This review focuses on new nasal delivery technologies designed to overcome inherent anatomical and physiological challenges and facilitate more efficient and targeted drug delivery for CNS disorders.

Objective: Endoscopic microdebrider-assisted inferior turbinoplasty (EMAIT) has been recognized as an efficient surgical technique in the management of hypertrophied inferior turbinate. In an attempt to further increase surgical successful outcomes, posterior nasal neurectomy (PNN) was developed. The aim of this retrospective case-control study was to assess the position of PNN in the surgery of hypertrophied turbinate., Methods: Seventy patients were assigned to the two treatment groups: Group A (EMAIT) and Group B (EMAIT and PNN). Subjective outcomes were represented by symptom score and quality of life scores (Rhinoconjunctivitis Quality of Life Questionnaire - RQLQ). Objective outcomes were nasal resistance, saccharin transit time and acoustic rhinometry parameters., Results: The survey demonstrated that symptoms and objective parameters improved postoperatively in both groups, with no statistical significant differences in objective and subjective outcomes between the surgical groups., Conclusion: The addition of PNN appears to offer no additional benefit in the subjective and objective outcome related with surgery of hypertrophied inferior turbinate. However, longer follow-up studies and larger number of patients are required in order to validate our results., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Fragaria chiloensis (L.) Mill spp. chiloensis form chiloensis, is a strawberry that produces white fruits with unique aromas. This species, endemic to Chile, is one of the progenitors of Fragaria x ananassa Duch. In order to identify the volatile compounds that might be responsible for aroma, these were extracted, and analyzed by gas chromatography-mass spectrometry (GC-MS), gas chromatography-olfactometry (GC-O) and compared with sensory analyses., Results: Three methods of extraction were used: solvent-assisted evaporation (SAFE), headspace solid phase micro-extraction (HS-SPME) and liquid-liquid extraction (LLE). Ninety-nine volatile compounds were identified by GC-MS, of which 75 showed odor activity using GC-O. Based on the highest dilution factor (FD = 1000) and GC-O intensity ≥2, we determined 20 major compounds in white strawberry fruit that contribute to its aroma. We chose 51 compounds to be tested against their commercial standards. The identities were confirmed by comparison of their linear retention indices against the commercial standards. The aroma of white strawberry fruits was reconstituted with a synthetic mixture of most of these compounds., Conclusion: The volatile profile of white strawberry fruit described as fruity, green-fresh, floral, caramel, sweet, nutty and woody will be a useful reference for future strawberry breeding programs., (© 2013 Society of Chemical Industry.)

The nervus terminalis (NT; terminal nerve) was clearly identified as an additional cranial nerve in humans more than a century ago yet remains mostly undescribed in modern anatomy textbooks. The nerve is referred to as the nervus terminalis because in species initially examined its fibers were seen entering the brain in the region of the lamina terminalis. It has also been referred to as cranial nerve 0, but because there is no Roman symbol for zero, an N for the Latin word nulla is a better numerical designation. This nerve is very distinct in human fetuses and infants but also has been repeatedly identified in adult human brains. The NT fibers are unmyelinated and emanate from ganglia. The fibers pass through the cribriform plate medial to those of the olfactory nerve fila. The fibers end in the nasal mucosa and probably arise from autonomic/neuromodulatory as well as sensory neurons. The NT has been demonstrated to release luteinizing-releasing luteinizing hormone and is therefore thought to play a role in reproductive behavior. Based on the available evidence, the NT appears to be functional in adult humans and should be taught in medical schools and incorporated into anatomy/neuroanatomy textbooks., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Introduction: The blood-brain barrier (BBB) represents a stringent barrier for delivery of neurotherapeutics in vivo. An attempt to overcome this barrier is represented by the direct transport of drugs from the nose to the brain along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain. An enormous range of neurotherapeutics, both macromolecules and low molecular weight drugs, can be delivered to the central nervous system (CNS) via this route., Areas Covered: Present review highlights the literature on the anatomy-physiology of the nasal cavity, pathways and mechanisms of neurotherapeutic transport across nasal epithelium and their biofate and various strategies to enhance direct nose to brain drug delivery. The authors also emphasize a variety of drug molecules and carrier systems delivered via this route for treating CNS disorders. Patents related to direct nose to brain drug delivery systems have also been listed., Expert Opinion: Direct nose to brain drug delivery system is a practical, safe, non-invasive and convenient form of formulation strategy and could be viewed as an excellent alternative approach to conventional dosage forms. Existence of a direct transport route from the nasal cavity to the brain, bypassing the BBB, would offer an exciting mode of delivering neurotherapeutic agents.

Background and Purpose: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis., Experimental Approach: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined., Key Results: SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03-1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ∼50% at 10 mg·kg⁻¹ (oral), non-micronized 10 mg·mL⁻¹ or 1 mg·mL⁻¹ micronized SB-705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB-705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg·mL⁻¹, intranasal) inhibited 10% hypertonic saline responses by 70%., Conclusions and Implications: The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin-induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB-705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis., (© 2013 GlaxoSmithKline. British Journal of Pharmacology © 2013 The British Pharmacological Society.)

In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n=12), seasonal allergic rhinitis (n=7) and controls (n=10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty fourhours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist., Methods: Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension. The affinity and functional activity of compound B for α2C-adrenoceptors were determined by binding analysis and the ability of compound B to stimulate [(35)S]GTPγS binding to the receptors. Compound B was also tested in a postjunctional α2C-adrenoreceptor bioassay., Results: EFS-induced contractions were partly blocked by the α2-adrenoreceptor antagonist yohimbine (41.1%) and the α2C-adrenoreceptor antagonist JP-1302 had no effect. The α2-adrenoreceptor agonist clonidine, but not compound B, exerted a significant blockade (70.6%). Compound B had high affinity (K(i) = 18 nM), produced potent agonist (EC50 = 279 nM) and good efficacy (E(max) = 73%) responses at the α2C-adrenoceptors, and displayed good functional agonist potency in the human saphenous vein α2C-adrenoreceptor bioassay (pD2 = 6.2)., Conclusion: (1) Neurogenic vasomotor contractility is largely regulated through an α-adrenergic mechanism; (2) pig nasal mucosa possesses post- and prejunctional α2-adrenoceptors; (3) the α2C-adrenoreceptor subtype does not seem to be involved; and (4) compound B is a novel, highly selective, and potent α2C-adrenoreceptor agonist.

Physiological investigation of olfactory receptor function in hyposmic or anosmic patients is rare. Pioneers examined the electro-olfactogram in patients with olfactory disturbance. Although the electro-olfactogram is an established method to record olfactory responses from human olfactory epithelium, the response is only measured at specific sites of the olfactory mucosa. In contrast to that the response of the olfactory epithelium to chemosensory stimuli can be studied in a specific nasal area by means of intrinsic optical signal recording. Five functionally anosmic patients were included in the present study. In all patients, responses could be obtained following trigeminal stimulation with CO2. In some patients, responses could be obtained after olfactory stimulation with H2S and PEA. The present data show that in the studied patients trigeminal function seems to be preserved, while it appears that in some patients olfactory function is preserved to a certain degree.

Objective: Transnasal resection of the posterior nasal nerve (TRPN) is the surgical procedure for drug therapy-resistant, intractable allergic rhinitis (AR). Submucous inferior turbinectomy also improves nasal symptoms in severe AR. Surgical injury to this peripheral nerve fibre may be the major cause of the decrease in allergic symptoms. During submucous turbinectomy, we have identified the peripheral branches of the posterior nasal nerve in the inferior turbinate and resected them (SRPN). The aim of this study was to evaluate the therapeutic effects of turbinoplasty with SRPN in severe AR., Methods: Improvements in subjective symptoms were compared between 13 patients who underwent SRPN with turbinoplasty (Group 1) and 11 who underwent TRPN combined with turbinoplasty and SRPN (Group 2) by retrospective chart review. Pre- and postoperative sneezing, rhinorrhea, and nasal obstruction were evaluated with questionnaires. Postoperative complications and drug therapy before and after surgery were investigated., Results: All symptoms improved postoperatively in both groups, with no significant differences in the improvements in nasal symptom scores between the groups., Conclusions: SRPN combined with submucosal turbinectomy was shown to be a safe, useful, and efficient approach to patients with AR unresponsive to medical therapy. Although this is a short-term study, the results of this study suggest that SRPN represents one of the treatment options for intractable AR., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by the nociceptive sensory nerve and are involved in blood flow, pain and inflammation in the nasal mucosa. The purpose of this study was to assess the distribution of the SP and CGRP nerve fibres related to blood supply within human Schneiderian membrane of the maxillary sinus (MS)., Material and Methods: In this study, the MS from Japanese cadavers was examined by whole-mount immunohistochemistry. Human male cadavers (ranging in age from 80 to 90 years) were used in this study., Results: SP- and CGRP-positive fibres were found around large vessels of the medialis superior alveolar branches and also within the floor region of the MS. The floor region of the MS was composed of complex branches of these fibres., Conclusion: Our results give useful information for surgical sinus floor elevation in this region of the MS. These anatomical features may assist in the execution of a successful surgical procedure., (Copyright © 2011 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Vasomotor rhinitis (VMR) is a commonly encountered entity that may be difficult to diagnose. The classic symptoms are clear rhinorrhea and nasal congestion, commonly brought on by exercise, stress, heat, cold, and environmental irritants. The diagnosis is one of exclusion, and management usually involves avoidance of inciting agents and treatment with an anticholinergic nasal spray. We describe a case of VMR in a 22-year-old woman who presented with symptoms of clear, left-sided rhinorrhea and epiphora that had begun shortly after a motor vehicle accident approximately 1.5 years earlier, but which she had not reported at that time. The patient's left carotid canal had been fractured and the surrounding sympathetic plexus injured in the accident, resulting in an overactive parasympathetic system. Both exercise and heat exacerbated her symptoms. Allergy was excluded by negative allergy testing, and the patient did not respond to fluticasone nasal spray. Given the mechanism of injury, the unilaterality of symptoms, and the patient's lack of response to nasal steroids, it was thought that the VMR was due to the earlier traumatic injury, which had resulted in imbalance of the autonomic neural input. A trial of ipratropium was given to directly treat the parasympathetic overactivity. This treatment resulted in immediate improvement in both the nasal and lacrimal secretions.

Background: Previous investigations in humans suggest topographical differences in intranasal trigeminal chemosensitivity with the highest sensitivity in the anterior part. The present study aimed to investigate whether different sites in the human nasal mucosa react differently to unspecific electrical stimuli., Methodology: Participants were 50 young, healthy volunteers (24 men, 26 women; age 22-38 years). Detection and pain threshold of electrical trigeminal stimuli were investigated at 5 different sites: anterior septum, posterior septum, inferior turbinate, middle turbinate and anterior lateral wall., Results: In healthy subjects, a significantly higher trigeminal sensitivity was found at the anterior parts of the nose compared to the posterior part. There was a similar distribution pattern of the sensitivity for detection and pain thresholds., Conclusions: Results suggest that there are consistent topographical differences in the arrangement of trigeminal receptors of the human nasal cavity; highest somatosensory sensitivity seems to be located in the anterior part. This finding is compatible with the idea that the trigeminal system acts as a sentinel of the human airways with regard to toxic agents.

Non-allergic rhinitis (NAR) is a common disorder, which can be defined as chronic nasal inflammation, independent of systemic IgE-mediated mechanisms. Symptoms of NAR patients mimic those of allergic rhinitis (AR) patients. However, AR patients can easily be diagnosed with skin prick test or allergen-specific IgE measurements in the serum, whereas NAR patients form a heterogeneous group and are difficult to diagnose because of an extensive list of different phenotypes, all varying in severity, underlying etiology and type of inflammation. Characterization of those phenotypes, mechanisms and management of NAR represents one of the major unmet needs in the field of allergic and non-allergic diseases. This review aims at providing a comprehensive overview of the state of the art in classifying the NAR patients and focuses on the neuro-immune mechanisms involved in allergic and non-allergic rhinitis, including reflections on the pathophysiology and the currently available treatment options.

Conclusions: The olfactory and intranasal trigeminal systems are closely connected. With regard to intranasal trigeminal event-related potential (ERP), patients with olfactory dysfunction (OD) showed longer latency and lower amplitude, which indicated decreased trigeminal sensitivity. Different age, etiology, and olfactory status also affect trigeminal sensitivity differently., Objective: OD is a common symptom in the rhinology clinic. ERP is considered an important method to evaluate chemosensitivity. The aim of this study was to investigate changes of intranasal trigeminal sense in patients with postviral OD (PVOD) and post-traumatic OD (PTOD)., Methods: A total of 96 participants (30 healthy adults and 66 patients with OD) aged 20-65 years were investigated. The T&T olfactometer, the Sniffin' Sticks olfactory test, and trigeminal ERPs (tERPs) were used. We evaluated trigeminal sensitivity influenced by different factors (age, etiology, and olfactory status) in healthy subjects with normal olfactory function and in patients with PVOD and PTOD., Results: Patients with OD showed higher trigeminal thresholds than normal controls. Compared with controls, N1/P2 latencies of tERPs increased and amplitudes decreased in patients with OD. Older subjects showed longer latencies and lower amplitudes than young subjects in both controls and the OD group. Patients with PTOD exhibited worse psychophysical olfactory function and decreased trigeminal sensitivity.

Comparing pain is done in daily life and involves short-term memorizing and attention focusing. This event-related functional magnetic resonance imaging study investigated the short-term brain activations associated with the comparison of pain stimuli using a delayed discrimination paradigm. Fourteen healthy young volunteers compared two successive pain stimuli administered at a 10 s interval to the same location at the nasal mucosa. Fourteen age- and sex-matched subjects received similar pain stimuli without performing the comparison task. With the comparison task, the activations associated with the second pain stimulus were significantly greater than with the first stimulus in the anterior insular cortex and the primary somatosensory area. This was observed on the background of a generally increased stimulus-associated brain activation in the presence of the comparison task that included regions of the pain matrix (insular cortex, primary and secondary somatosensory area, midcingulate cortex, supplemental motor area) and regions associated with attention, decision making, working memory and body recognition (frontal and temporal gyri, inferior parietal lobule, precuneus, lingual cortices). This data provides a cerebral correlate for the role of pain as a biological alerting system that gains the subject's attention and then dominates most other perceptions and activities involving pain-specific and non-pain-specific brain regions.

Background: Recent endoscopic dissection studies have redefined the postganglionic pterygopalatine autonomic pathways suggesting that neurovascular rami, termed "accessory posterolateral nerves," project directly through the palatine bone to innervate the posterolateral nasal mucosa rather than traveling with trigeminal arborizations. The goal of this study was to characterize these accessory posterolateral nerves by immunohistochemistry to determine their morphology and composition., Methods: This is an Institutional Review Board approved study in seven patients in whom the presence of accessory posterolateral nerves were surgically identified exiting the perpendicular plate of the palatine bone and sampled. The presence of neural tissue was confirmed by hematoxylin and eosin and S-100 protein staining. Nerves were then stained with anti-human choline acetyl-transferase (ChAT; 1:100) and anti-human dopamine beta-hydroxylase (DBH; 1:100) followed by a fluorescein isothiocyanate-labeled secondary antibody to test for the presence of peripheral parasympathetic and sympathetic fibers, respectively. Human cadaveric sensory nerves were used as a negative control., Results: All seven samples contained neural elements. Two specimens were also associated with arteries. All nerves were comprised of a single fascicle containing an approximately equal distribution of ChAT(+) and DBH(+) fibers., Conclusion: This histological study supports prior descriptions defining a newly recognized neural pathway for innervation of the nasal mucosa. Our data confirm that these accessory posterolateral nerves project directly through the perpendicular plate of the palatine bone and are composed of autonomic fibers. Recognition of this pathway may be exploited in the treatment of sinonasal disease resulting from autonomic dysregulation.

Purpose of Review: Allergic rhinitis is a very common disorder that affects millions of patients annually and the hallmark complaint of nasal obstruction significantly impacts the quality of life. Many surgical options exist for the treatment of allergic rhinitis, directed primarily at the underlying nasal obstructive component. The purpose of this review is to highlight and discuss the various surgical modalities and their historical efficacy., Recent Findings: Much of the literature has focused on reduction of the inferior turbinate for symptomatic improvement in patients afflicted with allergic rhinitis. Endoscopic sinus surgery and septoplasty play little role in the management of allergic rhinitis, unless when seen in conjunction with other conditions such as rhinosinusitis., Summary: Although no single modality has evolved as the gold standard for the treatment of allergic rhinitis, the mainstay of surgical intervention targets the inferior turbinate. It is very important for the otolaryngologist to be familiar with an armamentarium of surgical techniques.

Purpose of Review: To discuss current evidence of global climate change and its implications for allergic rhinitis and other allergic respiratory diseases., Recent Findings: Global climate change is evidenced by increasing average earth temperature, increasing anthropogenic greenhouse gas levels, and elevated pollen levels. Pollutants of interest include carbon dioxide (CO2), ozone (O3), and nitrous oxide (NO2) because they can enhance the allergic response and lead to increased symptoms of allergic respiratory diseases. Heightened CO2 levels stimulate pollen production via photosynthesis and increased growth in multiple plant species investigated. Although worsened air quality appears to increase prevalence of allergic rhinitis, the effects of increased temperature are less certain. The findings of increased aeroallergen levels likely contribute to increases in presentation of allergic diseases, although more healthcare impact studies are necessary., Summary: Although recent literature indicates and strongly supports changes in temperature, pollution levels, and aeroallergen levels, more longitudinal epidemiologic surveillance of allergic diseases in relation to climate change as well as pathophysiologic studies on changing aeroallergen effects on allergic diseases are needed.

Background: Vasomotor rhinitis (VR) seems to be related to an imbalance between cholinergic and adrenergic activity in the autonomic nervous system. The nerve fibers of the sympathetic and parasympathetic nervous systems reach the nose through the posterior nasal nerve, which, after crossing the sphenopalatine foramen, distributes to the mucosa following the branches of the sphenopalatine vessels. This study was designed to evaluate the effect of sphenopalatine artery ligation on nasal function and nasal cytology in patients with VR., Methods: Thirty patients with VR and bilateral inferior turbinate hypertrophy (ITH) were randomly assigned to receive endoscopic inferior turbinoplasty either with or without sphenopalatine artery ligation. Pre- (baseline) and postsurgical (1-year follow-up) assessment included fiber endoscopy, active anterior rhinomanometry, measurement of mucociliary transport time (MTt), and nasal cytology examination., Results: At 1-year follow-up there was a statistically significant improvement in nasal resistances in both groups but not on intergroup comparison; MTt significantly decreased in both groups (p < 0.01) and was significantly better (p < 0.05) in the group that had undergone sphenopalatine artery ligation. Among the patients in this group, significantly fewer were found to have altered ciliated cells (p < 0.005) or a hyperchromatic supranuclear stria (p < 0.005) on nasal cytology; the differences were statistically significant also on intergroup comparison (p < 0.005 and p < 0.001, respectively)., Conclusion: In patients with vasomotor rhinopathy and ITH, improvement in symptoms, nasal resistance, ciliated cell trophism, and MTt was observed after sphenopalatine artery ligation.

In order to improve brain uptake of nanoparticles following nasal administration, odorranalectin (OL), the smallest lectin with much less immunogenicity than other members of lectin family, was conjugated to the surface of poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP) in this study. The bioactivity of OL conjugated to the nanoparticles was verified by haemagglutination tests.Tissue distribution of OL-modified and unmodified nanoparticles (OL-NP and NP) was evaluated following intranasal (i.n.) administration by in vivo fluorescence imaging technique using DiR as a tracer, comparing with that of unmodified nanoparticles after intravenous (i.v.) injection. Besides, the nasal toxicity of OL-NP was evaluated on Calu-3 cell lines, toad palate and rat nasal mucosa.The results of TEM examination and dynamic light scattering showed a generally spherical shape of OL-NP with an average volume-based diameter around 90 nm. The haemagglutination test proved that OL retained its haemagglutination activity when conjugated to nanoparticles. The brain targeting indexes of NP and OL-NP following i.n. administration and NP following i.v. injection were 5.8, 11.6 and 0.08, respectively.Thus,i.n. administration demonstrated much better brain targeting efficiency than i.v. injection, and OL modification facilitated the nose-to-brain delivery of nanoparticles.Moreover, the toxicity assessment suggested good safety of OL-NP both in vitro and in vivo. In summary, odorranalectin-conjugated nanoparticle could be potentially used as a nose-to-brain drug delivery carrier for the treatment of CNS diseases.

Background: Menthol and cold sensation trigger symptoms and reflex responses in the upper airway, but the underlying molecular mechanisms are unknown. We have therefore studied nerve fibres expressing the menthol and cold receptor TRPM8 in normal human mucosa, and in rhinitis. TRPM8 nerve fibres were compared with those expressing other TRP receptors including TRPV1 (capsaicin and heat receptor), and TRPA1 (mechano-cold receptor)., Methods: Immunohistology and image-analysis were used to study TRP receptors in biopsies of nasal turbinate from control subjects, patients with allergic rhinitis, and non-allergic rhinitis., Results: TRPM8-immunoreactive nerve fibres were observed in the sub-epithelium, and were profuse around blood vessels in deeper regions, where they were markedly greater in number than TRPV1+ fibers. Image analysis of TRPM8 in sub-epithelial and vascular regions showed no significant differences between control and the rhinitis patient groups. TRPA1-immunoreactivity was weak and seen rarely in nerve fibres., Conclusion: We show that TRPM8 nerve fibres are abundant in nasal mucosa particularly around blood vessels, and may mediate neurovascular reflexes. TRPM8 antagonists deserve consideration for therapeutic trial in rhinitis.

Conclusion: These preliminary data show a decrease in nasal tactile sensitivity and point out interesting aspects of the nasal chronic inflammatory condition in allergic rhinitis., Objectives: The aim of this study was to evaluate the effects of allergic rhinitis on nasal tactile sensitivity during the intercritical period., Methods: A total of 70 patients aged between 18 and 67 years (average 42 years), with a positive history of allergy caused by seasonal outdoor allergens, were included (group A). Patient outcome was assessed by the nasal monofilament test: a set of 20 Semmes-Weinstein monofilaments was used to detect nasal sensitivity for both nasal cavities. The sensitivity threshold was recorded as the minimum monofilament size with which patients could detect at least two of three stimuli., Results: When compared to the control group (group B), subjects in group A required a significantly (p < 0.05) higher stimulus to trigger a touch response in the monofilament test, for both the inferior (195.1 ± 0.39 mg vs 67.7 ± 0.19 mg) and middle turbinate (108.7 ± 0.23 mg vs 67.7 ± 0.19 mg).

Vertebrate olfactory receptor neurons (ORNs) are stimulated in a rhythmic manner in vivo, driven by delivery of odorants to the nasal cavity carried by the inhaled air, making olfaction a sense where animals can control the frequency of stimulus delivery. How ORNs encode repeated stimulation at resting, low breathing frequencies and at increased sniffing frequencies is not known, nor is it known if the olfactory transduction cascade is accurate and fast enough to follow high frequency stimulation. We investigated mouse olfactory responses to stimulus frequencies mimicking odorant exposure during low (2Hz) and high (5Hz) frequency sniffing. ORNs reliably follow low frequency stimulations with high fidelity by generating bursts of action potentials at each stimulation at intermediate odorant concentrations, but fail to do so at high odorant concentrations. Higher stimulus frequencies across all odorant concentrations reduced the likelihood of action potential generation, increased the latency of response, and decreased there liability of encoding the onset of stimulation. Thus an increase in stimulus frequency degrades and at high odorant concentrations entirely prevents action potential generation in individual ORNs, causing reduced signalling to the olfactory bulb. These results demonstrate that ORNs do not simply relay timing and concentration of an odorous stimulus, but also process and modulate the stimulus in a frequency-dependent manner which is controlled by the chosen sniffing rate.

Objective: The aim of the current study was to determine the proportion of trigeminal primary afferent neurons that innervate the intracranial vasculature, and other craniofacial tissues, that are also 5 hydroxy triptamine (5-HT)(1D) receptor immunoreactive., Methods: Retrograde tracing and immunohistochemistry was used to identify 5-HT(1D) receptor labeled trigeminal primary afferent neurons that innervate the lacrimal gland (n = 3 animals), nasal mucosa (n = 3 animals), and the intracranial vasculature (middle meningeal artery in the dura [n = 3 animals] and middle cerebral artery [n = 3 animals])., Results: The percentage of neurons that were 5-HT(1D) receptor immunoreactive was greater for primary afferent neurons innervating the middle meningeal artery (41.8 ± 1%) than those innervating the middle cerebral artery (28.4 ± 0.8%), nasal mucosa (25.6 ± 1%), or lacrimal gland (23.5 ± 3%). For each retrograde labeled population, the 5-HT(1D) receptor immunoreactive cells were among the smallest of the retrograde labeled cells., Conclusions: These findings provide a basis for understanding the role of 5-HT(1D) receptor agonists (eg, triptans) in the treatment of primary vascular headaches and suggest that the selectivity of triptans in the treatment of these headaches does not appear to result from specific localization of the 5-HT(1D) receptor to trigeminovascular neurons alone., (© 2011 American Headache Society.)

Objective: To determine if 5-HT(1D) receptors are located in the sphenopalatine ganglion., Background: While the 5-HT(1D) receptor has been described in sensory and sympathetic ganglia in the head, it was not known whether they were also located in parasympathetic ganglia., Methods: We used retrograde labeling combined with immunohistochemistry to examine 5-HT(1D) receptor immunoreactivity in rat sphenopalatine ganglion neurons that project to the lacrimal gland, nasal mucosa, cerebral vasculature, and trigeminal ganglion., Results: We found 5-HT(1D) receptor immunoreactivity in nerve terminals around postganglionic cell bodies within the sphenopalatine ganglion. All 5-HT(1D) -immunoreactive terminals were also immunoreactive for calcitonin gene-related peptide but not vesicular acetylcholine transporter, suggesting that they were sensory and not preganglionic parasympathetic fibers. Our retrograde labeling studies showed that approximately 30% of sphenopalatine ganglion neurons innervating the lacrimal gland, 23% innervating the nasal mucosa, and 39% innervating the trigeminal ganglion were in apparent contact with 5-HT(1D) receptor containing nerve terminals., Conclusion: These data suggest that 5-HT(1D) receptors within primary afferent neurons that innervate the sphenopalatine ganglion are in a position to modulate the excitability of postganglionic parasympathetic neurons that innervate the lacrimal gland and nasal mucosa, as well as the trigeminal ganglion. This has implications for triptan (5-HT(1D) receptor agonist) actions on parasympathetic symptoms in cluster headache., (© 2011 American Headache Society.)

Background: Recent anatomic dissections have redefined the sinonasal parasympathetic pathway suggesting that individual rami project from the pterygopalatine ganglion (PPG) to innervate the nasal mucosa via multiple small nerve fascicles. The purpose of this study is correlate these anatomic descriptions with endoscopic findings and to define the pattern and location of the posterolateral neurovascular rami., Methods: Eight cadaver heads were utilized for a total of 16 individual sides. A lateral nasal submucosal flap was elevated while preserving all neurovascular bundles perforating the palatine bone. All nerves were traced proximally to confirm their origin., Results: Excluding the sphenopalatine foraminal contents, accessory posterolateral nerves were noted in 87.5% (14/16) of specimens, 50% (7/14) of which contained greater than one. All nerves could be traced directly to the PPG or greater palatine nerve. Of the 25 accessory nerves identified, the most common location was posterosuperior to the horizontal attachment of the inferior turbinate (40%, 10/25)., Conclusion: This study supports prior work suggesting that neurons project from the PPG via multiple individual postganglionic rami to supply the nasal mucosa. This new anatomic insight may be exploited to selectively lesion these nerve fascicles in patients with vasomotor rhinitis to improve outcomes while avoiding the morbidities associated with vidian neurectomy., (Copyright © 2011 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.)