Lars Lundblad

Origin and Distribution of Capsaicin-Sensitive Substance P-Immunoreactive Nerves in the Nasal Mucosa

In immunohistochemical studies, substance P-immunoreactivity (SP-IR) was found in a population of trigeminal ganglion cells in guinea pig, rat and cat. SP-IR nerve endings were found in the spinal trigeminal nucleus, around sphenopalatine ganglion cells, around blood vessels, as well as under and within the epithelium of the nasal mucosa. Ligation and denervation experiments in the cat indicated that the SP-IR nerves in the sphenopalatine ganglion and the nasal mucosa are of trigeminal origin. Capsaicin pretreatment of guinea pigs and rats resulted in a selective loss of the SP-IR nerves in the nasal mucosa and sphenopalatine ganglion, while the parasympathetic and sympathetic nerves were still present.

Increased Vascular Permeability in Rat Nasal Mucosa Induced by Substance P And Stimulation of Capsaicin-Sensitive Trigeminal Neurons

Electrical stimulation of the maxillary branches of the trigeminal nerve induced an increase in vascular permeability to macromolecules and an interstitial edema in the nasal mucosa of the rat, as indicated by extravasation of Evans blue. In animals that had been treated neonatally with capsaicin, the effect of trigeminal nerve stimulation was abolished. Local application of capsaicin or substance P (SP) also induced a significant Evans blue extravasation in the nasal mucosa. In capsaicin-pretreated animals the effect of SP was still present, while the permeability increase induced by capsaicin was abolished. In conclusion, chemogenic irritation of the nasal mucosa by capsaicin induces edema probably via a local axon reflex inducing release of SP. Capsaicin-sensitive SP-containing afferents in the nasal mucosa may also be involved in the pathogenesis of nasal congestion seen in various types of rhinitis.

Capsaicin and nicotine-sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis.

1 Applications of capsaicin, nicotine and methacholine were made locally onto the nasal mucosa in human controls and patients suffering from hyperreactive nasal disorders. Perception of sensation was registered as a sympton score and secretion quantified. The sensory reaction (irritation ‐pain) to capsaicin was similar in the three groups studied, i.e. controls, a group of patients with the diagnosis of vasomotor rhinitis and a group of patients with increased nasal secretion as the main symptom of the hyperreactive disorder. Nicotine induced only a mild itching sensation in the three groups. However, capsaicin and nicotine challenge caused a significantly larger secretory response in the last group than in the unselected vasomotor rhinitis group and in the control group. 2 Pretreatment with muscarinic receptor antagonists almost completely abolished the secretory response to both capsaicin and nicotine, and blocked methacholine‐induced secretion. Furthermore, pretreatment with a combination of local anaesthetic and vasoconstrictor agent abolished the capsaicin‐induced irritation, as well as the capsaicin‐ and nicotine‐induced secretion on both the ipsilateral and the contralateral side. Therefore, no clearcut contribution seems to be exerted by locally released peptides from sensory neurones as direct trigger substances for the secretory response to capsaicin. 3 In conclusion, the nasal secretory response, in man, to both capsaicin and nicotine, seems to be mediated via cholinergic parasympathetic reflexes. In patients with hyperreactive non‐allergic disorders of the nasal mucosa with rhinorrhea as the main complaint, the enhanced secretion may be due to a hyperreactive efferent cholinergic mechanism rather than hypersensitive irritant receptors on capsaicin‐ and nicotine‐sensitive sensory neurones. Challenge with irritant agents seems a useful test for the evaluation of both afferent and efferent reflexogenic responses in hyperreactive disorders of the nasal mucosa.

Tachykinins and calcitonin gene-related peptide: co-existence in sensory nerves of the nasal mucosa and effects on blood flow.

SummaryThe presence and co-existence of calcitonin generelated peptide (CGRP)- and substance P (SP)-like immunoreactivity (-LI) in sensory neurons of the nasal mucosa and trigeminal ganglion in several vertebrate species, including man, were established using immunohistochemistry. In the nasal mucosa the CGRP- and SP-immunoreactive (IR) nerve fibers were localized within the epithelium, around arteries, arterioles, venules, venous sinusoids and close to exocrine elements, mainly ducts. Double-staining experiments revealed that the CGRP-LI-containing nerve profiles and cell bodies also contained SP-LI. In the pig, CGRP- and SP-IR fibers were also detected in the maxillary portion of the trigeminal nerve and around the sphenopalatine artery and vein, as well as around the nasal dorsal vein. The nasal mucosal content of CGRP-LI, as determined by radioimmunoassay, was almost 5-fold higher in the pig and guinea pig compared to man. The nasal CGRP-IR nerves disappeared after capsaicin pretreatment in the guinea pig. In the cat, local intra-arterial infusions of capsaicin, SP, neurokinin A (NKA), neuropeptide K (NPK) and CGRP caused a concentration-dependent increase in nasal blood flow. CGRP caused a longer-lasting vasodilatation than the tachykinins. In conclusion, the morphological findings of co-localization of CGRP-LI and SP-LI in capsaicin-sensitive nerve fibers of the nasal mucosa and trigeminal ganglia of different species including man, coupled with the in vivo description of the high vasodilator potency of CGRP and tachykinins, imply co-release of several vasoactive agents upon activation of the nasal sensory nerves. Furthermore, the similarity of the morphological findings among the different species indicates that experimental data from animals may reflect the existence of similar mechanisms in humans.

Capsaicin-sensitive nerves and the cutaneous allergy reaction in man: possible involvement of sensory neuropeptides in the flare reaction

The effects of local capsaicin pretreatment on the cutaneous triple response reaction induced by allergen exposure or anti‐IgE were studied in man. Acute exposure of the human skin to capsaicin caused a burning sensation and a clearcut flare reaction but no wheal response. Upon repeated administration these local reactions to capsaicin disappeared. The Hare component and the subjective itching sensation of the cutaneous allergy reaction to rat antigen in sensitized persons or anti‐IgE in non‐allergic persons were then markedly reduced. Two weeks after capsaicin pretreatment the flare response to allergen was not significantly changed compared to the control reaction, suggesting a reversible effect of capsaicin treatment. The wheal component of the allergy or anti‐IgE reaction was, however, not influenced by capsaicin pretreatment, indicating that the wheal and flare components are caused by different mechanisms. It is concluded that capsaicin sensitive sensory nerves are of importance for the human cutaneous triple response reaction induced by allergen exposure. Thus, secondary release of mediators, such as CGRP or tachykinins from sensory nerve branches, may contribute to the flare component of this reaction. Furthermore the itching sensation seems to be dependent to a large extent on capsaicin‐sensitive nerves. However, sensory nerves seem to have less importance for the wheal reaction, i.e. the protein extravasation response.

Placebo-controlled, randomized, double-blind study evaluating the efficacy of fluticasone propionate nasal spray for the treatment of patients with hyposmia/anosmia

OBJECTIVE: To compare the effect on olfaction of topical glucocorticoid treatment versus placebo given for an extended period in addition to oral short-term glucocorticoids in patients with anosmia/hyposmia. MATERIAL AND METHODS: This was a randomized, double-blind, placebo-controlled study. The criterion for inclusion in the blinded phase was an improvement of at least 2 steps in the butanol odor threshold test following open treatment for 10 days with oral and nasal corticosteroids. Forty patients were included: 20 were randomized to treatment with fluticasone propionate, 10 to placebo and 10 others as controls. The topical treatment was continued for 6 months. RESULTS: The 3 groups showed similar improvements in their sense of smell after the initial 10-day treatment with combined oral and nasal corticosteroids. Patients who continued the local treatment maintained the same level of improvement throughout the study, whether or not they had been given nasal corticosteroids or placebo. We found no significant differences between the treatment groups. CONCLUSIONS: In patients with anosmia/hyposmia partly caused by local inflammation, no further improvement in the olfactory threshold is achieved by continuing with a topical intranasal glucocorticoid after an initial combined topical and systemic glucocorticoid treatment.

Inhibition of cigarette smoke-induced oedema in the nasal mucosa by capsaicin pretreatment and a substance P antagonist.

Summary1.The effect of cigarette smoke on vascular permeability in the rat nasal mucosa was studied using the Evans blue extravasation method. Exposure to smoke from cigarettes induced a significant extravasation of Evans blue in the nasal mucosa of normal rats, suggesting an increased vascular permeability to plasma proteins. The oedema response was correlated to tar, nicotine and vapour phase components in the smoke.2.The smoke-induced permeability effect was abolished in rats pretreated neonatally with capsaicin. Also, systemic or local pretratment with [D-Arg1, D-Pro2, D-Trp7,9, Leu11]Substance P, a substance P antagonist, inhibited the permeability response to cigarette smoke.3.Insertion of a glass-fibre filter, which removes the particulate phase of the smoke (including nicotine), did not significantly reduce the permeability response.4.The present findings suggest that the smoke-induced oedema in the rat nasal mucosa is not caused by nicotine but by vapour-phase irritants, which activate capsaicinsensitive C-fibre afferents. These neurons then release agents such as substance P or a related tachykinin which increase permeability to plasma proteins.

Local and systemic capsaicin pretreatment inhibits sneezing and the increase in nasal vascular permeability induced by certain chemical irritants

Summary1.The effects of local exposure to chemical irritants and mechanical stimulation on sneezing reflexes have been studied in normal and capsaicin-pretreated, conscious guinea-pigs. The influence of local and systemic capsaicin pretreatment on vascular permeability to plasma proteins and the cardiovascular effects of local application of capsaicin to the nasal mucosa have also been studied in anaesthetized animals.2.Local application of capsaicin (threshold dose 3 µM), nicotine (threshold dose 300 µM) or formalin to the nasal mucosa induced reflex sneezing discharges. Systemic or local capsaicin pretreatment abolished or reduced the sneezing responses to capsaicin and formalin. The response to nicotine was also reduced following local pretreatment with capsaicin, while the response to systemic pretreatment with capsaicin was only slightly affected. The sneezing response to mechanical stimulation was not affected by capsaicin pretreatment.3.Pretreatment with a local anaesthetic induced a similar dose-dependent inhibition of the sneezing responses to both capsaicin and nicotine.4.Local application of disodium cromoglycate to the nasal mucosa reduced the sneezing response to capsaicin, but not that to nicotine.5.Local pretreatment with the 3 mM and 30 mM capsaicin solution inhibited the increase in vascular permeability to plasma proteins in the nasal mucosa induced by i.v. capsaicin. Local pretreatment with capsaicin did not result in any reduction in the capsaicin-induced permeability in the ureter, suggesting that such treatment did not have any major systemic toxic effects.However, a small, acute increase in respiratory insufflation pressure, indicating broncho constriction, was seen when the 30 mM capsaicin solution was applied to the nasal mucosa. The application of capsaicin (3 mM and 30 mM) to the nasal mucosa resulted in an increase in arterial blood pressure and tachycardia due to reflex sympathetic activation.6.Exposure of normal guinea-pigs to an atmosphere saturated with ether caused excited avoidance behaviour and intense nose wipings with the fore paws. This response was abolished by systemic pretreatment with capsaicin and reduced by local capsaicin pretreatment.7.Local application of serotonin, histamine, leucotriene C4, bradykinin, phenyldiguanide, substance P (SP) or [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP, an SP-antagonist, did not induce any sneezing. High concentrations of compound 48/80 caused a small sneezing response. Local pretreatment with the SP-antagonist (7 x10-4 M) did not influence the sneezing responses to nicotine or capsaicin.8.It is concluded that only substances that are known to activate sensory nerves induce sneezing. Furthermore, there seems to be at least two types of afferent nerves in the nasal mucosa which respond to specific chemical irritation. One type, capsaicin-sensitive nerves, which respond to capsaicin, formalin, ether and nicotine, while another type of afferent nerves involved in sneezing reflexes is largely resistant to capsaicin pretreatment and is activated by nicotine. Local application of capsaicin to the nasal mucosa may thus be a selective way of reducing nasal reactivity to certain chemical irritants without causing systemic degeneration of capsaicin-sensitive C-fibre afferents.

Effects of Nasal Capsaicin Pretreatment and Cryosurgery on Sneezing Reflexes, Neurogenic Plasma Extravasation, Sensory and Sympathetic Neurons

Local and systemic capsaicin pretreatment as well cryosurgery induced a long-lasting loss of sensory substance P-immunoreactive nerves in the guinea-pig nasal mucosa. In addition, cryosurgery caused a loss of noradrenergic sympathetic nerves, sclerosis of blood vessels, epithelial damage and fibrosis of the mucosa. The sneezing response to local application of capsaicin--but not that to nicotine--was reduced or abolished by capsaicin pretreatment and cryosurgery, while the response to tactile stimulation was unaffected. These effects were long-lasting and still present 2 months after treatment. Local capsaicin pretreatment of the nasal mucosa had no effects on the substance P levels or the Evans Blue extravasation response to i.v. capsaicin in the ureter, indicating that this treatment has no systemic effects on other afferent SP-neurons. It is suggested that local capsaicin pretreatment is a more selective and less traumatic method than cryosurgery to induce a long-lasting desensitization of the nasal mucosa to chemical irritants in hyperreactive disorders of the nose.

Local Capsaicin Treatment of the Nasal Mucosa Reduces Symptoms in Patients with Nonallergic Nasal Hyperreactivity

Ten patients with nonallergic nasal hyperreactivity were selected from the outpatient department at the ENT clinic of the Karolinska Hospital. Traditional treatment had been ineffective. Local capsaicin treatment (30 μM solution) was performed on 3 consecutive days after careful nasal decongestion and local anesthesia with naphazoline and lidocaine. The treatment was evaluated using a diary where the patients were asked to score their subjective symptoms of nasal discharge, nasal blockage, and sneezing on a visual analogue scale. At the follow-up, the desensitization to local capsaicin application of the nasal mucosa was also tested. After 1 month the patients reported a 63% and 69% reduction of nasal blockage and nasal discharge respectively, which was parallel to a desensitization of the nasal mucosa to capsaicin. The results were similar after 3 months. After 6 months the patients had reverted to a score similar to that before the treatment. At this time the response of the nasal mucosa to capsaicin was normalized. In conclusion, capsaicin treatment of the nasal mucosa in patients with nonallergic nasal hyperreactivity induces a long-lasting reversible desensitization and a parallel subjective reduction of symptoms.