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Effect of the TRPV1 antagonist SB ‐705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig
Author(s) -
Changani Kumar,
Hotee Sarah,
Campbell Simon,
Pindoria Kashmira,
Dinnewell Laura,
Saklatvala Paula,
Thompson SallyAnne,
Coe Diane,
Biggadike Keith,
Vitulli Giovanni,
Lines Marion,
Busza Albert,
Denyer Jane
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12145
Subject(s) - capsaicin , nasal administration , hypertonic saline , trpv1 , mucous membrane of nose , guinea pig , trigeminal ganglion , medicine , saline , pharmacology , reflex , chemistry , anesthesia , immunology , sensory system , receptor , biology , transient receptor potential channel , neuroscience
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.