title: Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Platform Technology and Science, GlaxoSmithKline, Stevenage, UK. kumar.k.changani@gsk.com
authors: Kumar
authors: K
authors: Changani
authors: Sarah
authors: S
authors: Hotee
authors: Simon
authors: S
authors: Campbell
authors: Kashmira
authors: K
authors: Pindoria
authors: Laura
authors: L
authors: Dinnewell
authors: Paula
authors: P
authors: Saklatvala
authors: Sally-Anne
authors: SA
authors: Thompson
authors: Diane
authors: D
authors: Coe
authors: Keith
authors: K
authors: Biggadike
authors: Giovanni
authors: G
authors: Vitulli
authors: Marion
authors: M
authors: Lines
authors: Albert
authors: A
authors: Busza
authors: Jane
authors: J
authors: Denyer
mesh_terms: D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002211:Capsaicin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010276:Parasympatholytics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010316:Particle Size; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055571:Secretory Pathway / Q000187:drug effects; D018689:Sensory System Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018926:Anti-Allergic Agents; D010276:Parasympatholytics; D011759:Pyrrolidines; C512301:SB 705498; D018689:Sensory System Agents; D050916:TRPV Cation Channels; D014508:Urea; D002211:Capsaicin