Effect of the TRPV1 antagonist SB‐705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig

Abstract

BACKGROUND AND PURPOSENasal 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 APPROACHThe 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 IMPLICATIONSThe 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. AbbreviationsRARE factor, spin echo multi echo pulse sequence; TE, echo time; TR, repetition time; TRPV1, transient receptor potential cation channel (subfamily V, member 1)

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis

“…Results were consistent across all efficacy endpoints, including symptom scores, nasal cavity geometry, and RQLQ scores. The PK results supported the once daily regimen and were consistent with other studies, showing an ~ 2-fold accumulation over the dosing period [13], and therefore insufficient plasma concentrations cannot account for the lack of efficacy shown. Earlier studies with this compound were positive in both a pre-clinical guinea pig rhinitis model [13] and in a single dose evaluation in patients with NAR [14], both showing a reduction in capsaicin-induced nasal secretions and symptoms.…”

“…The PK results supported the once daily regimen and were consistent with other studies, showing an ~ 2-fold accumulation over the dosing period [13], and therefore insufficient plasma concentrations cannot account for the lack of efficacy shown. Earlier studies with this compound were positive in both a pre-clinical guinea pig rhinitis model [13] and in a single dose evaluation in patients with NAR [14], both showing a reduction in capsaicin-induced nasal secretions and symptoms. Although the previous studies used a capsaicin challenge model, compared with the CDA model used in this study, cold air-induced symptoms are the result of mucosal drying and increased osmolarity of surface lining fluid, which activates the same TRPV1 receptor as capsaicin [17,18], thus the different phenotypes would not be expected to respond differently.…”

“…How this links to TRPV1 activation has been explored in rodent systems; in rat isolated trigeminal ganglion cells, changes in osmolarity have been shown to augment capsaicin-induced currents and cell surface expression of TRPV1 [17]. In addition, the finding that SB-705498 inhibits hypertonic saline induced parasympathetic nasal fluid responses in the guinea pig also suggest that tonicity changes involve TRPV1 dependent pathways [13]. An alternative mechanism based on physical trauma to nasal mucosa resulting in nociceptor exposure and development of symptoms has also been proposed.…”

“…It was anticipated that a 12 mg intranasal dose would result in high levels of local receptor occupancy and a higher level of receptor engagement than observed with oral doses in the cough study. In a pre-clinical rhinitis guinea pig model where nasal parasympathetic fluid secretory responses were measured by MRI, intranasal SB-705498 was shown to block both capsaicin-induced and hypertonic salineinduced contralateral reflex fluid secretory responses [13]. In the first clinical study in patients with NAR, single doses of 12 mg SB-705498 resulted in a marked reduction in nasal symptoms following capsaicin challenge, compared with placebo [14].…”

Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels

“…The validation of TRPV1 as a therapeutic target for pain prompted the development of several TRPV1 antagonists that have entered clinical trials for the treatment of acute, chronic and neuropathic pain (Basbaum et al ., ; Ferrer‐Montiel et al ., ). Additionally, in the nose, stimulation of TRPV1 in nasal fibres elicits release of proinflammatory mediators, which contribute to rhinitic symptoms, so that blockade of the channel with SB‐705498 counteracts such symptoms (Changani et al ., ). The TRPV1 antagonists SB‐705498 and PF‐04065463 also inhibited evoked‐airway hyper‐responsiveness to histamine.…”