RESUMEN
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 â¼50% at 10 mg·kg⻹ (oral), non-micronized 10 mg·mL⻹ or 1 mg·mL⻹ 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⻹, 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.
Asunto(s)
Modelos Animales de Enfermedad , Mucosa Nasal/efectos de los fármacos , Sistema Nervioso Parasimpático/efectos de los fármacos , Parasimpatolíticos/uso terapéutico , Pirrolidinas/uso terapéutico , Rinitis Alérgica Perenne/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Urea/análogos & derivados , Administración Intranasal , Administración Oral , Animales , Antialérgicos/administración & dosificación , Antialérgicos/química , Antialérgicos/farmacología , Antialérgicos/uso terapéutico , Capsaicina/administración & dosificación , Capsaicina/antagonistas & inhibidores , Capsaicina/toxicidad , Células Cultivadas , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Femenino , Cobayas , Masculino , Mucosa Nasal/inervación , Mucosa Nasal/metabolismo , Sistema Nervioso Parasimpático/metabolismo , Sistema Nervioso Parasimpático/patología , Parasimpatolíticos/administración & dosificación , Parasimpatolíticos/química , Parasimpatolíticos/farmacología , Tamaño de la Partícula , Pirrolidinas/administración & dosificación , Pirrolidinas/química , Pirrolidinas/farmacología , Rinitis Alérgica , Rinitis Alérgica Perenne/metabolismo , Rinitis Alérgica Perenne/patología , Vías Secretoras/efectos de los fármacos , Fármacos del Sistema Sensorial/administración & dosificación , Fármacos del Sistema Sensorial/antagonistas & inhibidores , Fármacos del Sistema Sensorial/toxicidad , Canales Catiónicos TRPV/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/patología , Urea/administración & dosificación , Urea/química , Urea/farmacología , Urea/uso terapéuticoRESUMEN
The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABA(B) agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the mu-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors.
Asunto(s)
Inhibición Neural/fisiología , Umbral del Dolor/fisiología , Dolor/fisiopatología , Médula Espinal/fisiología , Transmisión Sináptica/fisiología , Analgésicos/antagonistas & inhibidores , Animales , Baclofeno/farmacología , Capsaicina/antagonistas & inhibidores , Interacciones Farmacológicas/fisiología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Antagonistas de Receptores de GABA-B , Masculino , Antagonistas de Narcóticos/farmacología , Inhibición Neural/efectos de los fármacos , Dolor/inducido químicamente , Umbral del Dolor/efectos de los fármacos , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Fármacos del Sistema Sensorial/antagonistas & inhibidores , Médula Espinal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
Vanilloid receptor 1 (VR1) is a noxious receptor and a novel target for pain therapy. Cochinchinenin B (6-hydroxy-7-methoxy-3-(4'-hydroxybenzyl) chromone; CB) is one of the small-molecular components from the flavonoids of Dragon's Blood, a well-known herbal medicine to treat various types of pain. Using whole-cell patch clamp technique, we found that capsaicin (CAP)-activated currents (ICAP) was inhibited by CB with an IC50 of 0.92 mM in acutely isolated rat dorsal root ganglion (DRG) neurons. The inhibition was reversible and not competitive. We also found that the inhibition was neither voltage- nor agonist-dependent. The bind site was on the extracellular part of the channel since intracellular application of CB did not alter the inhibition effect on ICAP. In addition, CB inhibited CAP-evoked depolarization under current-clamp condition. Our findings indicate that CB may be a candidate in developing new analgesic drugs targeting the VR1 receptor.