Targeting Cannabinoid CB2 Receptors to Attenuate Airway Inflammation and Hyperresponsiveness in Allergic Asthma: Does the TRPV1 ReceptorPlay a Role?

INTRODUCTION: Asthma is a chronic airway disease characterized by inflammation, remodeling, and airway hyperresponsiveness. Cannabinoid CB2 receptors are emerging as modulators of immune responses, while cross-talk with TRPV1 channels may also influence disease mechanisms. This study investigated the effects of the CB2 agonist JWH133 on airway inflammation and hyperreactivity in ovalbumin (OVA)-induced asthma and evaluated the involvement of CB2 and TRPV1 receptors. METHODS: Female BALB/c mice were sensitized and challenged with OVA. JWH133 (0.5, 3, 5 mg/kg) was administered intraperitoneally, alone or in combination with the CB2 antagonist AM630 or the TRPV1 antagonist capsazepine (CPZ). Airway responsiveness was assessed using a methacholine challenge in whole-body plethysmography. Inflammatory cell counts in bronchoalveolar lavage fluid (BALF), serum cytokine levels (IL-4, IL-5, IL-13), and lung histology were analyzed. RESULTS: OVA exposure significantly increased Penh values, BALF inflammatory cells, Th2 cytokines, and histological inflammation. JWH133 produced a dose-dependent reduction in airway hyperresponsiveness, eosinophilic infiltration, and Th2 cytokines, along with improved histopathology. AM630 alone did not alter asthma parameters but partially reversed JWH133's effects when co-administered. CPZ treatment reduced lymphocytes, and CPZ+JWH133 co-treatment further decreased IL-5 and IL-13 levels compared to CPZ alone. DISCUSSION: The present study demonstrates that selective activation of CB2 receptors with JWH133 effectively suppresses key pathological features of allergic asthma, including airway hyperresponsiveness, eosinophilic inflammation, and Th2 cytokine production. Although AM630 attenuated several of these beneficial effects, JWH133 maintained partial activity even in the presence of CB2 antagonism, suggesting that additional CB2-independent mechanisms contribute to its actions. Moreover, partial overlap between the effects of TRPV1 inhibition and JWH133 indicates that cannabinoid-TRP interactions may influence the inflammatory response. These findings highlight the multifactorial nature of cannabinoid signaling in asthma and underscore the need to explore alternative pathways-including neuroimmune and non-CB2 mechanisms-that may mediate the protective effects of CB2 agonists. CONCLUSION: JWH133 markedly reduces airway hyperresponsiveness and inflammation in OVAinduced asthma, primarily through CB2 receptor activation but also through additional pathways not fully blocked by CB2 antagonism. The partial contribution of TRPV1 modulation further suggests complex receptor crosstalk. Overall, these results support CB2 agonists as promising candidates for asthma therapy and emphasize the importance of future mechanistic studies to clarify their receptor-specific and non-receptor-dependent effects.