CB1 receptor-dependent desensitisation of TRPV1 channels contributes to the analgesic effect of dipyrone in sensitised primary sensory neurons

Abstract

Background and Purpose: While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently, we have reported that the dipyrone metabolite 4-aminoantipyrine (4-AA) reduces PGE2-induced pain-related behaviour through cannabinoid CB1 receptors. Here, we ascertained, in naive and PGE2-induced “inflamed” conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4-AA-induced analgesic effects. Experimental Approach: The effect of local administration of 4-AA (160 μg per paw) on capsaicin (0.12 μg per paw) injection-induced pain-related behaviour and 4-AA's effect on 500-nM capsaicin-induced changes in intracellular calcium concentration ([Ca2+]i) in cultured primary sensory neurons were assessed in vivo and in vitro, respectively. Key Results: 4-AA reduced capsaicin-induced nociceptive behaviour in naive and inflamed conditions through CB1 receptors. 4-AA (100 μM) reduced capsaicin-induced increase in [Ca2+]i in a CB1 receptor-dependent manner, when PGE2 was not present. Following PGE2 application, 4-AA (1–50 μM) increased the [Ca2+]i. Although 4-AA activated both TRPV1 and TRPA1 channels, increased [Ca2+]i was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB1 receptors reduced both the excitatory and desensitising effects of 4-AA. Conclusion and Implications: CB1 receptor-mediated inhibition of TRPV1 channels and TRPV1-mediated Ca2+-influx- and CB1 receptor-dependent desensitisation of TRPV1 channels contribute to the anti-nociceptive effect of 4-AA in naive and inflamed conditions respectively. Agonists active at both CB1 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions.