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

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-aminoantipirine (4-AA) reduces prostaglandin E2 (PGE2 )-induced pain-related behaviour through the cannabinoid type 1 (CB1) receptor. 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/paw) on capsaicin (0.12 μg/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 the CB1 receptor. 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 (1-50μM) increased the [Ca2+ ]i . Although, 4-AA was able to activate both the transient receptor potential ion channel (TRP), vanilloid subfamily, member 1 (TRPV1) and the TRP, ankyrin subfamily, member 1 (TRPA1), the increase in the [Ca2+ ]i . was mediated through TRPV1. The TRPV1 activation resulted in TRPV1 desensitisation. Blocking the CB1 receptor reduced both the excitatory and desensitising effects of 4-AA. CONCLUSIONS AND IMPLICATIONS CB1 receptor-mediated inhibition on TRPV1, and TRPV1-mediated Ca2+ -influx- and CB1 receptor-dependent TRPV1 desensitisation contribute to the antinociceptive effect of 4-AA in naive and inflamed condition, respectively. Double CB1/TRPV1 agonists might be useful as analgesics, particularly in inflammatory conditions.