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 PGE 2 ‐induced pain‐related behaviour through cannabinoid CB 1 receptors. Here, we ascertained, in naive and PGE 2 ‐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 ([Ca 2+ ] 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 CB 1 receptors. 4‐AA (100 μM) reduced capsaicin‐induced increase in [Ca 2+ ] i in a CB 1 receptor‐dependent manner, when PGE 2 was not present. Following PGE 2 application, 4‐AA (1–50 μM) increased the [Ca 2+ ] i . Although 4‐AA activated both TRPV1 and TRPA1 channels, increased [Ca 2+ ] i was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB 1 receptors reduced both the excitatory and desensitising effects of 4‐AA. Conclusion and Implications CB 1 receptor‐mediated inhibition of TRPV1 channels and TRPV1‐mediated Ca 2+ ‐influx‐ and CB 1 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 CB 1 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions.

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