CB receptor-dependent desensitisation of TRPV1 channels 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-aminoantipyrine (4-AA) reduces PGE -induced pain-related behaviour through cannabinoid CB receptors. Here, we ascertained, in naive and PGE -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 ] ) 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 receptors. 4-AA (100 μM) reduced capsaicin-induced increase in [Ca ] in a CB receptor-dependent manner, when PGE was not present. Following PGE application, 4-AA (1-50 μM) increased the [Ca ] . Although 4-AA activated both TRPV1 and TRPA1 channels, increased [Ca ] was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB receptors reduced both the excitatory and desensitising effects of 4-AA.

CONCLUSION AND IMPLICATIONS

CB receptor-mediated inhibition of TRPV1 channels and TRPV1-mediated Ca -influx- and CB 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 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions.