CB1 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 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.
['Goncalves Dos Santos|Gilson|G|0000-0002-2704-3006', 'Li|Ruihui|R|0000-0003-2892-6086', 'Ng|Melissa Pui Een|MPE|0000-0001-9700-4910', 'Lemes|Julia Borges Paes|JBP|0000-0003-2212-6803', 'Vieira|Willians Fernando|WF|0000-0003-3022-7997', 'Nagy|Istvan|I|0000-0003-3475-6108', 'Tambeli|Cláudia Herrera|CH|0000-0001-5566-710X', 'Parada|Carlos Amilcar|CA|0000-0001-5209-8853']
D000700:Analgesics D002211:Capsaicin D004177:Dipyrone D005727:Ganglia, Spinal D011984:Sensory Receptor Cells D050916:TRPV Cation Channels
CB1 TRPV1 dipyrone TRPA1 calcium imaging dorsal root ganglion