Interaction between the dopaminergic and endocannabinoid systems promotes peripheral antinociception

Dopamine has been widely related to pain modulation, at central and peripheral levels. In this study we aimed to investigate the mechanisms involved in peripheral antinociception, evaluating the interaction between the dopaminergic and endocannabinoid systems in this event.

Male Swiss mice (30-40 g) were pre-sensitized by administration of the hyperalgesic PGE₂ (2 μg/paw). The nociceptive threshold was measured using the paw withdrawal test.

Dopamine (80 ng/paw) promoted antinociception. This effect was reversed by the CB₁ and CB₂ cannabinoid receptor antagonists AM251 (20, 40, and 80 μg/paw) and AM630 (25, 50, and 100 μg/paw). JZL (4 μg/paw), an inhibitor of the degradation of the 2-arachidonylglycerol (2-AG), potentiated the antinociceptive action of the submaximal dose of dopamine (5 ng/paw). While anandamide degradation and reuptake inhibitors (MAFP 0.5 μg/paw and VDM11 2.5 μg/paw) did not promote changes in intermediate antinociception induced by dopamine. Anandamide at a submaximal dose (12.5 ng/paw) promoted intermediate antinociception that was not potentiated by the administration of the dopamine reuptake inhibitor GBR 12783 (16 μg/paw). In contrast, the administration of GBR potentiated the intermediate antinociception induced by a submaximal dose of 2-AG (10 μg/paw). Furthermore, the dopaminergic receptor antagonists D₂ Remoxipride (4 μg/paw) and D₃ U99194 (16 μg/paw) reversed the antinociception mediated by the maximum dose of this endocannabinoid (20 μg/paw). In contrast, the D₄ receptor antagonist L-745,870 (16 μg/paw) did not change the nociceptive threshold.

In this way, we demonstrate the interaction between the dopaminergic and endocannabinoid systems to promote analgesia peripherally.