Dopaminergic and Opioid Systems Interact to Produce Peripheral Antinociception in Mice

The overall pain experience results from the balance between the nociceptive pathway and the body's endogenous modulation of nociception. The interaction of these systems reduces nociception. Therefore, this study aimed to evaluate how the opioid and dopaminergic systems collaborate to inhibit pain at the peripheral level.

Swiss mice (30-40 g) had their pain sensitivity increased through paw administration of the prostaglandin E2 (2 μg). They then received opioid and dopaminergic receptor antagonists and agonists, along with an inhibitor of endogenous opioid peptide degradation and a dopamine (DA) reuptake inhibitor. The nociceptive threshold was measured using the paw withdrawal test. Groups were compared using one-way analysis of variance (ANOVA), with p < 0.05 considered significant.

The nonselective opioid receptor antagonist naloxone (50 μg/paw) and the selective κ nor-BNI (200 μg/paw; nor-Binaltorphimine) and δ naltrindole (60 μg/paw) receptor antagonists reversed the antinociception caused by peripheral administration of DA (80 ng/paw), but not the μ-opioid receptor antagonist CTOP (20 μg/paw; D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2). The antinociception induced by a submaximal dose of DA (5 ng/paw) was enhanced by bestatin (400 μg/paw), an inhibitor of endogenous opioid peptide degradation. Conversely, peripheral antinociception from submaximal doses of the μ-, δ-, and κ-opioid agonists DAMGO (0.25 μg/paw; [D-Ala², N-Me-Phe⁴, Gly⁵-ol]-Enkephalin), SNC 80 (5 μg/paw; (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide), and bremazocine (200 ng/paw) was increased by the DA reuptake inhibitor GBR 12783 (16 μg/paw; 1-(2-Diphenylmethoxyethyl)-4-(3-phenyl-2-propenyl)-piperazine). Furthermore, the antinociception from these agonists' maximum doses was reversed by dopaminergic D2 (remoxipride, 4 μg/paw) and D3 (U99194, 16 μg/paw; 2,3-Dihydro-5,6-dimethoxy-N, N-dipropyl-1H-inden-2-amine) receptor antagonists, but not by the D4 (L-745, 870, 16 μg/paw; 3-(4-[4-Chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride) receptor antagonist.

Overall, the data suggest that opioid-mediated antinociception depends on the activation of the dopaminergic system. This demonstrates that pain modulation can be enhanced through the interaction of these systems. Controlling pain at a peripheral level by activating endogenous pathways could be a promising approach to pain management.