Contribution of dopamine receptors to periaqueductal gray-mediated antinociception

Abstract

Rationale Morphine relieves pain, in part, by acting on neurons within the periaqueductal gray (PAG). Given that the PAG contains a subpopulation of dopamine neurons, dopamine may contribute to the antinociceptive effects mediated by the PAG. Methods This hypothesis was tested by measuring the behavioral and electrophysiological effects of administering dopamine agonists and antagonists into the ventrolateral PAG (vPAG). An initial histological experiment verified the existence of dopamine neurons within the vPAG using dopamine transporter and tyrosine hydroxylase antibodies visualized with confocal microscopy. Results Microinjection of cumulative doses of morphine into the vPAG caused antinociception that was dose-dependently inhibited by the dopamine receptor antagonist α-flupenthixol. α-Flupenthixol had no effect on nociception when administered alone. Injection of the dopamine receptor agonist (-) apomorphine into the vPAG caused a robust antinociception that was inhibited by the D2 antagonist eticlopride but not the D1 antagonist SCH-23390. The effects of dopamine on GABAA-mediated evoked inhibitory post-synaptic potentials (eIPSCs) were measured in PAG slices. Administration of met-enkephalin inhibited peak evoked inhibitory post-synaptic potentials (eIPSCs) by 20-50%. Dopamine inhibited eIPSC by approximately 20-25%. Administration of α-flupenthixol (20 μM) attenuated eIPSC inhibition by dopamine, but had no effect on met-enkephalin-induced inhibition. Conclusions These data indicate that PAG dopamine has a direct antinociceptive effect in addition to modulating the antinociceptive effect of morphine. The lack of an effect of α-flupenthixol on opioid-inhibition of eIPSCs indicates that this modulation occurs in parallel or subsequent to inhibition of GABA release.

Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation

“…These findings were consistent with previous studies which showed that selective D2-like dopamine receptor antagonists systemically attenuated the analgesia induced by systemic amphetamine, morphine and cocaine in the formalin test [38,39]. Moreover, the antinociceptive effects of apomorphine were blocked by the D2-like receptor antagonist, eticlopride [40]. In line with this, administration of a selective D2-like dopamine receptor agonist intracerebroventricularly or in the striatum produced antinociceptive effects [19,41].…”

Blockade of D1-like dopamine receptors within the ventral tegmental area and nucleus accumbens attenuates antinociceptive responses induced by chemical stimulation of the lateral hypothalamus

“…In addition, microinjection of SKF-38393into the ventrolateral orbital cortex did not exhibit any effects on formalin induced nociceptive behaviors [8]. Another study also showed that the antinociceptive effects of apomorphine were blocked by administration of eticlopride, D2-like receptor antagonist, but notSCH-23390 into the periaqueductal gray [16]. These inconsistent results may be due to different reasons such as, protocol (models of pain induction), animal models, and the brain areas investigated.…”

Catechol-O-methyltransferase gene polymorphism and chronic human pain

“…Dopamine neurons may communicate with neural areas that are involved in the affective aspects of pain [105,106]. Dopaminergic neuron depletion in the vPAG with 6-hydroxydopamine (6-OHDA) decreases opioid-induced antinociception in rats [107], and a more recent study suggests that dopamine may have a direct antinociceptive effect in addition to the modulation of the antinociceptive effects of morphine [108]. Both D 1 and D 2 dopamine receptors are expressed by PAG neurons; the former receptors are associated with morphine analgesia [107] and the latter receptors are associated with dopamine analgesia [108].…”

“…Dopaminergic neuron depletion in the vPAG with 6-hydroxydopamine (6-OHDA) decreases opioid-induced antinociception in rats [107], and a more recent study suggests that dopamine may have a direct antinociceptive effect in addition to the modulation of the antinociceptive effects of morphine [108]. Both D 1 and D 2 dopamine receptors are expressed by PAG neurons; the former receptors are associated with morphine analgesia [107] and the latter receptors are associated with dopamine analgesia [108]. It has been suggested that there are synaptic connections between dopaminergic and GABAergic neurons in the vPAG, which implicates the participation of dopaminergic neurons in analgesia.…”