Potent in vivo antinociception and opioid receptor preference of the novel analogue [Dmt1]endomorphin-1

[Dmt1]Endomorphin-1 is a novel analogue of the potent μ-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: β-funaltrexamine (μ1/μ2-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (μ1-subtype) was ineffective in both neural pathways and naltrindole (δ-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by μ2-subtypes without involvement of μ1-opioid receptors; however, although a slight enhancement of antinociception by δ-receptors cannot be completely ruled out since functional bioactivity indicated mixed μ-agonism/δ-antagonism. In terms of the CNS action, [Dmt1]endomorphin-1 appears to act through μ2-opioid receptor subtypes.