Involvement of endogenous opioid peptides in the antinociception induced by the novel dermorphin tetrapeptide analog amidino-TAPA

The antinociceptive effect of i.t. administered Nα-amidino-Tyr-d-Arg-Phe-β-Ala (amidino-TAPA), an N-terminal tetrapeptide analog of dermorphin, was characterized in ddY mice. In the opioid receptor ligand-binding assays using mouse brain membranes, amidino-TAPA showed a very high affinity for μ-opioid receptors, a low affinity to δ-opioid receptors and no affinity for κ-opioid receptors. In the mouse tail-flick test, i.t. treatment with amidino-TAPA produced a potent antinociception. The antinociception induced by amidino-TAPA was significantly attenuated by i.t. pretreatment with the μ-opioid receptor antagonist β-funaltrexamine, the κ-opioid receptor antagonist nor-binaltorphimine and the δ-opioid receptor antagonist naltrindole. Moreover, the antinociception induced by amidino-TAPA was significantly attenuated by i.t. pretreatment with antisera against the endogenous κ-opioid peptides dynorphin A, dynorphin B and α-neo-endorphin; and the endogenous δ-opioid peptide [Leu5]enkephalin. In mice lacking prodynorphin, the precursor of the endogenous κ-opioid peptides, the antinociceptive effect of amidino-TAPA was significantly attenuated compared to that in wild-type C57BL/6J mice. However, there was no difference in G-protein activation by amidino-TAPA in the spinal cord membranes from prodynorphin knockout mice and C57BL/6J mice. The present results suggest that the spinal antinociception induced by the μ-opioid receptor selective peptide amidino-TAPA is mediated in part by the release of endogenous opioid peptides in the spinal cord, which is caused by the direct stimulation of μ-opioid receptors.