Involvement of endogenous opioid peptides in the antinociception induced by the novel dermorphin tetrapeptide analog amidino-TAPA.
The antinociceptive effect of i.t. administered N(alpha)-amidino-Tyr-d-Arg-Phe-beta-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 mu-opioid receptors, a low affinity to delta-opioid receptors and no affinity for kappa-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 mu-opioid receptor antagonist beta-funaltrexamine, the kappa-opioid receptor antagonist nor-binaltorphimine and the delta-opioid receptor antagonist naltrindole. Moreover, the antinociception induced by amidino-TAPA was significantly attenuated by i.t. pretreatment with antisera against the endogenous kappa-opioid peptides dynorphin A, dynorphin B and alpha-neo-endorphin; and the endogenous delta-opioid peptide [Leu(5)]enkephalin. In mice lacking prodynorphin, the precursor of the endogenous kappa-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 mu-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 mu-opioid receptors.
Mizoguchi
Hirokazu
H
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Watanabe
Chizuko
C
Watanabe
Hiroyuki
H
Moriyama
Kaori
K
Sato
Bunsei
B
Ohwada
Keiko
K
Yonezawa
Akihiko
A
Sakurada
Tsukasa
T
Sakurada
Shinobu
S
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000502:physiology*
D000700:Analgesics; C520058:N(alpha)-amidino-Tyr-D-Arg-Phe-beta-Ala; D009842:Oligopeptides; D018847:Opioid Peptides; C059393:tyrosyl-arginyl-phenylalanyl-glycinamide; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-; D019204:GTP-Binding Proteins