Jpn. J. Pharmacol. 87 (4), 261-267 (2001)

Spinorphin, an Endogenous Inhibitor of Enkephalin-Degrading Enzymes, Potentiates Leu-Enkephalin-Induced Anti-allodynic and Antinociceptive Effects in Mice

Motoko Honda1,2, Hiroko Okutsu1, Tomoyuki Matsuura1, Tomohiro Miyagi1, Yukio Yamamoto3, Tadahiro Hazato3 and Hideki Ono1,2,*

1Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
2Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
3Department of Molecular Oncology, The Tokyo Metropolitan Institute of Medical Science, Honkomagome 3-18-22, Bunkyo-ku, Tokyo 113-0021, Japan

*Corresponding author (affiliation #2). FAX: +81-52-836-3676, E-mail:

Abstract: Spinorphin (LVVYPWT) has been isolated from the bovine spinal cord as an endogenous inhibitor of enkephalin-degrading enzymes. It has been reported that spinorphin has an antinociceptive effect, inhibitory effect on contraction of smooth muscle and anti-inflammatory effect. In the present study, the effects of leu-enkephalin and spinorphin on allodynia and mechanical and thermal nociceptions were examined in vivo using mice. Intrathecal (i.t.) administration of leu-enkephalin or spinorphin inhibited the allodynia induced by intrathecal nociceptin in a dose-dependent manner. Furthermore, spinorphin enhanced the inhibitory effect of enkephalin on allodynia induced by nociceptin. Naloxone antagonized both inhibitory effects of leu-enkephalin and spinorphin, suggesting that the endogenous opioidergic system can modulate allodynia. Intracerebroventricular (i.c.v.) administration of leu-enkephalin increased the nociceptive threshold of heat or mechanical stimulation to a mouse. Although i.c.v. administration of spinorphin had no effect on the threshold of heat or mechanical stimulation, spinorphin enhanced and prolonged the antinociceptive effect of leu-enkephalin. The enhancement of spinorphin on the antinociception produced by leu-enkephalin was reversed by pretreatment with naloxone. From these results, it is suggested that the effects of spinorphin on enkephalin-induced anti-allodynic and antinociceptive effects are due to inhibition of enkephalin-degrading enzymes.

Keywords: Spinorphin, Enkephalin-degrading enzyme, Antinociception, Allodynia

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