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Am J Physiol Regul Integr Comp Physiol (April 17, 2003). doi:10.1152/ajpregu.00760.2002
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Submitted on December 16, 2002
Accepted on April 11, 2003

Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord

Ken-ichiro Hayashida1, Takashi Takeuchi1, Hirohiko Shimizu2, Kunio Ando2, and Etsumori Harada1*

1 Department of Veterinary Physiology, Tottori university, Tottori, Japan
2 Nuclear Receptor Ligand Co. Ltd., Kawasaki, Kanagawa, Japan

* To whom correspondence should be addressed. E-mail: harada{at}muses.tottori-u.ac.jp.

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via µ-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by co-administration with a nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), during phase 1 and phase 2 in the formalin test. Spinal co-administration of a µ-opioid receptor agonist, morphine, with sub-effective dose of BLF produced a much more highly potentiated analgesia compared to that of morphine alone during both phases in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a µ-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-NH2 (CTOP), or by L-NAME. In the tail-flick test, continuous spinal infusion of morphine via a mini-osmotic pump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via a NO-mediated mechanism.




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