Vol. 292, Issue 1, 331-336, January 2000

Effect of Intrathecal Nocistatin on the Formalin-Induced Pain in Mice Versus That of Nociceptin/Orphanin FQ¹

Hiroyuki Nakano, Toshiaki Minami, Kohji Abe, Tohko Arai, Miwa Tokumura, Nobuhiro Ibii, Emiko Okuda-Ashitaka, Hidemaro Mori and Seiji Ito

Department of Anesthesiology, Osaka Medical College, Takatsuki (H.N., T.M., H.M.); Department of Pharmacology, Developmental Research Laboratories, Shionogi and Co., Ltd., Toyonaka (K.A., T.A., M.T., N.I.); and Department of Medical Chemistry, Kansai Medical University, Moriguchi (E.O.A., S.I.), Japan

The effect of intrathecal nocistatin on formalin-induced pain in mice was investigated and compared with that of nociceptin/orphanin FQ (Noc/OFQ) to get information on the functional relationship between nocistatin and Noc/OFQ in the spinal cord. Subcutaneous injection of formalin into the hindpaw induced biphasic pain behaviors. Nocistatin, 1 pg, given intrathecally 1 min before 2% formalin injection, significantly attenuated the first phase of the formalin-induced pain. Also, 10 to 1000 pg of nocistatin, given 10 min after formalin injection, significantly inhibited the second phase of the formalin test. Naloxone, 5 mg/kg i.p., failed to antagonize inhibitory effects of nocistatin on either phase of the formalin-induced pain, indicating that analgesic effects of nocistatin were unrelated to the classic opioid system. At 1 to 100 pg, Noc/OFQ exerted no influence on either phase of the 2% formalin-induced pain. However, at 1% formalin, Noc/OFQ significantly aggravated the second phase at 10 pg but not the first phase at 1 to 1000 pg. This aggravating effect of Noc/OFQ was completely reversed by 10 pg of nocistatin. At 0.3 and 1 µg, Noc/OFQ, but not nocistatin, significantly inhibited both phases of the 2% formalin-induced pain. Suppressive effects of 1 µg of Noc/OFQ on the formalin-induced pain were not affected by 1 µg of nocistatin. These results suggest that Noc/OFQ might be involved in the second phase of the mouse formalin test and that, under such pathophysiological conditions, nocistatin could exhibit antagonism against Noc/OFQ at the spinal level.