PT  - JOURNAL ARTICLE
AU  - Makoto Inoue
AU  - Shinobu Matsunaga
AU  - M. Harunor Rashid
AU  - Akira Yoshida
AU  - Kiyonobu Mizuno
AU  - Tsukasa Sakurada
AU  - Hiroshi Takeshima
AU  - Hiroshi Ueda
TI  - Pronociceptive Effects of Nociceptin/Orphanin FQ (13–17) at Peripheral and Spinal Level in Mice
DP  - 2001 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 213--219
VI  - 299
IP  - 1
4099  - http://jpet.aspetjournals.org/content/299/1/213.short
4100  - http://jpet.aspetjournals.org/content/299/1/213.full
SO  - J Pharmacol Exp Ther2001 Oct 01; 299
AB  - The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is reported to be metabolized by aminopeptidase N and endopeptidase 24.15. In the present study, N/OFQ C-terminal fragments elicited nociceptive responses in the peripheral nociceptors and in the spinal cord, whereas N-terminal fragments had no significant nociception. The nociceptive effect of N/OFQ (13–17) was most potent and remained unchanged in N/OFQ peptide receptor (NOPR) gene knockout mice, indicating that N/OFQ (13–17)-induced nociception is mediated through a novel mechanism independent of the activation of NOPR. This finding was further confirmed by in vitro guanosine 5′-O-(3-[35S]thio)triphosphate binding experiments, in which N/OFQ (13–17) showed no significant binding activity in baculovirus/sf21 cells expressing NOPR together with G protein αi1-, β1-, and γ2-subunits, whereas N/OFQ showed stimulation in a concentration-dependent manner. On the other hand, although a typical bell-shaped dose-response relationship was observed with a wide range of N/OFQ doses in both peripheral and central nociception tests, N/OFQ (13–17) did not show bell-shaped dose-response relationship in the central nociception test. This finding indicates that N/OFQ (13–17), in contrast to N/OFQ, lacks the postsynaptic antinociceptive actions modulating substance P signaling in the spinal cord. Together, our results suggest that C-terminal fragments of N/OFQ have potent nociceptive actions, and N/OFQ (13–17) could have the potential to mediate its actions through a novel mechanism independent of the activation of NOPR in the nociceptors and in spinal synapses. The American Society for Pharmacology and Experimental Therapeutics