RT Journal Article
SR Electronic
T1 Dose-Related Opposite Modulation by Nociceptin/Orphanin FQ of Substance P Nociception in the Nociceptors and Spinal Cord
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 308
OP 313
VO 291
IS 1
A1 Inoue, Makoto
A1 Shimohira, Ichiro
A1 Yoshida, Akira
A1 Zimmer, Andreas
A1 Takeshima, Hiroshi
A1 Sakurada, Tsukasa
A1 Ueda, Hiroshi
YR 1999
UL http://jpet.aspetjournals.org/content/291/1/308.abstract
AB We previously reported that the intraplantar (i.pl.) application of nociceptin/orphanin FQ (N/OFQ) at extremely low doses elicited a nociception through a substance P (SP) release from nociceptor endings. In the present study, the nociception induced by SP (and N/OFQ) was abolished by intrathecal (i.t.) injection of neurokinin1(SP receptor) antagonist, suggesting the involvement of the stimulation of nociceptive primary SP neuron and SP release into spinal synapses. On the other hand, similar low doses of N/OFQ (i.t.) exerted nociceptive responses, characterized by scratching, biting, and licking, and these responses were blocked by an neurokinin1antagonist (i.t.) or capsaicin pretreatment or in tachykinin 1 gene knockout mice (tac1−/− mice), suggesting that N/OFQ receptor (NOR) also exists on the spinal terminals of SP neurons. When wide ranges of N/OFQ doses were used, a typical bell-shaped dose-response relationship was observed in both peripheral and central nociception tests. Furthermore, N/OFQ (1 nmol) administered i.pl. blocked SP (i.pl.)-induced flexor responses, which were abolished by pertussis toxin pretreatment or in NOR gene knockout (NOR−/− ) mice. On the other hand, N/OFQ administered i.t. blocked SP (i.t.)-induced scratching, biting, and licking in capsaicin-pretreated and tac1−/− mice, and this antinociception was abolished in NOR−/− mice. All these findings suggest that N/OFQ has biphasic actions depending on doses in the nociceptors and spinal synapses and has postsynaptic antinociceptive actions in spinal cord by modulating SP signaling. The American Society for Pharmacology and Experimental Therapeutics