Nocistatin reverses the effect of orphanin FQ/nociceptin in antagonizing morphine analgesia

Abstract

Nocistatin is a recently characterized neuropeptide derived from the preprohormone containing nociceptin (Orphanin FQ, OFQ). Nocistatin was reported to antagonize OFQ induced allodynia, hyperalgesia and prostaglandin E2-elicited pain responses. The aim of the present study was to determine whether nocistatin, injected intracerebroventricularly (i.c.v.), would reverse the anti-morphine effect of OFQ in rats using the tail-flick latency (TFL) as the nociceptive index. I.c.v. injection of nocistatin at doses of 0.005, 0.05, 0.5, 5, 50, and 500 ng produced no significant changes in the basal TFL, nor did it affect morphine analgesia. However, it significantly reversed the antagonistic effect of OFQ on morphine analgesia when co-injected i.c.v. at doses of 0.05, 0.5, 5, 50 and 500 ng per rat with OFQ. The dose-response curve was bell-shaped and the most effective dose was 0.5 ng. The results suggest that nocistatin can reverse the anti-morphine effect of OFQ in rat brain.

Central injections of nocistatin or its C‐terminal hexapeptide exert anxiogenic‐like effect on behaviour of mice in the plus‐maze test

“…Similarly, the curve for i.c.v. NST for reversal of the antagonism of morphine-induced analgesia by N/OFQ in the rat is also bell-shaped (Zhao et al, 1999), as is that for the allodynic e ect of i.t. N/OFQ in mice (Okuda-Ashitaka et al, 1998).…”

“…Interestingly, although the other ppN/OFQ-derived peptide, NST, does not bind to the NOP receptor, it seems to act as a functional antagonist of N/OFQ. Indeed, several biological e ects of N/OFQ are antagonized by NST, such as nociception in various experimental conditions (Martin et al, 1998;Okuda-Ashitaka et al, 1998;Yamamoto & Sakashita, 1999;Nakano et al, 2000), morphine analgesia (Zhao et al, 1999), N/OFQ impairing e ects on learning/memory (Hiramatsu & Inoue, 1999), food intake (Olszewski et al, 2000) and glutamate release (Nicol et al, 1998). Jenck et al (1997) have described anxiolytic-like e ects of i.c.v.…”

Pharmacological Characterization of the Nociceptin Receptor, ORL1

“…It does not bind to ORL1 but blocks allodynia and hyperalgesia induced by intrathecally injected OFQ/N and prostaglandin E 2 -induced pain response [44]. In addition, it was reported to also antagonize the reversal effect of OFQ/N in morphineinduced supraspinal analgesia [61]. This functional antagonism was also proved in the inhibition of glutamate release from rat brain slices [39] and memory impairment [25].…”

Pain Regulation by Nocistatin-Targeting Molecules

“…Furthermore, the i.c.v. administration of NST reverses N/OFQ-induced biological activities such as hyperalgesia, anti-opioid analgesia (Liu, Nishiuchi, Kimura, & Tachibana, 2006;Scoto, Santangelo, & Parenti, 2005;Zhao et al, 1996), impairment of learning and memory (Hiramatsu & Inoue, 1999), anxiolytic and anxiogenic actions (Gavioli, Rae, Calo, Guerrini, & de Lima, 2002;Kamei, Matsunawa, Miyata, Tanaka, & Saitoh, 2004), and an increase in food intake (Olszewski, Shaw, Grace, Billington, & Levine, 2000). NST has no effects under physiologically normal conditions, but NST itself has inhibitory effects on inflammatory pain responses induced by formalin and carrageenan/kaolin (Nakagawa, Kaneko, Inamura, & Satoh, 1999;Nakano et al, 2000;Yamamoto & Sakashita, 1999), hyperalgesia in chronic constriction injury (CCI) to the sciatic nerve, and morphine tolerance (Ge et al, 2007;Sun et al, 2001).…”