Involvement of Local Orphanin FQ in the Tolerance Induced by Repeated Microinjections of Morphine into Ventrolateral Periaqueductal Gray in Rats

Abstract

The present study evaluated the role of ventrolateral periaqueductal gray (vlPAG)-located orphanin-FQ (OFQ) in the opioid tolerance induced by repeated microinjections of morphine (MOR) into vlPAG. Microinjection of MOR (5 µg/0.5 µl) into vlPAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if MOR microinjection was preceded by the OFQ receptor antagonist nocistatin (NST; 1 ng/0.5 µl), the microinjections of MOR did not induce tolerance. If NST microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single NST microinjection into vlPAG was enough to restore the antinociceptive effect of MOR. Furthermore, if OFQ (1 ng/0.5 µl) was microinjected into vlPAG, then a MOR microinjection administered 15 min later into vlPAG did not elicit antinociception. Finally, opioid tolerance induced by repeated systemic MOR injections (5 mg/kg, i.p.) was reversed by a single microinjection of NST into vlPAG. This emphasizes the central importance of vlPAG-located OFQ in the MOR tolerance.

Prohormone convertase 2 (PC2) null mice have increased mu opioid receptor levels accompanied by altered morphine-induced antinociception, tolerance and dependence

“…Interestingly, chronic morphine treatment has been shown to increase the level of pro-nociceptive peptides (Yuan et al, 1999). Additionally, OFQ/N has been shown to be involved in tolerance induced by repeated microinjections of morphine into ventrolateral periaqueductal gray in rats (Ge et al, 2007). Likewise, endogenous enkephalins have also been implicated in analgesic tolerance to morphine using tail flick assay (Nitsche et al, 2002, Marquez et al, 2006).…”

“…Orphanin FQ/Nociceptin (OFQ/N) production has also been found to be significantly lower in PC2 deficient mice (Allen et al, 2001). Interestingly, OFQ/N has been implicated in tolerance induced by repeated microinjections of morphine into ventrolateral periaqueductal gray in rats (Ge et al, 2007). Furthermore, endogenous enkephalins have been linked to analgesic tolerance to morphine (Nitsche et al, 2002, Marquez et al, 2006).…”

The Functional Antiopioid Action of the Ventrolateral Periaqueductal Gray Nociceptin/Orphanin FQ and Nociceptin Receptor System Underlies DAMGO Analgesic Tolerance

“…The role of N/OFQ as an antiopioid peptide is further strengthened by the observation that tolerance induced by repeated systemic morphine injections was reversed by a single vlPAG microinjection of nocistatin, a functional N/OFQ peptide antagonist [39] and another pre-pro-N/OFQ-derived peptide [46] . Thus, our results support the existence of a dynamic interaction between N/OFQ and the opioid system in the vlPAG.…”

Pain Regulation by Nocistatin-Targeting Molecules

“…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). NST at high doses (nmol) has also been reported to induce pronociceptive effects on the inflammatory pain response by formalin (Ahmadi et al, 2003;Zeilhofer, Selbach, G€ uhring, Erb, & Ahmadi, 2000), hyperalgesia in CCI, and nociceptive flexor reflexes (Inoue, Kawashima, Allen, & Ueda, 2003).…”