To elucidate the mechanism of the cellular antiopioid activity of neuropeptide FF (NPFF), we have transfected the SH-SY5Y neuroblastoma cell line, which expresses -and ␦-opioid receptors, with the human NPFF 2 receptor. The selected clone, SH 2 -D9, expressed high-affinity NPFF 2 receptors in the same range order as -and ␦-opioid receptors (100 -300 fmol/mg of protein channels by opioid agonists. In the presence of carbachol, acting on muscarinic receptors to release Ca 2ϩ from the intracellular stores, deltorphin-I and 1DMe enhanced this release. Preincubation with 1DMe reduced the maximal effect of deltorphin-I by 40%, demonstrating an antiopioid effect in this experimental model for the first time. By using peptides corresponding to the carboxyl terminus of the ␣ i1,2 , ␣ i3 , ␣ o , and ␣ s subunits of G proteins, which specifically uncouple receptors from G proteins, we demonstrated that -opioid and NPFF 2 receptors couple to the four subunits assayed. The Ca 2ϩ release from the intracellular stores by 1DMe resulted from the coupling of NPFF 2 receptors with G␣ o and G␣ i1,2 , whereas the coupling with G␣ s reduced the antiopioid effect of 1DMe in the modulation of N-type channels. This SH 2 -D9 cell line now provides the opportunity to study the interaction between both receptors.Neuropeptide FF (NPFF), FLFQPQRFamide, is representative of a family of mammalian amidated neuropeptides whose precursors pro-NPFF A and pro-NPFF B and G proteincoupled receptors NPFF 1 and NPFF 2 have been recently cloned (Zajac, 2001). Although NPFF does not interact with opioid receptors (Gouardères et al., 1998), a close relationship between neuropeptide FF and opioid systems has been clearly demonstrated in the central nervous system, especially in pain perception (Harrison et al., 1998;Roumy and Zajac, 1998;Panula et al., 1999). For instance, supraspinal injection of NPFF analogs, which has little or no effect in pain tests, decreases morphine-induced analgesia (antiopioid activity, Roumy and Zajac, 1998;Panula et al., 1999), whereas spinal administration induces a naloxone-sensitive analgesia and potentiates morphine-induced analgesia (proopioid activity, Roumy and Zajac, 1998;Panula et al., 1999).In neurons, opioids, including nociceptin, 1) inhibit adenylyl cyclase activity and 2) stimulate inwardly rectifying K ϩ channels and inhibit voltage-dependent Ca 2ϩ currents by activating four types, , ␦, , and Opioid Receptor-Like 1, of opioid receptors (Law et al., 2000). This leads to postsynaptic neuronal inhibition and to presynaptic inhibition of transmitter release, respectively. In contrast to opioids, no data report a direct modulation of K ϩ and Ca 2ϩ conductances by NPFF or analogs but rather describe a blockade of the opioid activity on ionic conductances when cells are pretreated with NPFF. NPFF or analogs, which are inactive by themselves, reverse the opioid-induced inhibition of Ca 2ϩ conductance in NPFF 2 receptor-expressing neurons dissociated from rat dorThis work was supported by the Centre National de l...
Opioids are involved in the physiological control of numerous functions of the central nervous system, particularly nociception. It appears that some endogenous neuropeptides, called anti-opioids, participate in an homeostatic system tending to reduce the effects of opioids. Neuropeptide FF (NPFF) and cholecystokinin (CCK) possess these properties and, paradoxically, the opioid peptides nociceptin and dynorphin display some anti-opioid activity. All these peptides exhibit complex properties as they are able to both counteract and potentiate opioid activity, acting rather as modulators of opioid functions. The purpose of this review is to highlight that two different mechanisms are clearly involved in the control of opioid functions by opioid-modulating peptides: a circuitry-induced mechanism for nociceptin and dynorphin, and a cellular anti-opioid mechanism for NPFF and CCK. The knowledge of these mechanisms has potential therapeutic interest in the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.