Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance
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Abstract:
Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.Keywords:
Nociceptin receptor
Endogenous opioid
Crosstalk
Nociceptin receptor
Periaqueductal gray
Neurochemical
Met-enkephalin
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A peptide termed nociceptin/orphanin FQ (N/OFQ) was recently identified as an endogenous agonist for the opioid receptor-like receptor currently specified as NOP receptor. Despite many structural homologies to the opioid system, the NOP receptor shows low-affinity binding to selective opioid agonists or antagonists. Vice versa, N/OFQ selectively activates the NOP receptor but not any opioid receptor subtype. This novel receptor/ligand system is widely expressed in the brain. At the cellular level, the actions of N/OFQ resemble those elicited by opioid peptides. The NOP receptor is coupled to G-proteins, whose activation results in inhibition of adenylate cyclase, modulation of calcium and potassium conductances, and regulation of transmitter systems. At the behavioral level, systemic application of N/OFQ elicits a unique range of responses, including a wide range of effects on pain processing such as hyperalgesia, analgesia, and allodynia, as well as anxiolytic actions, modulation of opioid-mediated processes, and influences on learning and memory. NEUROSCIENTIST 9(2): 158–168, 2003.
Nociceptin receptor
NOP
Allodynia
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Endogenous opioid
Endorphins
Opioid antagonist
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Nociceptin receptor
Dynorphin
Dynorphin A
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Nociceptin receptor
NOP
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The aim of the present study was to delineate the functional domains of nociceptin (noc), a neuropeptide which is structurally related to dynorphin A (dyn). The binding and biological potencies towards the nociceptin (ORL1) and dynorphin A (kappa-opioid) receptors of twenty dyn/noc and noc/dyn hybrid peptides were compared with those of the parent heptadecapeptides. Replacement of as many as eleven residues in the C-terminus of dynorphin by the corresponding nociceptin sequence has no significant effect on binding and biological activity towards the kappa-opioid receptor. In marked contrast, replacement of as few as six residues (RKLANQ) in the C-terminus of nociceptin by the corresponding dynorphin sequence (LKWDNQ) dramatically impairs both affinity and activity towards the ORL1 receptor. This clearly indicates that the two neuropeptides have different functional architectures, despite the dual structural homology of both ligands and receptors. Moreover, the recombinant peptide approach led us to identify hybrids whose sequences differ only at positions 5 and 6 and displaying opposite or no receptor selectivity. One contains the dynorphin Leu5-Arg6 sequence and prefers the kappa-opioid receptor, whereas the other comprises the nociceptin Thr5-Gly6 sequence and prefers the ORL1 receptor. A third, containing the mixed dynorphin/nociceptin Leu5-Gly6 sequence, does not discriminate between the two types of receptor.
Nociceptin receptor
Dynorphin
Dynorphin A
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Background : The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1 . Methods and Results: In the present study, responses to nociceptin, [Tyr 1 ]-nociceptin, noci ceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the systemic vascu lar bed of the rabbit. Nociceptin and [Tyr 1 ]-nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr 1 ]-nociceptin and nociceptin were similar in potency. However, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to nociceptin and [Tyr 1 ]-nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to noci ceptin and [Tyr 1 ]-nociceptin arc mediated by the activation of a naloxone-insensitive opioid receptor and arc not dependent on the presence of Phc at the N-terminus of the nociceptin sequence. Moreover, the present results show that nociceptin-(2-17). nociceptin-(1-11), and nociccptin-(1-7) do not after SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.
Nociceptin receptor
NOP
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Endogenous opioid
Opioid antagonist
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A new type of endogenous opioid peptide, Nociceptin was discovered at the end of 1995. It is the endogenous ligand of opioid receptor-like1 receptor (ORL1 or LC132). Now, the studies on its hyperalgesia and analgesia, locomotion ability, ion chance, blood pressure and heart rates, analogues, antagonist and structure activity relationship are reviewed.
Nociceptin receptor
Endogenous opioid
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