title: Biphasic regulation of the acute μ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum.
abstract: The cloning of the opioid-receptor-like receptor (ORL-1) and the identification of the orphaninFQ/nociceptin (OFQ/N) as its endogenous agonist has revealed a new G-protein-coupled receptor signalling system. The structural and functional homology of ORL-1 to the opioid receptor systems has posed a number of challenges in the understanding the often competing physiological responses elicited by these G-protein-coupled receptors. We had previously shown that in guinea pig ileum (GPI), the acute μ-withdrawal response is under the inhibitory control of several systems. Specifically, we found that the exposure to a μ-opioid receptor agonist activates indirectly the κ-opioid, the A(1)-adenosine and the cannabinoid CB(1) systems, that in turn inhibit the withdrawal response. The indirect activation of these systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated whether the ORL-1 system is also involved in the regulation of the acute μ-withdrawal response. Interestingly, we found that in GPI preparation, the ORL-1 system is not indirectly activated by the μ-opioid receptor stimulation, but instead the system is able by itself to directly regulate the acute μ-withdrawal response. Moreover, we have demonstrated that the ORL-1 system behaves both as anti-opioid or opioid-like system based on the level of activation. The same behaviour has also been observed in presence of CCk-8. Furthermore, in GPI, the existence of an endogenous tone of the ORL-1 system has been demonstrated. We concluded that the ORL-1 system acts as a neuromodulatory system, whose action is strictly related to the modulation of excitatory neurotrasmitters released in GPI enteric nervous system.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. p.marini@abdn.ac.uk
authors.forename: Pietro
authors.initials: P
authors.lastname: Marini
authors.forename: Luca
authors.initials: L
authors.lastname: Romanelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Valeri
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Paolo
authors.initials: P
authors.lastname: Tucci
authors.forename: Pacifico
authors.initials: P
authors.lastname: Valeri
authors.forename: Maura
authors.initials: M
authors.lastname: Palmery
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D012844:Sincalide / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000701:Analgesics, Opioid; D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D012844:Sincalide; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C030058:dermorphin