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.