Biphasic regulation of the acute µ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum

Pietro Marini, Luca Romanelli, Daniela Valeri, Maria Grazia Cascio, Paolo Tucci, Pacifico Valeri, Maura Palmery

Research output: Contribution to journalArticle

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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 A1-adenosine and the cannabinoid CB1 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.
Original languageEnglish
Pages (from-to)100-110
Number of pages11
JournalPharmacological Research
Volume65
Issue number1
DOIs
Publication statusPublished - Jan 2012

Fingerprint

Opioid Receptors
Contracture
Ileum
Guinea Pigs
Opioid Analgesics
G-Protein-Coupled Receptors
Enteric Nervous System
Cannabinoids
Adenosine
Organism Cloning
Peptides
cholecystokinin 8

Keywords

  • acute µ-withdrawal
  • cholecystokinin-8 (CCk-8)
  • opioid-receptor like receptor (ORL-1)
  • orphaninFQ/nociceptin (OFQ/N)
  • UFP-101
  • guinea pig ileum (GPI)

Cite this

Biphasic regulation of the acute µ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum. / Marini, Pietro; Romanelli, Luca; Valeri, Daniela ; Cascio, Maria Grazia; Tucci, Paolo; Valeri, Pacifico; Palmery, Maura.

In: Pharmacological Research, Vol. 65, No. 1, 01.2012, p. 100-110.

Research output: Contribution to journalArticle

Marini, Pietro ; Romanelli, Luca ; Valeri, Daniela ; Cascio, Maria Grazia ; Tucci, Paolo ; Valeri, Pacifico ; Palmery, Maura. / Biphasic regulation of the acute µ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum. In: Pharmacological Research. 2012 ; Vol. 65, No. 1. pp. 100-110.
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AB - 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 A1-adenosine and the cannabinoid CB1 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.

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