PMID- 19773529
OWN - NLM
STAT- MEDLINE
DCOM- 20091222
LR  - 20221207
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 331
IP  - 3
DP  - 2009 Dec
TI  - Comparison of the antinociceptive and antirewarding profiles of novel 
      bifunctional nociceptin receptor/mu-opioid receptor ligands: implications for 
      therapeutic applications.
PG  - 954-64
LID - 10.1124/jpet.109.157446 [doi]
AB  - The nociceptin receptor (NOPr), a member of the opioid receptor family, is a 
      target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), 
      the endogenous peptide for NOPr, not only modulates opioid antinociception, but 
      also blocks the rewarding effects of several abused drugs, such as morphine, 
      cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional 
      activity at the mu-opioid receptor (MOPr), may function as nonaddicting 
      analgesics or as drug abuse medications. Bifunctional small-molecule NOPr 
      agonists possessing different selectivities and efficacies at MOPr were evaluated 
      in an acute thermal antinociception assay, and for their ability to induce 
      conditioned place preference (CPP) and their effect on morphine-induced CPP. 
      1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr 
      partial agonist, with low MOPr affinity and efficacy, produced analgesia that was 
      naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate 
      morphine-induced CPP. 
      3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), 
      which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, 
      and partial agonist activity at MOPr, was also a potent analgesic and produced 
      CPP alone, but also modestly attenuated morphine CPP. 
      1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one 
      (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not 
      antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our 
      results suggest that NOPr full-agonist activity is required to modulate 
      opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile 
      may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the 
      NOPr ligands may be used effectively to produce better medications for treatment 
      of drug abuse and pain.
FAU - Toll, Lawrence
AU  - Toll L
AD  - Neuropharmacology Program, SRI International, Menlo Park, California, USA.
FAU - Khroyan, Taline V
AU  - Khroyan TV
FAU - Polgar, Willma E
AU  - Polgar WE
FAU - Jiang, Faming
AU  - Jiang F
FAU - Olsen, Cris
AU  - Olsen C
FAU - Zaveri, Nurulain T
AU  - Zaveri NT
LA  - eng
GR  - R01 DA023281/DA/NIDA NIH HHS/United States
GR  - R01 DA014026/DA/NIDA NIH HHS/United States
GR  - R01DA023281/DA/NIDA NIH HHS/United States
GR  - R01DA14026/DA/NIDA NIH HHS/United States
GR  - R01 DA027811/DA/NIDA NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090922
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Ligands)
RN  - 0 (Receptors, Opioid)
RN  - 0 (Receptors, Opioid, mu)
RN  - 0 (Nociceptin Receptor)
SB  - IM
MH  - Analgesics, Opioid/adverse effects/chemistry/pharmacology/*therapeutic use
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - CHO Cells
MH  - Conditioning, Classical/drug effects
MH  - Cricetinae
MH  - Cricetulus
MH  - Humans
MH  - Ligands
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Molecular Structure
MH  - Opioid-Related Disorders/etiology/metabolism/*prevention & control/psychology
MH  - Pain/*drug therapy/metabolism/psychology
MH  - Protein Binding
MH  - Radioligand Assay
MH  - Receptors, Opioid/*agonists
MH  - Receptors, Opioid, mu/*agonists
MH  - *Reward
MH  - Transfection
MH  - Nociceptin Receptor
PMC - PMC2784720
EDAT- 2009/09/24 06:00
MHDA- 2009/12/23 06:00
PMCR- 2010/12/01
CRDT- 2009/09/24 06:00
PHST- 2009/09/24 06:00 [entrez]
PHST- 2009/09/24 06:00 [pubmed]
PHST- 2009/12/23 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - jpet.109.157446 [pii]
AID - 3537513 [pii]
AID - 10.1124/jpet.109.157446 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2009 Dec;331(3):954-64. doi: 10.1124/jpet.109.157446. Epub 
      2009 Sep 22.