PMID- 9721727
OWN - NLM
STAT- MEDLINE
DCOM- 19980921
LR  - 20231213
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 71
IP  - 3
DP  - 1998 Sep
TI  - Nociceptin (ORL-1) and mu-opioid receptors mediate mitogen-activated protein 
      kinase activation in CHO cells through a Gi-coupled signaling pathway: evidence 
      for distinct mechanisms of agonist-mediated desensitization.
PG  - 1024-33
AB  - The recently identified 17-amino acid peptide nociceptin (orphanin FQ) is the 
      endogenous ligand for the opioid receptor-like-1 (ORL-1) receptor. A physiologic 
      role for nociceptin (OFQ) activation of the ORL-1 receptor (OFQR) may be to 
      modulate opioid-induced analgesia. The molecular mechanism by which nociceptin 
      (OFQ) and ORL-1 (OFQR) modify opioid-stimulated effects, however, is unclear. 
      Both ORL-1 (OFQR) and opioid receptors mediate pertussis toxin (PTX)-sensitive 
      signal transduction, indicating these receptors are capable of coupling to Gi/Go 
      proteins. This study determines that nociceptin stimulates an intracellular 
      signaling pathway, leading to activation of mitogen-activated protein (MAP) 
      kinase in CHO cells expressing ORL-1 receptor (OFQR). Nociceptin (OFQ)-stimulated 
      MAP kinase activation was inhibited by PTX or by expression of the carboxyl 
      terminus of beta-adrenergic receptor kinase (betaARKct), which specifically 
      blocks Gbetagamma-mediated signaling. Expression of the proline-rich domain of 
      SOS (SOS-PRO), which inhibits SOS interaction with p21ras, also attenuated 
      nociceptin (OFQ)-stimulated MAP kinase activation. The phosphatidylinositol 
      3-kinase (PI-3K) inhibitors wortmannin and LY294002 reduced nociceptin 
      (OFQ)-stimulated MAP kinase activation, whereas inhibition of protein kinase C 
      (PKC) activity by bisindolylmaleimide I or cellular depletion of PKC had no 
      effect. In a similar manner, in cells expressing mu-opioid receptor, 
      [D-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO; a mu-opioid receptor-selective 
      agonist) stimulated PTX-sensitive MAP kinase activation that was inhibited by 
      wortmannin, LY294002, betaARKct expression, or SOS-PRO expression but not 
      affected by inhibition of PKC activity. These results indicate that both ORL-1 
      (OFQR) and mu-opioid receptors mediate MAP kinase activation via a signaling 
      pathway using the betagamma-subunit of Gi, a PI-3K, and SOS, independent of PKC 
      activity. In cells expressing both ORL-1 (OFQR) and mu-opioid receptors, 
      pretreatment with nociceptin decreased subsequent nociceptin (OFQ)- or 
      DAMGO-stimulated MAP kinase activation. In contrast, pretreatment of cells with 
      DAMGO decreased subsequent DAMGO-stimulated MAP kinase but had no effect on 
      subsequent nociceptin (OFQ)-stimulated MAP kinase activation. These results 
      demonstrate that nociceptin (OFQ) activation of ORL-1 (OFQR) can modulate 
      mu-opioid receptor signaling in a cellular system.
FAU - Hawes, B E
AU  - Hawes BE
AD  - Department of CNS and Cardiovascular Research, Schering Plough Research 
      Institute, Kenilworth, New Jersey 07033, USA.
FAU - Fried, S
AU  - Fried S
FAU - Yao, X
AU  - Yao X
FAU - Weig, B
AU  - Weig B
FAU - Graziano, M P
AU  - Graziano MP
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Opioid Peptides)
RN  - 0 (Receptors, Opioid)
RN  - 0 (Receptors, Opioid, mu)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - 0 (Nociceptin Receptor)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cricetinae
MH  - Enzyme Activation/physiology
MH  - GTP-Binding Proteins/*physiology
MH  - Humans
MH  - Opioid Peptides/pharmacology
MH  - Receptors, Opioid/agonists/drug effects/*physiology
MH  - Receptors, Opioid, mu/agonists/drug effects/*physiology
MH  - Signal Transduction/*physiology
MH  - Nociceptin Receptor
MH  - Nociceptin
EDAT- 1998/08/29 00:00
MHDA- 1998/08/29 00:01
CRDT- 1998/08/29 00:00
PHST- 1998/08/29 00:00 [pubmed]
PHST- 1998/08/29 00:01 [medline]
PHST- 1998/08/29 00:00 [entrez]
AID - 10.1046/j.1471-4159.1998.71031024.x [doi]
PST - ppublish
SO  - J Neurochem. 1998 Sep;71(3):1024-33. doi: 10.1046/j.1471-4159.1998.71031024.x.