PMID- 26235542
OWN - NLM
STAT- MEDLINE
DCOM- 20160608
LR  - 20221207
IS  - 1873-2747 (Electronic)
IS  - 0361-9230 (Linking)
VI  - 117
DP  - 2015 Aug
TI  - A new potent analgesic agent with reduced liability to produce morphine 
      tolerance.
PG  - 32-8
LID - S0361-9230(15)30015-0 [pii]
LID - 10.1016/j.brainresbull.2015.07.005 [doi]
AB  - The therapeutic use of opioids is limited by the development of tolerance to the 
      analgesic effect and the cellular and molecular mechanisms underlying this 
      phenomenon are still not completely understood. For this reason the search for 
      new analgesic derivatives, endowed with lower tolerance, is always an active 
      field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows 
      high efficacy in in vitro assays and a strong analgesic action in the rat tail 
      flick test. The aim of present work was to investigate: the analgesic effect of 
      14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 
      14-O-MeM6SU compared to morphine in mice, the effects of test compounds on 
      glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic 
      currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and 
      the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene 
      expression in SH-SY5Y neuroblastoma cells expressing mu-opioid (MOP) and 
      nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more 
      potent than morphine in analgesia and had long duration of action in analgesic 
      dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 
      200 mumol/kg morphine or with 14-O-MeM6SU (12 mumol/kg) twice daily for three days. 
      The magnitude of tolerance or cross-tolerance indicated by the shift in 
      antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. 
      Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal 
      neurons of rat prefrontal cortical slices in the presence of bicuculline were 
      performed. Both 14-O-MeM6SU (0.1 muM) and morphine (1 muM) decreased the frequency 
      of sEPSCs, indicating reduction of glutamate release. The effect of the novel 
      compound was reversed by the opioid receptor antagonist naloxone, indicating an 
      opioid mediated action. In contrast, the amplitude was not affected. Finally, 
      gene expression data showed a dose dependent down-regulation of MOP receptor 
      after 24h and 48 h exposure to 14-O-MeM6SU. Interestingly, no changes were 
      detected for NOP receptor gene expression. The specific lack of this effect could 
      be related to the lower tolerance development to analgesic effect of 14-O-MeM6SU. 
      Furthermore, 14-O-MeM6SU displayed high intrinsic efficacy possibly an important 
      factor in the observed effects. Further, the observed inhibition of glutamatergic 
      signaling might be attributed also to the reduction of opioid tolerance. Based on 
      our results the development of a new clinically important, safe analgesic agent 
      might be possible.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Kiraly, Kornel
AU  - Kiraly K
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Caputi, Francesca Felicia
AU  - Caputi FF
AD  - Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, 
      University of Bologna, Via Irnerio 48, Bologna 40126, Italy.
FAU - Hanuska, Adrienn
AU  - Hanuska A
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Kato, Erzsebet
AU  - Kato E
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Balogh, Mihaly
AU  - Balogh M
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Koles, Laszlo
AU  - Koles L
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Palmisano, Martina
AU  - Palmisano M
AD  - Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, 
      University of Bologna, Via Irnerio 48, Bologna 40126, Italy.
FAU - Riba, Pal
AU  - Riba P
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Hosztafi, Sandor
AU  - Hosztafi S
AD  - Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u., 
      9. H-1092 Budapest, Hungary.
FAU - Romualdi, Patrizia
AU  - Romualdi P
AD  - Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, 
      University of Bologna, Via Irnerio 48, Bologna 40126, Italy.
FAU - Candeletti, Sanzio
AU  - Candeletti S
AD  - Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, 
      University of Bologna, Via Irnerio 48, Bologna 40126, Italy.
FAU - Ferdinandy, Peter
AU  - Ferdinandy P
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Furst, Susanna
AU  - Furst S
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary.
FAU - Al-Khrasani, Mahmoud
AU  - Al-Khrasani M
AD  - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad 
      ter 4, H-1089 Budapest, Hungary. Electronic address: 
      al-khrasani.mahmoud@med.semmelweis-univ.hu.
LA  - eng
PT  - Journal Article
DEP - 20150730
PL  - United States
TA  - Brain Res Bull
JT  - Brain research bulletin
JID - 7605818
RN  - 0 (14-O-methylmorphine-6-O-sulfate)
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Narcotic Antagonists)
RN  - 0 (Receptors, Opioid)
RN  - 0 (Receptors, Opioid, mu)
RN  - 36B82AMQ7N (Naloxone)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 76I7G6D29C (Morphine)
RN  - UX6OWY2V7J (Codeine)
RN  - 0 (Nociceptin Receptor)
SB  - IM
MH  - Analgesics, Opioid/adverse effects/*pharmacology
MH  - Animals
MH  - Cell Line, Tumor
MH  - Codeine/adverse effects/*analogs & derivatives/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Drug Tolerance
MH  - Excitatory Postsynaptic Potentials/drug effects
MH  - Glutamic Acid/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Morphine/adverse effects/*pharmacology
MH  - Naloxone/pharmacology
MH  - Narcotic Antagonists/pharmacology
MH  - Nociceptive Pain/drug therapy
MH  - Prefrontal Cortex/drug effects/physiology
MH  - Pyramidal Cells/drug effects/physiology
MH  - Rats, Wistar
MH  - Receptors, Opioid/genetics/metabolism
MH  - Receptors, Opioid, mu/genetics/metabolism
MH  - Synaptic Transmission/drug effects/physiology
MH  - Tissue Culture Techniques
MH  - Nociceptin Receptor
OTO - NOTNLM
OT  - 14-O-Methylmorphine-6-sulfate
OT  - Analgesia
OT  - Glutamatergic transmission
OT  - MOP receptor down-regulation
OT  - Tolerance
EDAT- 2015/08/04 06:00
MHDA- 2016/06/09 06:00
CRDT- 2015/08/04 06:00
PHST- 2015/06/04 00:00 [received]
PHST- 2015/07/22 00:00 [revised]
PHST- 2015/07/24 00:00 [accepted]
PHST- 2015/08/04 06:00 [entrez]
PHST- 2015/08/04 06:00 [pubmed]
PHST- 2016/06/09 06:00 [medline]
AID - S0361-9230(15)30015-0 [pii]
AID - 10.1016/j.brainresbull.2015.07.005 [doi]
PST - ppublish
SO  - Brain Res Bull. 2015 Aug;117:32-8. doi: 10.1016/j.brainresbull.2015.07.005. Epub 
      2015 Jul 30.