PMID- 31024314
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 10
DP  - 2019
TI  - Efficacy-Based Perspective to Overcome Reduced Opioid Analgesia of Advanced 
      Painful Diabetic Neuropathy in Rats.
PG  - 347
LID - 10.3389/fphar.2019.00347 [doi]
LID - 347
AB  - Reduction of the opioid analgesia in diabetic neuropathic pain (DNP) results from 
      mu-opioid receptor (MOR) reserve reduction. Herein, we examined the 
      antinociceptive and antiallodynic actions of a novel opioid agonist 
      14-O-methymorphine-6-O-sulfate (14-O-MeM6SU), fentanyl and morphine in rats with 
      streptozocin-evoked DNP of 9-12 weeks following their systemic administration. 
      The antinociceptive dose-response curve of morphine but not of 14-O-MeM6SU or 
      fentanyl showed a significant right-shift in diabetic compared to non-diabetic 
      rats. Only 14-O-MeM6SU produced antiallodynic effects in doses matching 
      antinociceptive doses obtained in non-diabetic rats. Co-administered naloxone 
      methiodide (NAL-M), a peripherally acting opioid receptor antagonist failed to 
      alter the antiallodynic effect of test compounds, indicating the contribution of 
      central opioid receptors. Reduction in spinal MOR binding sites and loss in MOR 
      immunoreactivity of nerve terminals in the spinal cord and dorsal root ganglia in 
      diabetic rats were observed. G-protein coupling assay revealed low efficacy 
      character for morphine and high efficacy character for 14-O-MeM6SU or fentanyl at 
      spinal or supraspinal levels (E (max) values). Furthermore, at the spinal level 
      only 14-O-MeM6SU showed equal efficacy in G-protein activation in tissues of 
      diabetic- and non-diabetic animals. Altogether, the reduction of spinal opioid 
      receptors concomitant with reduced analgesic effect of morphine may be 
      circumvented by using high efficacy opioids, which provide superior analgesia 
      over morphine. In conclusion, the reduction in the analgesic action of opioids in 
      DNP might be a consequence of MOR reduction, particularly in the spinal cord. 
      Therefore, developing opioids of high efficacy might provide analgesia exceeding 
      that of currently available opioids.
FAU - Balogh, Mihaly
AU  - Balogh M
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Zador, Ferenc
AU  - Zador F
AD  - Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of 
      Sciences, Szeged, Hungary.
FAU - Zadori, Zoltan S
AU  - Zadori ZS
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Shaqura, Mohammed
AU  - Shaqura M
AD  - Department of Anaesthesiology and Intensive Care Medicine, Charite University 
      Berlin, Berlin, Germany.
FAU - Kiraly, Kornel
AU  - Kiraly K
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Mohammadzadeh, Amir
AU  - Mohammadzadeh A
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Varga, Bence
AU  - Varga B
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Lazar, Bernadette
AU  - Lazar B
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Mousa, Shaaban A
AU  - Mousa SA
AD  - Department of Anaesthesiology and Intensive Care Medicine, Charite University 
      Berlin, Berlin, Germany.
FAU - Hosztafi, Sandor
AU  - Hosztafi S
AD  - Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
FAU - Riba, Pal
AU  - Riba P
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Benyhe, Sandor
AU  - Benyhe S
AD  - Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of 
      Sciences, Szeged, Hungary.
FAU - Gyires, Klara
AU  - Gyires K
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Schafer, Michael
AU  - Schafer M
AD  - Department of Anaesthesiology and Intensive Care Medicine, Charite University 
      Berlin, Berlin, Germany.
FAU - Furst, Susanna
AU  - Furst S
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
FAU - Al-Khrasani, Mahmoud
AU  - Al-Khrasani M
AD  - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis 
      University, Budapest, Hungary.
LA  - eng
PT  - Journal Article
DEP - 20190409
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC6465774
OTO - NOTNLM
OT  - 14-O-methylmorphine-6-O-sulfate
OT  - diabetes
OT  - fentanyl
OT  - morphine
OT  - neuropathic pain
OT  - opioid efficacy
EDAT- 2019/04/27 06:00
MHDA- 2019/04/27 06:01
PMCR- 2019/04/09
CRDT- 2019/04/27 06:00
PHST- 2018/12/20 00:00 [received]
PHST- 2019/03/20 00:00 [accepted]
PHST- 2019/04/27 06:00 [entrez]
PHST- 2019/04/27 06:00 [pubmed]
PHST- 2019/04/27 06:01 [medline]
PHST- 2019/04/09 00:00 [pmc-release]
AID - 10.3389/fphar.2019.00347 [doi]
PST - epublish
SO  - Front Pharmacol. 2019 Apr 9;10:347. doi: 10.3389/fphar.2019.00347. eCollection 
      2019.