PMID- 22920535
OWN - NLM
STAT- MEDLINE
DCOM- 20130524
LR  - 20191112
IS  - 1874-4745 (Electronic)
IS  - 1874-4737 (Linking)
VI  - 5
IP  - 3
DP  - 2012 Sep
TI  - Direct association of Mu-opioid and NMDA glutamate receptors supports their 
      cross-regulation: molecular implications for opioid tolerance.
PG  - 199-226
AB  - In the nervous system, the interaction of opioids like morphine and its 
      derivatives, with the G protein-coupled Mu-opioid receptor (MOR) provokes the 
      development of analgesic tolerance, as well as physical dependence. Tolerance 
      implies that increasing doses of the drug are required to achieve the same 
      effect, a phenomenon that contributes significantly to the social problems 
      surrounding recreational opioid abuse. In recent years, our understanding of the 
      mechanisms that control MOR function in the nervous system, and that eventually 
      produce opioid tolerance, has increased greatly. Pharmacological studies have 
      identified a number of signaling proteins involved in morphine-induced tolerance, 
      including the N-methyl-D-aspartate acid glutamate receptor (NMDAR), nitric oxide 
      synthase (NOS), protein kinase C (PKC), protein kinase A (PKA), calcium 
      (Ca(2)(+))/calmodulin (CaM)-dependent kinase II (CaMKII), delta-opioid receptor (DOR) 
      and the regulators of G-protein signaling (RGS) proteins. There is general 
      agreement on the critical role of the NMDAR/nNOS/CaMKII pathway in this process, 
      which is supported by the recent demonstration of a physical association between 
      MORs and NMDARs in post-synaptic structures. Indeed, it is feasible that 
      treatments that diminish morphine tolerance may target distinct elements within 
      the same regulatory MOR-NMDAR pathway. Accordingly, we propose a model that 
      incorporates the most relevant signaling components implicated in opioid 
      tolerance in which, certain signals originating from the activated MOR are 
      perceived by the associated NMDAR, which in turn exerts a negative feedback 
      effect on MOR signaling. MOR- and NMDAR-mediated signals work together in a 
      sequential and interconnected manner to ultimately induce MOR desensitization. 
      Future studies of these phenomena should focus on adding further components to 
      this signaling pathway in order to better define the mechanism underlying MOR 
      desensitization in neural cells.
FAU - Garzon, Javier
AU  - Garzon J
AD  - Neurofarmacologia, Instituto de Neurobiologia Santiago Ramon y Cajal, Madrid 
      E-28002, Spain. jgarzon@cajal.csic.es
FAU - Rodriguez-Munoz, Maria
AU  - Rodriguez-Munoz M
FAU - Sanchez-Blazquez, Pilar
AU  - Sanchez-Blazquez P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United Arab Emirates
TA  - Curr Drug Abuse Rev
JT  - Current drug abuse reviews
JID - 101468123
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Receptors, Opioid, mu)
RN  - 76I7G6D29C (Morphine)
SB  - IM
MH  - Analgesics, Opioid/administration & dosage/*pharmacology
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Drug Tolerance
MH  - Humans
MH  - Models, Biological
MH  - Morphine/administration & dosage/pharmacology
MH  - Opioid-Related Disorders/physiopathology
MH  - Receptor Cross-Talk
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Receptors, Opioid, mu/*metabolism
MH  - Signal Transduction
EDAT- 2012/08/28 06:00
MHDA- 2013/05/28 06:00
CRDT- 2012/08/28 06:00
PHST- 2012/04/02 00:00 [received]
PHST- 2012/07/03 00:00 [revised]
PHST- 2012/07/20 00:00 [accepted]
PHST- 2012/08/28 06:00 [entrez]
PHST- 2012/08/28 06:00 [pubmed]
PHST- 2013/05/28 06:00 [medline]
AID - CDAR-EPUB-20120816-1 [pii]
AID - 10.2174/1874473711205030199 [doi]
PST - ppublish
SO  - Curr Drug Abuse Rev. 2012 Sep;5(3):199-226. doi: 10.2174/1874473711205030199.