PMID- 19453631
OWN - NLM
STAT- MEDLINE
DCOM- 20090729
LR  - 20211020
IS  - 1460-9568 (Electronic)
IS  - 0953-816X (Print)
IS  - 0953-816X (Linking)
VI  - 29
IP  - 10
DP  - 2009 May
TI  - Molecular architecture of endocannabinoid signaling at nociceptive synapses 
      mediating analgesia.
PG  - 1964-78
LID - 10.1111/j.1460-9568.2009.06751.x [doi]
AB  - Cannabinoid administration suppresses pain by acting at spinal, supraspinal and 
      peripheral levels. Intrinsic analgesic pathways also exploit endocannabinoids; 
      however, the underlying neurobiological substrates of endocannabinoid-mediated 
      analgesia have remained largely unknown. Compelling evidence shows that, upon 
      exposure to a painful environmental stressor, an endocannabinoid molecule called 
      2-arachidonoylglycerol (2-AG) is mobilized in the lumbar spinal cord in temporal 
      correlation with stress-induced antinociception. We therefore characterized the 
      precise molecular architecture of 2-AG signaling and its involvement in 
      nociception in the rodent spinal cord. Nonradioactive in situ hybridization 
      revealed that dorsal horn neurons widely expressed the mRNA of diacylglycerol 
      lipase-alpha (DGL-alpha), the synthesizing enzyme of 2-AG. Peroxidase-based 
      immunocytochemistry demonstrated high levels of DGL-alpha protein and CB(1) 
      cannabinoid receptor, a receptor for 2-AG, in the superficial dorsal horn, at the 
      first site of modulation of the ascending pain pathway. High-resolution electron 
      microscopy uncovered postsynaptic localization of DGL-alpha at nociceptive 
      synapses formed by primary afferents, and revealed presynaptic positioning of 
      CB(1) on excitatory axon terminals. Furthermore, DGL-alpha in postsynaptic 
      elements receiving nociceptive input was colocalized with metabotropic glutamate 
      receptor 5 (mGluR(5)), whose activation induces 2-AG biosynthesis. Finally, 
      intrathecal activation of mGluR(5) at the lumbar level evoked 
      endocannabinoid-mediated stress-induced analgesia through the DGL-2-AG-CB(1) 
      pathway. Taken together, these findings suggest a key role for 2-AG-mediated 
      retrograde suppression of nociceptive transmission at the spinal level. The 
      striking positioning of the molecular players of 2-AG synthesis and action at 
      nociceptive excitatory synapses suggests that pharmacological manipulation of 
      spinal 2-AG levels may be an efficacious way to regulate pain sensation.
FAU - Nyilas, Rita
AU  - Nyilas R
AD  - Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 
      43., H-1083 Budapest, Hungary.
FAU - Gregg, Laura C
AU  - Gregg LC
FAU - Mackie, Ken
AU  - Mackie K
FAU - Watanabe, Masahiko
AU  - Watanabe M
FAU - Zimmer, Andreas
AU  - Zimmer A
FAU - Hohmann, Andrea G
AU  - Hohmann AG
FAU - Katona, Istvan
AU  - Katona I
LA  - eng
GR  - R01 DA021644-04/DA/NIDA NIH HHS/United States
GR  - R21 DA022702/DA/NIDA NIH HHS/United States
GR  - R01 DA021644-03S1/DA/NIDA NIH HHS/United States
GR  - DA022702/DA/NIDA NIH HHS/United States
GR  - K05 DA021696-05/DA/NIDA NIH HHS/United States
GR  - DA11322/DA/NIDA NIH HHS/United States
GR  - K05 DA021696/DA/NIDA NIH HHS/United States
GR  - DA021644/DA/NIDA NIH HHS/United States
GR  - R21 DA022702-03/DA/NIDA NIH HHS/United States
GR  - R01 DA021644/DA/NIDA NIH HHS/United States
GR  - R01 DA011322/DA/NIDA NIH HHS/United States
GR  - R01 DA021644-05/DA/NIDA NIH HHS/United States
GR  - R21 DA022478-02/DA/NIDA NIH HHS/United States
GR  - R01 DA011322-10/DA/NIDA NIH HHS/United States
GR  - DA21696/DA/NIDA NIH HHS/United States
GR  - R21 DA022478/DA/NIDA NIH HHS/United States
GR  - DA022478/DA/NIDA NIH HHS/United States
GR  - K05 DA021696-02/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090509
PL  - France
TA  - Eur J Neurosci
JT  - The European journal of neuroscience
JID - 8918110
RN  - 0 (Arachidonic Acids)
RN  - 0 (Cannabinoid Receptor Modulators)
RN  - 0 (Endocannabinoids)
RN  - 0 (Glycerides)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 8D239QDW64 (glyceryl 2-arachidonate)
RN  - EC 3.1.1.34 (Lipoprotein Lipase)
SB  - IM
MH  - Analgesia
MH  - Animals
MH  - Arachidonic Acids/*metabolism
MH  - Cannabinoid Receptor Modulators/*metabolism
MH  - *Endocannabinoids
MH  - Glycerides/*metabolism
MH  - Image Processing, Computer-Assisted
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Lipoprotein Lipase/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microscopy, Electron, Transmission
MH  - Nociceptors/metabolism/ultrastructure
MH  - Pain/*metabolism
MH  - Presynaptic Terminals/metabolism/ultrastructure
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Rats, Wistar
MH  - Receptor, Cannabinoid, CB1/genetics/metabolism
MH  - Receptor, Metabotropic Glutamate 5
MH  - Receptors, Metabotropic Glutamate/metabolism/ultrastructure
MH  - Signal Transduction/*physiology
MH  - Spinal Cord/metabolism
MH  - Synapses/*metabolism/ultrastructure
PMC - PMC2692098
MID - NIHMS109082
EDAT- 2009/05/21 09:00
MHDA- 2009/07/30 09:00
PMCR- 2010/05/01
CRDT- 2009/05/21 09:00
PHST- 2009/05/21 09:00 [entrez]
PHST- 2009/05/21 09:00 [pubmed]
PHST- 2009/07/30 09:00 [medline]
PHST- 2010/05/01 00:00 [pmc-release]
AID - EJN6751 [pii]
AID - 10.1111/j.1460-9568.2009.06751.x [doi]
PST - ppublish
SO  - Eur J Neurosci. 2009 May;29(10):1964-78. doi: 10.1111/j.1460-9568.2009.06751.x. 
      Epub 2009 May 9.