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Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia
Author(s) -
Nyilas Rita,
Gregg Laura C.,
Mackie Ken,
Watanabe Masahiko,
Zimmer Andreas,
Hohmann Andrea G.,
Katona István
Publication year - 2009
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2009.06751.x
Subject(s) - endocannabinoid system , neuroscience , nociception , diacylglycerol lipase , retrograde signaling , 2 arachidonoylglycerol , postsynaptic potential , cannabinoid receptor , cannabinoid , chemistry , metabotropic glutamate receptor , glutamate receptor , biology , microbiology and biotechnology , receptor , monoacylglycerol lipase , signal transduction , biochemistry , agonist
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‐α), the synthesizing enzyme of 2‐AG. Peroxidase‐based immunocytochemistry demonstrated high levels of DGL‐α 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‐α at nociceptive synapses formed by primary afferents, and revealed presynaptic positioning of CB 1 on excitatory axon terminals. Furthermore, DGL‐α 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.