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Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia

Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia 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 CB1 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 CB1 on excitatory axon terminals. Furthermore, DGL‐α in postsynaptic elements receiving nociceptive input was colocalized with metabotropic glutamate receptor 5 (mGluR5), whose activation induces 2‐AG biosynthesis. Finally, intrathecal activation of mGluR5 at the lumbar level evoked endocannabinoid‐mediated stress‐induced analgesia through the DGL–2‐AG–CB1 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Neuroscience Wiley

Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia

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References (97)

Publisher
Wiley
Copyright
© The Authors (2009). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd
ISSN
0953-816X
eISSN
1460-9568
DOI
10.1111/j.1460-9568.2009.06751.x
pmid
19453631
Publisher site
See Article on Publisher Site

Abstract

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 CB1 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 CB1 on excitatory axon terminals. Furthermore, DGL‐α in postsynaptic elements receiving nociceptive input was colocalized with metabotropic glutamate receptor 5 (mGluR5), whose activation induces 2‐AG biosynthesis. Finally, intrathecal activation of mGluR5 at the lumbar level evoked endocannabinoid‐mediated stress‐induced analgesia through the DGL–2‐AG–CB1 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.

Journal

European Journal of Neuroscience – Wiley

Published: May 1, 2009

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