Peripherally administered cannabinoid receptor 2 (CB2R) agonists lose anti-allodynic effects in TRPV1 knockout mice, while intrathecal administration leads to anti-allodynia and reduced GFAP, CCL2 and TRPV1 expression in the dorsal spinal cord and DRG.

Abstract

The transient receptor potential (TRP) superfamily of cation channels, of which the TRP vanilloid type 1 (TRPV1) receptor plays a critical role in inflammatory and neuropathic pain, is expressed on nociceptors and spinal cord dorsal horn neurons. TRPV1 is also expressed on spinal astrocytes and dorsal root ganglia (DRG) satellite cells. Agonists of the cannabinoid type 2 receptor (CB2R) suppress allodynia, with some that can bind TRPV1. The neuroimmune C-C class chemokine-2 (CCL2) expressed on injured DRG nociceptor cell bodies, Schwann cells and spinal astrocytes, stimulates immune cell accumulation in DRG and spinal cord, a known critical element in chronic allodynia. The current report examined whether two CB2R agonists, AM1710 and AM1241, previously shown to reverse light touch mechanical allodynia in rodent models of sciatic neuropathy, require TRPV1 activation that leads to receptor insensitivity resulting in reversal of allodynia. Global TRPV1 knockout (KO) mice with sciatic neuropathy given intrathecal or intraperitoneal AM1710 were examined for anti-allodynia followed by immunofluorescent microscopy analysis of lumbar spinal cord and DRG of astrocyte and CCL2 markers. Additionally, immunofluorescent analysis following intrathecal AM1710 and AM1241 in rat was performed. Data reveal that intrathecal AM1710 resulted in mouse anti-allodynia, reduced spinal astrocyte activation and CCL2 expression independent of TRPV1 gene deletion. Conversely, peripheral AM1710 in TRPV1-KO mice failed to reverse allodynia. In rat, intrathecal AM1710 and AM1241 reduced spinal and DRG TRPV1 expression, with CCL2-astrocyte and -microglial co-expression. These data support that CB2R agonists can impact spinal and DRG TRPV1 expression critical for anti-allodynia.

• Authors: Jenny L Wilkerson, Lauren B Alberti, Ganesh A Thakur, Alexandros Makriyannis, Erin D Milligan
• Journal: Brain research (Brain Res) Vol. 1774 Pg. 147721 (01 01 2022) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 34774500 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• 3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one
• Cannabinoid Receptor Agonists
• Chemokine CCL2
• Chromones
• Glial Fibrillary Acidic Protein
• Receptor, Cannabinoid, CB2
• TRPV Cation Channels
• TRPV1 protein, mouse
• glial fibrillary astrocytic protein, mouse

Topics

• Animals
• Cannabinoid Receptor Agonists (pharmacology)
• Chemokine CCL2 (metabolism)
• Chromones (pharmacology)
• Ganglia, Spinal (drug effects, metabolism)
• Glial Fibrillary Acidic Protein (metabolism)
• Hyperalgesia (drug therapy, genetics, metabolism)
• Mice
• Mice, Knockout
• Receptor, Cannabinoid, CB2 (agonists)
• Spinal Cord (diagnostic imaging, metabolism)
• TRPV Cation Channels (genetics, metabolism)