Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain.
Selective activation of the peripheral cannabinoid receptor 1 (CB1R) has been shown to suppress neuropathic pain symptoms in rodents. However, relatively little is known about changes in CB1R and its endogenous ligands during development or maintenance of neuropathic pain. Using immunohistochemistry, Western blot, real-time reverse transcription polymerase chain reaction, as well as liquid chromatography/mass spectrometry, we studied the changes in CB1Rs and endocannabinoids N-arachidonoylethanolamine/anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in rat lumbar (L4 and L5) dorsal root ganglia (DRG) after neuropathic pain induction (L5 spinal nerve ligation: SNL). Immunohistochemistry revealed that in control rats, CB1R is expressed in the majority (76-83%) of nociceptive neurons as indicated by co-labeling with isolectin B4 (IB4) or antibodies recognizing transient receptor potential vanilloid (TRPV1), calcitonin gene related peptide (CGRP), and the NR2C/2D subunits of the N-methyl-D-aspartate receptor. After L5 SNL, CB1R mRNA and protein increases in the ipsilateral uninjured L4 DRG whereas the percentages of CB1R immunoreactive (CB1R-ir) neurons remain unchanged in L4 and L5 DRG. However, for these CB1R-ir neurons, we observe significant increases in percentage of TRPV1-ir cells in ipsilateral L4 DRG, and decreases in percentage of IB4- and CGRP-co-labeled cells in ipsilateral L5 DRG. Levels of both AEA and 2-AG increase significantly only in the ipsilateral L5 DRG. These results are consistent with the preserved analgesic effects of cannabinoids in neuropathic pain and provide a rational framework for the development of peripherally acting endocannabinoid-based therapeutic interventions for neuropathic pain.
Mitrirattanakul
Somsak
S
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
Ramakul
Navapoln
N
Guerrero
Andre V
AV
Matsuka
Yoshizo
Y
Ono
Takeshi
T
Iwase
Hirotate
H
Mackie
Ken
K
Faull
Kym F
KF
Spigelman
Igor
I
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D007150:Immunohistochemistry; D008024:Ligands; D008026:Ligation; D008161:Lumbosacral Region; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013127:Spinal Nerves; D014018:Tissue Distribution
D063385:Cannabinoid Receptor Modulators; D008024:Ligands; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid