Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury.
BACKGROUND
Cannabinoids induce analgesia by acting on cannabinoid receptor (CBR) types 1 and/or 2. However, central nervous system side effects and antinociceptive tolerance from CBR1 limit their clinical use. CBR2 exist on spinal glia and perivascular cells, suggesting an immunoregulatory role of these receptors in the central nervous system. Previously, the authors showed that spinal CBR2 activation reduces paw incision hypersensitivity and glial activation. This study tested whether CBR2 are expressed in glia and whether their activation would induce antinociception, glial inhibition, central side effects, and antinociceptive tolerance in a neuropathic rodent pain model.


METHODS
Rats underwent L5 spinal nerve transection or sham surgery, and CBR2 expression and cell localization were assessed by immunohistochemistry. Animals received intrathecal injections of CBR agonists and antagonists, and mechanical withdrawal thresholds and behavioral side effects were assessed.


RESULTS
Peripheral nerve transection induced hypersensitivity, increased expression of CR3/CD11b and CBR2, and reduced ED2/CD163 expression in the spinal cord. The CBR2 were localized to microglia and perivascular cells. Intrathecal JWH015 reduced peripheral nerve injury hypersensitivity and CR3/CD11b expression and increased ED2/CD163 expression in a dose-dependent fashion. These effects were prevented by intrathecal administration of the CBR2 antagonist (AM630) but not the CBR1 antagonist (AM281). JWH015 did not cause behavioral side effects. Chronic intrathecal JWH015 treatment did not induce antinociceptive tolerance.


CONCLUSIONS
These data indicate that intrathecal CBR2 agonists may provide analgesia by modulating the spinal immune response and microglial function in chronic pain conditions without inducing tolerance and neurologic side effects.
Romero-Sandoval
Alfonso
A
Department of Anesthesiology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire, USA. edgar.a.romero-sandoval@dartmouth.edu
Nutile-McMenemy
Nancy
N
DeLeo
Joyce A
JA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003511:Cyclohexanols / Q000494:pharmacology / Q000627:therapeutic use; D004361:Drug Tolerance / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000096:biosynthesis*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D003511:Cyclohexanols; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C402944:JHW 015