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The Journal of Neuroscience, February 15, 2003, 23(4):1398
Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell
Migration
Lisa
Walter1,
Allyn
Franklin1,
Anke
Witting1,
Christian
Wade1,
Yiheng
Xie2,
George
Kunos5,
Ken
Mackie3, and
Nephi
Stella1, 4
Departments of 1 Pharmacology, 2 Neurology,
3 Anesthesiology, and 4 Psychiatry and
Behavioral Sciences, University of Washington, Seattle, Washington
98195, and 5 National Institute on Drug Abuse and
Alcoholism, National Institutes of Health, Bethesda, Maryland 20892
During neuroinflammation, activated microglial cells migrate toward
dying neurons, where they exacerbate local cell damage. The signaling
molecules that trigger microglial cell migration are poorly understood.
In this paper, we show that pathological overstimulation of neurons by
glutamate plus carbachol dramatically increases the production of the
endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly
increases the production of anandamide and does not affect the
production of two putative endocannabinoids, homo- -linolenylethanolamide and docosatetraenylethanolamide. We
further show that pathological stimulation of microglial cells with ATP
also increases the production of 2-AG without affecting the amount of
other endocannabinoids. Using a Boyden chamber assay, we provide
evidence that 2-AG triggers microglial cell migration. This effect of
2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors,
with subsequent activation of the extracellular signal-regulated kinase
1/2 signal transduction pathway. It is important to note that
cannabinol and cannabidiol, two nonpsychotropic ingredients present in
the marijuana plant, prevent the 2-AG-induced cell migration by
antagonizing the CB2 and abnormal-cannabidiol-sensitive receptors,
respectively. Finally, we show that microglial cells express CB2
receptors at the leading edge of lamellipodia, which is consistent with
the involvement of microglial cells in cell migration. Our study
identifies a cannabinoid signaling system regulating microglial cell
migration. Because this signaling system is likely to be involved in
recruiting microglial cells toward dying neurons, we propose that
cannabinol and cannabidiol are promising nonpsychotropic therapeutics
to prevent the recruitment of these cells at neuroinflammatory lesion sites.
Key words:
microglia; migration; cannabinoids; glutamate; purinergic; kinase
Copyright © 2003 Society for Neuroscience 0270-6474/03/2341398-08$05.00/0
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