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Received October 17, 2003
Revised November 25, 2003
Accepted after revision December 9, 2003
1 Department of Pharmacology, College of Medicine,National Cheng-Kung University
2 Department of Pharmacology, College of Medicine, National Cheng-Kung University
3 Department of Neurophysiology, University of Tokyo Graduate School of Medicine
* To whom correspondence should be addressed. E-mail: richard{at}mail.ncku.edu.tw.
Systemic or intraventricular administration of
cannabinoids causes analgesic effects, but relatively
little is known for their cellular mechanism. Using
brainstem slices with the mandibular nerve attached, we
examined the effect of cannabinoids on glutamatergic
transmission in superficial trigeminal caudal nucleus of
juvenile rats. Exogenous cannabinoid receptor agonist
WIN 55,212-2 (WIN), as well as the endogenous agonist
anandamide, hyperpolarized trigeminal caudal neurons and
depressed the amplitude of excitatory postsynaptic
potentials (EPSPs) or currents (EPSCs) monosynaptically
evoked by stimulating mandibular nerves in a
concentration-dependent manner. The inhibitory action
of WIN was blocked or fully reversed by the CB1 receptor
antagonist SR 141716A. WIN had no effect on the
amplitude of miniature excitatory postsynaptic currents
(mEPSCs) recorded in the presence of tetrodotoxin or
cadmium. The inhibitory effect of WIN on EPSCs was
greater for those with longer synaptic latency,
suggesting that cannabinoids have a stronger effect on C-
fibre EPSPs than on Ad-fibre EPSPs. Ba2+ (100 µM)
blocked the hyperpolarizing effect of cannabinoids, but
did not affect their inhibitory effect on EPSPs. The N-
type Ca2+ channel blocker 
-conotoxin GVIA
(-CgTX) occluded the WIN-mediated presynaptic
inhibition, whereas the P/Q-type Ca2+ channel blocker
-agatoxin TK (-Aga) had no effect. These
results suggest that cannabinoids preferentially
activate CB1 receptors at the nerve terminal of small-
diameter primary afferent fibres. Upon activation, CB1
receptors may selectively inhibit presynaptic N-type
Ca2+ channels and exocytotic release machinery, thereby
attenuating the transmitter release at the trigeminal
nociceptive synapses.
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