528 J.M. Walker and A.G. Hohmann
3.4.1
Role of the Periaqueductal Gray
Studies of metabolically stable anandamide analogs and the effects of anandamide
in FAAH knockout mice lead to the conclusion that anandamide would produce
antinociceptive effects upon release in the appropriate brain, spinal, or peripheral
sites. Electrical stimulation of the dorsal aspect of the periaqueductal gray (PAG)
caused CB1R-mediated analgesia evidenced by a markedly reduced effect following
administration of SR141716A (Walker et al. 1999). This work suggested that the
dorsal PAG serves as a substrate for cannabinoid antinociception. Exogenously
applied cannabinoids have been shown to inhibit GABAergic and glutamatergic
neurons in rat PAG neurons through presynaptic mechanisms (Vaughan et al.
2000). These effects occurred in the absence of direct postsynaptic actions on PAG
neurons, thus providing a neurophysiological basis for cannabinoid modulation
of nociceptive transmission through presynaptic actions.
Metabotropic glutamate andN-methyl-d-aspartate (NMDA) receptors are re-
quired for cannabinoid antinociception at the level of the PAG. Infusion of the
CBR agonist WIN55,212-2 into the PAG produced dose-dependent increases in paw
withdrawal latencies to a noxious thermal stimulus (Palazzo et al. 2001). This effect
was blocked by pretreatment with SR141716A. Blockade of mGlu 5 metabotropic
glutamate receptors but not mGlu 1 receptors blocked the effects of WIN55,212-2.
Both mGlu 5 and mGlu 1 receptors belong to group I class of metabotropic glutamate
receptors that are G protein-coupled and positively coupled to phospholipase C.
Pretreatment with antagonists for group II (which includes mGlu 2 and mGlu 3 )and
group III (which includes mGlu 4 , mGlu 6 , mGlu 7 , and mGlu 8 ) metabotropic gluta-
mate receptors also suppressed WIN55,212-2-induced analgesia. This latter class
of receptors is negatively coupled to adenylate cyclase and preferentially localized
to presynaptic active zones associated with autoreceptors. In addition to these
metabotropic receptors, a selective antagonist for ionotropic glutamate (NMDA)
receptors also blocked the antinociceptive effects of WIN55,212-2.
It has been postulated that the effect of antagonism of group II and III meta-
botropic receptors on cannabinoid antinociception is attributable to an increased
release of GABA in the PAG (Palazzo et al. 2001). Because GABAergic interneurons
within the PAG tonically inhibit descending antinociceptive pathways (Moreau and
Fields 1986), an inhibition of PAG descending pathways may underlie the observed
blockade of cannabinoid antinociception through modulation of GABAergic in-
terneurons. In vitro studies demonstrate that cannabinoids inhibit GABA and
glutamate release presynaptically in the PAG in the absence of direct postsynaptic
effects on PAG neurons (Vaughan et al. 2000). By contrast, antagonists for mGlu 5
and NMDA, which are localized postsynaptically, could reduce the tonic excitatory
control of glutamate on descending antinociceptive pathways with cells of origin
in the PAG (Palazzo et al. 2001), thereby modulating cannabinoid antinociception
through a distinct mechanism.