Cannabinoid Mechanisms of Pain Suppression 533relationship between pain circuits, exogenous drugs, and CBRs provide a founda-
tion for understanding how these putative endocannabinoids may operate physi-
ologically to modify pain perception. Proving that a particular endocannabinoid
plays such a role requires first the demonstration that it can produce antinocicep-
tion within the proposed site of action, then the demonstration that it is formed
and released in the proposed site under conditions where pain sensitivity is altered.
In the following, we review the data for each endocannabinoid with these criteria
in mind.
5.1
Anandamide
Anandamide was the first putative endocannabinoid to be identified (Devane et
al. 1992) and has therefore been the focus of the majority of investigations of
endocannabinoid mechanisms of pain suppression.
5.1.1
Effects of Exogenous Anandamide on Pain Sensitivity
In studies of physiological pain (i.e., pain induced by noxious stimuli in animals
free of inflammation, nerve injury, or other pathology), anandamide typically
producedantinociceptiveeffects,buttheseeffectswerenotblockedbycannabinoid
antagonists (Adams et al. 1998; Vivian et al. 1998). This effect was likely due to the
rapid metabolism of anandamide by FAAH, since FAAH knockout mice exhibit
marked CB1R-mediated analgesic responses to anandamide (Cravatt et al. 2001).
However, in animals with nerve injury, at doses of 10 and 100 μg i.v., anandamide
reversed neuropathic mechanical hyperalgesia, and this effect was antagonized by
the CB1R and CB2R antagonists SR141716A and SR144528.
These findings above are in good agreement with electrophysiological and
neurochemical studies of the effects of anandamide on sensory neurons. In 64%
of neurons examined, anandamide (10 μM) depressed Aδfiber-evoked excitatory
postsynaptic currents (EPSCs) (Luo et al. 2002). By contrast, an inhibitory action of
anandamide on C fiber-evoked EPSCs was observed in only 31% of neurons tested.
AnandamidealsoinhibitedthereleaseofneuropeptidesevokedbyaTRPV1agonist
(Helyes et al. 2003). These findings are consistent with studies of the localization
of CBRs (see Sect. 3.2.1) and suggest that anandamide acts primarily on larger
caliber peripheral afferent fibers and cells (see Sect. 3.2.1).
5.1.2
Effects of Inhibition of the Putative Anandamide Transporter
Another approach to examining the role of endogenous anandamide in pain has
been to employ transport inhibitors such as AM404. Blocking transport would
be expected to block the reuptake of anandamide and cause increased levels to