Cannabinoid Mechanisms of Pain Suppression 537spinothalamic tract. FAAH is also found in Lissauer’s tract, which comprises pri-
mary afferent fibers entering the spinal cord, and in small neurons in the superficial
dorsal horn, which is the termination zone of nociceptive primary afferents. These
observations demonstrate that a mechanism capable of inactivating anandamide,
2-AG, and NADA is present in regions of the CNS related to nociceptive process-
ing and thus suggest a role for these ligands in pain modulation. Of course, the
presence of FAAH does not necessarily identify that cell as a site of synthesis of
endocannabinoids, as FAAH is a catabolic enzyme and also metabolizes fatty acid
amides that act through CBR-independent mechanisms.
5.7.1
Pain Sensitivity and Inflammatory Responses in FAAH Knockout Mice
Cravatt and colleagues (2001; Lichtman et al. 2004) developed transgenic mice
lacking FAAH and observed in these mutants enhanced analgesic effects of exoge-
nously administered anandamide (Fig. 4). These effects were reversed by the selec-
tive CB1R antagonist/inverse agonist SR141716A. Moreover, these animals exhibit
tonic CB1R-mediated analgesia, apparently due to the decreased metabolism of
FAAH-susceptible endocannabinoids. These findings support the hypothesis that
endocannabinoids susceptible to hydrolysis by FAAH serve to naturally suppress
painsensitivity.ThedevelopmentofFAAHandCB1Rknockoutsandpharmacolog-
ical approaches employing subtype selective antagonists or antisense knockdown
have been used to evaluate a role of endocannabinoids in pain modulation.
In a subsequent study, mice were generated that expressed FAAH in the nervous
system but not in peripheral tissues. These mice exhibited normal pain sensi-
Fig. 4Marked changes in anandamide levels, hot plate sensitivity, and basal effects of the CB1R antagonist
SR141716A in animals lacking the enzyme fatty acid amide hydrolase (FAAH). Wild-type mice (+/+,left panel)
exhibit relativelylowlevelsof anandamide( 50pmol/g) inbraincomparedtoFAAHknockout mice(–/–) which
exhibit 775 pmol/g, indicating that FAAH is the principal mechanism for the metabolism of anandamide.
FAAH knockout mice (–/–,middle panel) exhibit significantly reduced pain sensitivity under basal conditions
compared to wild-type (+/+) and heterozygous (+/-) mice, raising the possibility that the increased levels
of anandamide in the knockouts produce a constant state of hypoalgesia. The tonic hypoalgesia observed
in the FAAH knockout mice (–/–,right panel) is eliminated by the CB1R antagonist SR141716A (black bars)
compared to vehicle (white bars), whereas no significant effect of the antagonist is observed in wild-type
(+/+) or heterozygous (–/–) mice. Redrawn from Cravatt et al. (2001)