3. Umbruch 4.4..2005 - Online Pot

156 S.M. Huang and J.M. Walker
perhaps because they possess either modest (ajulemic acid) or virtually no
(HU-320) affinity for either CB 1 receptors or CB 2 receptors. While ajulemic
acid produces its effects via CB 1 receptors (unpublished findings from the
authors’ laboratory), HU-320 produces its effects by an unknown mechanism
that is unlikely to be the CB 1R. At sufficient doses, CT-3 produces catalepsy
[92] similar to that observed with ∆ 9 -THC. However, extensive dose studies
would be required to determine whether there is a greater dose separation
between its anti-nociceptive/anti-inflammatory effects and its psychomotor
side effects than that observed with typical cannabinoids. In a recent clinical
trial of patients suffering from neuropathic pain, ajulemic acid possessed some
efficacy [93]. While many questions about these and similar compounds are
awaiting further research, this appears to be an important line of inquiry.
Development of inhibitors of FAAH
Shortly after the isolation of the first endocannabinoid anandamide [5], the
enzyme responsible for anandamide hydrolysis, FAAH, was described [94]
and cloned [95]. In addition to anandamide two other endocannabinoids,
2-arachidonoyl glycerol (2-AG) and N-arachidonoyldopamine (NADA), also
appear to be susceptible to degradation by FAAH [96, 97].
Immunohistochemical studies show that FAAH is present in the ventral posterior
lateral nucleus of the thalamus [98–100], the termination zone of the
spinothalamic tract, which carries pain input from the periphery. FAAH is also
found in Lissauer’s tract, which comprises primary 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 central nervous system related to nociceptive processing
and thus suggest a role for these ligands in pain modulation.
FAAH-knockout mice exhibit enhanced analgesic effects of exogenously
administered anandamide in a CB 1 receptor-dependent manner, suggesting
that the lack of this degradatory enzyme prolonged the action of anandamide
[101]. Moreover, these animals exhibit tonic CB 1R-mediated analgesia in both
acute and chronic pain paradigms concurrent with a marked elevation of
endogenous anandamide levels [101, 102]. The results indicate that enhanced
activity of endogenous cannabinoid(s) from the lack of FAAH in the transgenic
animals caused blunted sensitivity to pain.
The studies discussed above suggest that inhibitors of FAAH would
enhance the action of endogenous cannabinoids, thereby inhibiting pain. In
fact, pharmacological agents that inhibit FAAH, such as phenylmethylsulfonyl
fluoride (PMSF), palmitylsulfonyl fluoride (AM-374), methyl arachidonyl fluorophosphonate
(MAFP) and arachidonoyl serotonin (AA-5-HT) produce a
number of effects [94, 103–105]. However, as FAAH inhibitors, these agents
have potential for improvement either in potency (often requiring micromolar