536 J.M. Walker and A.G. Hohmann
5.5
Virodhamine
O-Arachidonoylethanolamine was identified in rat brain and named virodhamine
(Porter et al. 2002). This compound is similar to anandamide in being formed
from arachidonic acid and ethanolamine, but virodhamine contains an ester link-
age rather than anandamide’s amide linkage. Like anandamide, it appears to act as
a partial agonist. However, a microdialysis study suggested that while its tissue con-
centrations are similar to anandamide, it is released in much higher amounts. The
existence of this compound has not been independently verified, and this author
has been unable to detect it in rat brain extracts using ultrasensitive LC/MS/MS
(liquid chromatography/tandem mass spectrometry) methods developed using
the synthetic compound (J.M. Walker, unpublished observations). Additional con-
firmatory studies of the existence of virodhamine are needed upon which further
study of its potential role in pain modulation would be warranted.
5.6
N-Arachidonoyldopamine
Another molecule with the arachidonic acid backbone, NADA was recently iden-
tified in rat and bovine brain (Huang et al. 2002). It activates CB1Rs and elicits
cannabimimetic effects (which include analgesia following systemic administra-
tion but not tested with a cannabinoid antagonist) (Bisogno et al. 2000; De Petro-
cellis et al. 2000; Huang et al. 2002). NADA significantly inhibited innocuous (8,
10 g) mechanically evoked responses of dorsal horn neurons, and these effects were
blocked by intraplantar injection of SR141716A (Sagar et al. 2004). In addition,
NADA activates TRPV1 receptors and causes hyperalgesia when administered pe-
ripherally (Huang et al. 2002). This effect is in contrast to anandamide, which also
activates TRPV1 (Smart et al. 2000; Zygmunt et al. 1999), though administration
of anandamide typically causes analgesia. The distribution of endogenous NADA
in various brain areas differs from that of anandamide, with the highest levels
found in the striatum and hippocampus (Huang et al. 2002). It also occurs in the
DRG in low levels. Given that NADA is capable of eliciting analgesia upon systemic
administration and hyperalgesia upon intradermal injection, it is possible that
endogenous NADA activates either TRPV1 or CB1Rs, depending upon location
and circumstance.
5.7
Regulation of Endocannabinoids by Fatty Acid Amide Hydrolase
Three putative endogenous cannabinoids, anandamide, 2-AG, and NADA, appear
to be susceptible to degradation by FAAH (Cravatt et al. 1996; Deutsch and Chin
1993; Di Marzo et al. 1998; Huang et al. 2002). Immunohistochemical studies
show that FAAH is present in the ventral posterior lateral nucleus of the thala-
mus (Egertová et al. 1998, 2003; Tsou et al. 1998b), the termination zone of the