Cannabinoid Mechanisms of Pain Suppression 535forskolin-stimulated cyclic AMP (cAMP) and electrically evoked contractions of
the mouse vas deferens with potencies similar to that of anandamide (Felder et
al. 1993; Pertwee et al. 1994; Vogel et al. 1994). Piomelli et al. (1999) reported
that HEA effectively competes against anandamide for the putative anandamide
transporter. As with anandamide, DEA exhibits weak activity at the TRPV1 (Ross
et al. 2001b). Taken together, the findings indicate that DEA and HEA are naturally
occurring compounds in mammals and exhibit a pharmacology that is very similar
to that of anandamide. Systemic administration of DEA and HEA causes analgesia
to acute thermal stimulation in mice (Fride and Mechoulam 1993), and tolerance
developstothiseffect(Fride1995).WhetherthiseffectisCBR-mediatediscurrently
unknown. More work with these poorly studied compounds is warranted.
5.3
2-Arachidonoylglycerol
2-AG was the second endocannabinoid to be identified (Mechoulam et al. 1995;
Sugiura et al. 1995). Compared to anandamide, less is known as to what role it
may play in pain modulation and whether its effects on nociceptive processing are
indeed CB1R-mediated. Intravenous administration of 2-AG caused a suppression
of pain behavior in the tail-flick test (Mechoulam et al. 1995). However, the inves-
tigators did not test whether the effects could be blocked by CBR antagonists. This
leaves open the possibility that active non-CB metabolites may have produced the
effect, as was apparently the case with anandamide discussed above. Ben-Shabat
et al. (1998) showed that at doses of 2-AG that fail to produce analgesic effects in
the hot plate test, the addition of two cannabinoid-inactive endogenous congeners
of 2-AG, 2-lineoylglycerol and 2-palmitoylglycerol, caused significant analgesia.
These effects were referred to as “entourage effects,” a reference to the notion that
endogenous mediators of similar structure are often released together and act in
concert.
5.4
Noladin Ether
The novel endocannabinoid noladin ether was recently identified by Hanus et al.
(2001). Subsequently, its existence in brain was reported by Fezza et al. (2002),
but Oka et al. (2003) were unable to detect the compound in the brains of any of
several mammalian species by gas chromatography/mass spectrometry. Noladin
ether was reported to occur in relatively high amounts in dissected thalamus, but
its localization to somatosensory areas of thalamus has not been established. It
was reported to occur in much lower amounts in spinal cord (Fezza et al. 2002).
Hanus et al. (2001) showed that the compound produces analgesic effects in the hot
plate test following systemic administration in mice (20 mg/kg, i.p.). However, as
with 2-AG, experiments have not been carried out to determine whether its effects
were due to an action at CBRs. More work is needed to verify the formation of this
compound in vivo and its potential role in pain modulation.