26 R.G. Pertwee
4 Other Pharmacological Targets for Cannabinoids in Mammalian Tissues...
As discussed in greater detail elsewhere (Hájos and Freund 2002b; Howlett et
al. 2002; Pertwee 1999b, 2004a; Pertwee and Ross 2002; Wiley and Martin 2002),
evidence is emerging that in addition to CB 1 and CB 2 receptors, there are other
pharmacologicaltargetsinmammaliantissueswithwhichatleastsomeestablished
CB 1 and/or CB 2 receptor agonists can interact to elicit pharmacological responses.
4.1 Receptors......................................
4.1.1VanilloidReceptors
It is now generally accepted that the endogenous CB 1 /CB 2 receptor agonist, anan-
damide, and certain of its analogues are agonists for the TRPV1 receptor (reviewed
in Howlett et al. 2002; Pertwee 2004a; Pertwee and Ross 2002; Ross 2003). This re-
ceptorisanon-selectivecationchannelthatispresentonsensoryneuronsintissues
such as skin, heart, blood vessels and lung, and an important consequence of its
activation is the release of sensory neuropeptides that then produce effects such as
pain,tachycardia,vasodilationandbronchoconstriction.It isnoteworthy,however,
that anandamide has less TRPV1 intrinsic activity than the well-known TRPV1
receptor agonist capsaicin (Ross 2003; Ross et al. 2001).R-(+)-methanandamide is
even less potent or effective than anandamide at activating TRPV1 receptors (Ross
et al. 2001; Zygmunt et al. 1999), whereas lipoxygenase metabolites of anandamide
show greater potency at these receptors than their parent compound, at least in
guinea-pig bronchus (Craib et al. 2001; Pertwee and Ross 2002). The TRPV1 re-
ceptor is not activated by 2-arachidonoyl glycerol or by non-eicosanoid CB 1 /CB 2
receptor agonists (Zygmunt et al. 1999), although it is activated by micromolar
concentrations of the phytocannabinoid cannabidiol (Bisogno et al. 2001). One
compound that behaves as a potent agonist at both TRPV1 and CB 1 receptors is
the synthetic anandamide analogue O-1861 (Fig. 8) (Di Marzo et al. 2001). TRPV1
and CB 1 receptors have opposite effects on calcium channel conductance, and
there are several reports that in cells such as cultured dorsal root ganglion neurons
that co-express these receptors, responses elicited by TRPV1 receptor activation
can be opposed by the simultaneous activation of CB 1 receptors (Ahluwalia et al.
2003; Ellington et al. 2002; Millns et al. 2001; Richardson et al. 1998; Ross 2003).
Unexpectedly, however, there is also a report that in human embryonic kidney
cells co-transfected with CB 1 and TRPV1 receptors, activation of the CB 1 receptors
increases the sensitivity of the TRPV1 receptors to subsequent (but not simulta-
neous) activation (Hermann et al. 2003). Under physiological conditions, TRPV1
receptors on primary sensory neurons are less sensitive to anandamide than CB 1
receptors (Németh et al. 2003; Tognetto et al. 2001). There is also evidence that
anandamide production increases during inflammation, raising the possibility that