522 J.M. Walker and A.G. Hohmann
Woods 1999). Topical administration of the cannabinoid agonist HU210 to human
skin also suppresses capsaicin-evoked thermal hyperalgesia and touch-evoked al-
lodynia (Rukwied et al. 2003), although pharmacological specificity has not been
assessed. Cannabinoid modulation of capsaicin-evoked hyperalgesia involves pe-
ripheral and central mechanisms. A CB1R mechanism is also implicated in the
attenuation of hyperalgesia induced by locally administered cannabinoids follow-
ing intradermal capsaicin (Johanek et al. 2001) or cutaneous heat injury (Johanek
and Simone 2004).
The efficacy of peripheral cannabinoid mechanisms in suppressing neuronal
activation evoked by corneal application of the small-fiber excitant mustard oil
has been documented at the level of the lower brainstem. Corneal nociceptor ac-
tivity, assessed using mustard oil-evoked Fos protein expression at the trigeminal
interpolaris/caudalis (Vi/Vc) transition, was suppressed by direct corneal appli-
cation of WIN55,212-2, and these effects were blocked by systemic administration
of SR141716A (Bereiter et al. 2002), but CB2R mechanisms were not assessed.
These suppressions occurred in the absence of changes in Fos at the subnucleus
caudalis junction, thereby suggesting a role for CB1R mechanisms, at least in part,
in regulating reflexive aspects of nociception and/or contributing to homeostasis
of the anterior eye. More work is necessary to determine if CB2R mechanisms are
implicated in regulation of corneal nociceptor activity.
Peripheral CB1R Modulation of Capsaicin-Evoked Neuropeptide Release
Anandamide suppressed capsaicin-evoked plasma extravasation in vivo through
a peripheral CB1R mechanism (Richardson et al. 1998c) and inhibits capsaicin-
evoked CGRP release in rat dorsal horn (Richardson et al. 1998a) and peripheral
paw skin in vitro (Richardson et al. 1998c). Although pharmacological specificity
was not assessed in the in vitro superfusion studies, these effects occurred at low
concentrations [100 nM; (Richardson et al. 1998c)], consistent with mediation by
CB1R.
Capsaicin-evoked CGRP release is enhanced in paw skin derived from rats
with diabetic neuropathy induced by streptozotocin (Ellington et al. 2002). The
mixed CB 1 /CB 2 agonist CP55,940 attenuated capsaicin-evoked CGRP release in
diabetic and nondiabetic animals, and these effects were blocked by a CB1R but
not a CB2R antagonist (Ellington et al. 2002). Interestingly, anandamide inhibited
capsaicin-evoked CGRP release in nondiabetic but not in diabetic rat skin, but
neither the CB1R nor the CB2R antagonist attenuated these effects. Functional
changes following diabetic neuropathy may have prevented these inhibitory effects
of anandamide on capsaicin-evoked CGRP release. Anandamide also increased
capsaicin-evoked CGRP release at high concentrations, possibly through a TRPV1
mechanism, although susceptibility to blockade by TRPV1 antagonists would be
required to establish pharmacological specificity. Anandamide also inhibits in
vivo release of CGRP and somatostatin induced by systemically administered
resiniferatoxin, a potent TRPV1 ligand; the inhibitory effects of anandamide on
plasma neuropeptide levels were blocked by a CB1R antagonist (Helyes et al. 2003).