Inhibiting the activity of
fatty-acid amide hydrolase (FAAH), the
enzyme that deactivates the
endocannabinoid anandamide, enhances
anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and
pain. We have previously shown that the peripherally restricted FAAH inhibitor,
URB937, prevents
nitroglycerin-induced
hyperalgesia - an animal model of
migraine - and attenuates the activation of brain areas that are relevant for
migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of
URB937 in animal models of acute and chronic
migraine. We evaluated the effects of
URB937 in two rat models that capture aspects of acute and chronic
migraine, and are based on single or repeated administration of the vasodilating drug,
nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured
mRNA levels of
neuropeptides and pro-inflammatory
cytokines along with tissue levels of
anandamide and
palmitoylethanolamide (PEA), an endogenous agonist of
peroxisome proliferator-activated receptor type-a (
PPAR-a), which is also a FAAH substrate. In the acute
migraine model, we also investigated the effect of subtype-selective antagonist for
cannabinoid receptors 1 and 2 (
AM251 and
AM630, respectively) on nocifensive behavior and on levels of
neuropeptides and pro-inflammatory
cytokines. In the acute
migraine paradigm,
URB937 significantly reduced
hyperalgesia in the orofacial
formalin test when administered either before or after NTG. This effect was accompanied by an increase in
anandamide and PEA levels in target neural tissue, depended upon
CB1 receptor activation, and was associated with a decrease in
calcitonin gene-related peptide (CGRP),
substance P and
cytokines TNF-alpha and
IL-6 mRNA. Similar effects were observed in the chronic
migraine paradigm, where
URB937 counteracted NTG-induced trigeminal
hyperalgesia and prevented the increase in
neuropeptide and
cytokine transcription. The results show that peripheral FAAH inhibition by
URB937 effectively reduces both acute and chronic NTG-induced trigeminal
hyperalgesia, likely via augmented
anandamide-mediated
CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.