The endogenous
ligand,
anandamide activates at least two receptors on nociceptors; the excitatory vanilloid type 1 transient receptor potential receptor, the activity of which is indispensable for the development and maintenance of inflammatory heat
hyperalgesia, and the inhibitory
cannabinoid 1 receptor, the activity of which reduces that pathological
pain sensation. Recent data are equivocal on whether increasing
anandamide levels at the peripheral terminals of nociceptors in pathological conditions increases or decreases inflammatory heat
hyperalgesia. Here, by using the
cobalt-uptake technique we examined whether vanilloid type 1 transient receptor potential receptor activity evoked by 10 nM-100 microM
anandamide is increased or decreased in inflammatory conditions. An inflammatory milieu for cultured rat primary sensory neurons was established by incubating the cells in the presence of the inflammatory mediators,
bradykinin and
prostaglandin E2.
Anandamide, similarly to the archetypical vanilloid type 1 transient receptor potential receptor agonist,
capsaicin induced concentration-dependent
cobalt-uptake in a proportion of neurons. However, the potency of
anandamide was significantly lower than that of
capsaicin. While pre-incubation of cultures with
bradykinin and
prostaglandin E2 alone did not evoke
cobalt-entry, the inflammatory mediators potentiated the effect of both
capsaicin and
anandamide. Application of the competitive vanilloid type 1 transient receptor potential receptor antagonist,
capsazepine, or inhibitors of
protein kinase A,
protein kinase C or
phospholipase C inhibited the
anandamide-evoked
cobalt-uptake both in the presence and absence of
bradykinin and
prostaglandin E2. These findings show that inflammatory mediators significantly increase the excitatory potency and efficacy of
anandamide on vanilloid type 1 transient receptor potential receptor, thus, increasing the
anandamide concentration in, or around the peripheral terminals of nociceptors might rather evoke than decrease inflammatory heat
hyperalgesia.