The endogenous ligand N-arachydonoylethanolamine (anandamide) is an
important modulator of nociceptive processing in primary sensory neurons
(PSN), because it activates both the excitatory transient receptor potential
vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type-1
(CB1) receptor, which are co-expressed in PSN and plays a pivotal role in the
development and maintenance of pain associated with peripheral pathologies.
However, the mechanisms involved in the anandamide-mediated modulation of
nociceptive processing in PSN are not well understood. Here, we studied some
important aspects of anandamide-mediated signaling in PSN.
We found that multiple anandamide-synthesising pathways are present in PSN.
The only Ca2+-sensitive anandamide-synthesising enzyme, Nacylphosphatidylethanolamine
phospholipase D (NAPE-PLD), exhibits a high
degree of co-expression with TRPV1, the CB1 receptor and the main
anandamide-hydrolysing enzyme, fatty acid amid hydrolase. Spinal nerve injury,
but not inflammation significantly alters this expression pattern. Although, the
excitatory effect of anandamide is mediated by TRPV1 in PSN, not all TRPV1-
expressing cells respond to anandamide. Blocking or deleting the CB1 receptor
significantly reduces anandamide responsiveness of TRPV1, and PSN either
express TRPV1 and the CB1 receptor in segregation or in close association.
Cultured spinal microglia, in addition to PSN, also synthesise anandamide and
that synthesis may depend on the activation state of spinal microglia and involve
the activity of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (Inpp5).
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Our findings support the view that anandamide-mediated signalling may occur
through autocrine mechanisms in PSN, and indicate that nerve injury may induce
deregulation of that signalling which may contribute to the development of
neuropathic pain. However, paracrine mechanisms, for example through anandamide
synthesis in spinal microglia may also contribute to anandamide-mediated signalling,
which is shaped, among others, by a complex crosstalk between the CB1 receptor and
TRPV1. Finally, our findings suggest that NAPE-PLD and Inpp5 might be targets for
future analgesics.