Role of the cannabinoid system in nociceptive processing in primary sensory neurons

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). 3 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.Open Acces