Inflammation of peripheral tissues and injury to peripheral nerves induce differing effects in the expression of the calcium‐sensitive N‐arachydonoylethanolamine‐synthesizing enzyme and related molecules in rat primary sensory neurons
Anandamide is synthesized in subpopulations of primary sensory neurons in both Ca2+‐sensitive and Ca2+‐insensitive manners (van der Stelt et al., 2005; Varga et al., 2014; Vellani et al., 2008). Consistent with the ability of a group of primary sensory neurons to synthesize anandamide in a Ca2+‐sensitive manner (van der Stelt et al., 2005) and the role of NAPE‐PLD in such anandamide synthesis (Okamoto et al., 2004; Ueda et al., 2001; Wang et al., 2006), NAPE‐PLD mRNA is expressed by primary sensory neurons (Nagy et al., 2009). Most of the NAPE‐PLD mRNA‐expressing cells are capsaicin sensitive (Nagy et al., 2009), so they should also express TRPV1 and the CB1 receptor (Agarwal et al., 2007; Ahluwalia et al., 2000; Binzen et al., 2006; Mitrirattanakul et al., 2006). Therefore, in addition to exogenous anandamide, anandamide of primary sensory neuron origin could also be able to control TRPV1 and CB1 receptor activity in a major subpopulation of nociceptive primary sensory neurons in an autocrine manner (van der Stelt & Di Marzo, 2005; van der Stelt et al., 2005).
In addition to NAPE‐PLD and the CB1 receptor, the great majority of TRPV1‐expressing primary sensory neurons also express the main anandamide‐hydrolyzing enzyme fatty acid amide hydrolase (FAAH; Cravatt et al., 1996; Lever et al., 2009). Blocking FAAH activity through increasing the level of anandamide also results in regulating the activity of a proportion of nociceptive primary sensory neurons through the CB1 receptor and TRPV1 (Lever et al., 2009). Based on the coexpression pattern of TRPV1, the CB1 receptor, NAPE‐PLD, FAAH, and the effects of those molecules, the presence of an endocannabinoid/endovanilloid autocrine signaling system built by those molecules has been proposed in a major subpopulation of nociceptive primary sensory neurons (Sousa‐Valente, Varga, Ananthan, Khajuria, & Nagy, 2014; van der Stelt & Di Marzo, 2005; van der Stelt et al., 2005).