Role of Concentration in Opposing Effects of Anandamide on Nociceptive Synapses versus Non-nociceptive Synapses

There is considerable interest in cannabinoid-based therapies to treat pain, but activation of the endogenous cannabinoid (endocannabinoid) system can elicit pro- and anti-nociceptive effects. This study tests the hypothesis that the concentration of the endocannabinoid arachidonoylethanolamine (AEA) contributes to whether pro- or anti-nociceptive effects are observed. Experiments were carried out using isolated ganglia from the medicinal leech Hirudo verbana where it is possible to selectively record from nociceptive and non-nociceptive synapses in the central nervous system (CNS). Previous studies using Hirudo have shown that endocannabinoids depress nociceptive (N) sensory cell synapses and potentiate of non-nociceptive pressure (P) sensory cell synapses. In this study, exogenously applied AEA produced depression of N synapses and potentiation of P synapses across the same range of concentrations. However, the results differed when using URB597, a drug that raises AEA by inhibiting fatty acid amine hydrolase (FAAH), the enzyme that metabolizes AEA. Potentiation of P synapses required higher concentrations of URB597 compared with the concentrations needed to elicit depression of N synapses. Interestingly, pairing somatosensory afferent activity with a normally subthreshold concentration of URB597 did elicit potentiation in P synapses. Sensitivity of the nociceptive and non-nociceptive synapses to cannabinoid receptor inhibitors differed when AEA versus UBR597 was applied. This study demonstrates the complexity of AEA-mediated effects on distinct synapse types that may be informative about the basic biology of endocannabinoid modulation of nociception.