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) synapses and potentiate of non-nociceptive pressure (P) 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 to 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 vs. 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. Significance Statement While there is considerable interest in developing cannabinoid-based analgesics, activation of the endocannabinoid system can produce pro- and anti-nociceptive effects. Which is produced may be due to the endocannabinoid concentration. This concentration hypothesis was examined by assessing the effects of arachidonoylethanolamine (AEA) on identifiable nociceptive and non-nociceptive synapses in Hirudo verbana (the medicinal leech). Both types of synapses were equally sensitive to exogenously applied AEA, but when endogenous AEA levels were increased using inhibitors of AEA metabolism, nociceptive synapses were much more sensitive compared to non-nociceptive synapses. These findings may inform why past cannabinoid-based therapies have failed as analgesics and how to develop effective analgesic therapies in the future.
Brian D. Burrell (Tue,) studied this question.