Enhanced signaling of the
endocannabinoid (eCB) system through inhibition of the catabolic
enzymes monoacylglycerol lipase (MAGL) and
fatty acid amide hydrolase (FAAH) has received increasing interest for development of candidate
analgesics. This study compared effects of MAGL and FAAH inhibitors with effects of ∆9-tetrahydrocannabinol (
THC) using a battery of
pain-stimulated,
pain-depressed, and
pain-independent behaviors in male and female mice.
Intraperitoneal injection of dilute
lactic acid (IP
acid) served as an acute visceral noxious stimulus to stimulate two behaviors (stretching, facial grimace) and depress two behaviors (rearing, nesting). Nesting and locomotion were also assessed in the absence of IP
acid as
pain-independent behaviors.
THC and a spectrum of six eCB catabolic
enzyme inhibitors ranging from MAGL- to FAAH-selective were assessed for effectiveness to alleviate
pain-related behaviors at doses that did not alter
pain-independent behaviors. The MAGL-selective inhibitor
MJN110 produced the most effective antinociceptive profile, with 1.0 mg/kg alleviating IP
acid effects on stretching, grimace, and nesting without altering
pain-independent behaviors.
MJN110 effects on IP
acid-depressed nesting had a slow onset and long duration (40 minutes to 6 hours), were blocked by
rimonabant, and tended to be greater in females. As inhibitors increased in FAAH selectivity, antinociceptive effectiveness decreased.
PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion.
THC decreased IP
acid-stimulated stretching and grimace at doses that did not alter
pain-independent behaviors; however, it did not alleviate IP
acid-induced depression of rearing or nesting. These results support further consideration of MAGL-selective inhibitors as candidate
analgesics for acute inflammatory
pain. SIGNIFICANCE STATEMENT: This study characterized a spectrum of
endocannabinoid catabolic
enzyme inhibitors ranging in selectivity from
monoacylglycerol lipase-selective to
fatty acid amide hydrolase-selective in a battery of
pain-stimulated,
pain-depressed, and
pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate
analgesics by effectiveness to alleviate
pain-related behaviors at doses that do not alter
pain-independent behaviors, with inclusion of
pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives.