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Assessment of Monoacyglycerol Lipase Inhibition for Acute and Chronic Antinociception in a Behavioral Battery for Testing Candidate Analgesics in Mice
Author(s) -
Diester Clare,
Lichtman Aron,
Negus S.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02325
Subject(s) - rimonabant , analgesic , medicine , pharmacology , monoacylglycerol lipase , opioid , cannabinoid receptor , cannabinoid , chronic pain , nociception , anesthesia , endocannabinoid system , agonist , receptor , physical therapy
Objective and Hypothesis There is a pressing need for discovery of novel, safe, and effective analgesics with improved preclinical‐to‐clinical translation. This study addressed these issues by evaluating the antinociceptive effectiveness of the monoacylglycerol lipase (MAGL)‐selective inhibitors MJN110 and JZL184 in a battery of pain‐stimulated, pain‐depressed, and pain‐independent behaviors in male and female mice. Ketoprofen (cyclooxygenase 1/2 inhibitor) was used as a clinically‐effective analgesic positive control, and ∆9‐tetrahydrocannabinol (THC; cannabinoid 1/2 receptor (CB 1/2 R) agonist) as a negative control that is not clinically effective to treat acute pain. We hypothesized that ketoprofen and MAGL‐selective inhibitors would produce antinociception on endpoints of pain‐stimulated and pain‐depressed behaviors at doses that did not alter pain‐independent behaviors, whereas THC would not. Methods Intraperitoneal dilute lactic acid (IP acid) served as an acute noxious stimulus in male and female ICR mice to produce two IP acid‐stimulated behaviors (stretching and facial grimace) and two IP acid‐depressed behaviors (rearing and nesting). Pain‐independent drug effects were assessed in nesting and locomotion in the absence of IP acid. All test drugs were delivered subcutaneously and evaluated for effectiveness to alleviate pain‐related behaviors at doses below those that altered pain‐independent behaviors. The assay of IP acid‐depressed nesting was also used to assess MJN110 time course, sensitivity to blockade by the CB 1 R‐ and CB 2 R‐selective antagonists rimonabant and SR144528, and effects of repeated dosing for 7 consecutive days. Results and Significance Ketoprofen (0.1‐10 mg/kg) produced robust antinociception without general behavioral disruption on all IP acid‐stimulated and IP acid‐depressed behaviors. MJN110 (0.1‐3.2 mg/kg) and JZL184 (1.0‐32 mg/kg) produced antinociception without motor disruption on endpoints of stretching (MJN110 only), grimace, and nesting, but not rearing. THC (1‐10 mg/kg) attenuated IP acid‐stimulated stretching and facial grimace at doses that did not produce general motor disruption; however, THC did not alleviate IP acid‐induced depression of either nesting or rearing. MJN110 (1.0 mg/kg) antinociception in the assay of IP acid‐induced nesting depression showed a long duration (40min – 6hr) mediated by CB 1 R but not CB 2 R and tended to be stronger in females. Chronic MJN110 (1.0 mg/kg/day × 7 days) showed sex‐dependent antinociception and tolerance, with females showing tolerance by Day 7 and males showing no significant antinociceptive effect across all 7 days. These results provide modest support for further consideration of MAGL‐selective inhibitors, especially MJN110, as candidate analgesics, with future work needed to assess sex‐dependent effects. However, it should be noted that none of the cannabinoids were as effective in this behavioral battery as ketoprofen.