Cyclooxygenase-2 inhibition reduces stress-induced affective pathology

Substrate selective COX-2 inhibitors have demonstrated robust anxiolytic effects in rodents.

“Substrate selective COX-2 inhibitors have demonstrated robust anxiolytic effects in rodents (Gamble-George et al., 2016;Patel et al., 2017).”

COX-2 regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition, and may have a role in anxiety-like behavior and stress-responsivity.

“emerging data that one of these pathways, COX-2, regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition (Hermanson et al., 2014; Hermanson et al., 2013), but nonetheless may have a role in the mediation of anxiety-like behavior and stress-responsivity (Gamble-George et al., 2016; Hermanson et al., 2013).”

None of the drugs tested affected sucrose preference or tail-suspension test immobility.

“none of the drugs tested affected sucrose preference or tail-suspension test immobility, two measures associated more with antidepressant than anxiolytic efficacy.”

The ability of LM-4131 and Lumiracoxib to decrease stress-induced measures of anxiety-related behavior in the novelty-induced hypophagia test is not blocked by a CB1R, TRPV1, or CB2R antagonist.

“the ability of LM-4131 and Lumiracoxib to decrease stress-induced measures of anxiety-related behavior in the novelty-induced hypophagia test was not blocked by a CB1R antagonist or, for that matter, a TRPV1 or CB2R antagonist (Gamble-George et al., 2016).”

LM-4131, Lumiracoxib, and Celecoxib produce an anxiolytic-like effect in the novelty-induced hypophagia test in mice subjected to acute foot-shock stress eight to twenty-four hours earlier.

“LM-4131, as well as two traditional COX-2 inhibitors, Lumiracoxib and Celecoxib, produced an anxiolytic-like effect in the novelty-induced hypophagia test in mice that had been subjected to acute foot-shock stress eight to twenty-four hours earlier (Gamble-George et al., 2016).”

Drug effects generalized across assays, sexes, and ages, and were maintained under conditions of repeated stress or drug treatment, consistent with a robust anxiolytic-like action resistant to tolerance.

“Drug effects generalized across assays (elevated plus-maze, conditioned fear), sexes and ages, and were maintained under conditions of repeated stress or drug treatment - consistent with a robust anxiolytic-like action that was resistant to tolerance.”

The effects of LM-4131 are prevented by the SK potassium channel blocker Apamin and mimicked by the SK channel activator 1-EBIO.

“the effects of LM-4131 could be prevented by administration of the small-conductance calcium activated (SK) potassium channel blocker, Apamin, and were mimicked by administration of the SK channel activator 1-EBIO (Gamble-George et al., 2016).”