Negative allosteric modulation of CB₁ cannabinoid receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception.

ABSTRACT: The direct blockade of CB₁ cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB₁ negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB₁. We recently reported that GAT358, a CB₁-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB₁-allosteric mechanism of action. Whether a CB₁-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted opioid side-effects remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine in

SUBMITTER: Iyer V 

PROVIDER: S-EPMC11261750 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature