2. Academic Validation
  3. Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated reward

Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated reward

  • Pharmacol Res. 2022 Nov;185:106474. doi: 10.1016/j.phrs.2022.106474.
Vishakh Iyer 1,  Claudia Rangel-Barajas 2,  Taylor J Woodward 1,  Abhijit Kulkarni 3,  Lucas Cantwell 3,  Jonathon D Crystal 1,  Ken Mackie 4,  George V Rebec 1,  Ganesh A Thakur 3,  Andrea G Hohmann 5
Affiliations

Affiliations

  • 1 Program in Neuroscience, Indiana University, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
  • 2 Program in Neuroscience, Indiana University, Bloomington, IN, USA.
  • 3 Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
  • 4 Program in Neuroscience, Indiana University, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
  • 5 Program in Neuroscience, Indiana University, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA. Electronic address: hohmanna@indiana.edu.
PMID: 36179954 DOI: 10.1016/j.phrs.2022.106474
Abstract

Blockade of cannabinoid type 1 (CB<sub>1</sub>)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB<sub>1</sub> antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB<sub>1</sub> signaling by decreasing affinity and/or efficacy of CB<sub>1</sub> ligands. We hypothesized that a CB<sub>1</sub>-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB<sub>1</sub> antagonists. GAT358, a CB<sub>1</sub>-NAM, failed to elicit cardinal signs of direct CB<sub>1</sub> activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB<sub>1</sub> agonist CP55,940, suggesting that a CB<sub>1</sub>-NAM blocked cardinal signs of CB<sub>1</sub> activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB<sub>1</sub> positive allosteric modulator (CB<sub>1</sub>-PAM), and absent in CB<sub>1</sub>-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CB<sub>1</sub>-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.

Keywords

Allosteric modulator; CB(1); Endocannabinoid; Morphine; Opioid; Reward.

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