Negative allosteric modulation of cannabinoid CB 1 receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception.

negative allosteric modulator (NAM) GAT358 attenuated morphine tolerance GAT358 reduced morphine-induced slowing of colonic motility but not fecal productionGAT358 was antinociceptive for formalin pain alone and when combined with morphineGAT358 reduced formalin-evoked Fos protein expression in the lumbar spinal cordGAT358 mitigated naloxone precipitated withdrawal after chronic morphine dosing.