Negative allosteric modulation of cannabinoid CB₁receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception

Abstract

The direct blockade of CB1cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB1negative 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 side-effects of opioids remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar dorsal horn. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception. GAT358 also reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal dorsal horn. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing in mice. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB1-NAMs.HighlightsCB1negative allosteric modulator (NAM) GAT358 attenuated morphine toleranceGAT358 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

Negative allosteric modulation of CB1 cannabinoid receptor signaling decreases intravenous morphine self-administration and relapse in mice

“…In addition to the results presented here, a recent study from our lab also explored the application of the CB1R NAM GAT358 on antinociceptive and effects of morphine as well as morphine tolerance and naloxone-precipitated opioid withdrawal 27 . We showed that GAT358 did not impede morphine antinociception but was effective in reducing morphine tolerance as well as naloxone-precipitated opioid withdrawal 27 . As such, GAT358 provide new options for non-addictive pain management, as it produced antinociception on its own, and also potentially reduce the reliance and addiction liability of opioids.…”