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Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence

      Abstract

      Background

      Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist.

      Methods

      GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group.

      Results

      GAT211 suppressed allodynia induced by complete Freund’s adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion.

      Conclusions

      Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

      Keywords

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      Linked Article

      • Cannabinoids and Pain: Weeding Out Undesired Effects With a Novel Approach to Analgesia
        Biological PsychiatryVol. 84Issue 10
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          During the time that this remarkable drug is relieving pain a very curious psychical condition manifests itself; namely, that the diminution of the pain seems to be due to its fading away in the distance, so that the pain becomes less and less, just as the pain in a delicate ear would grow less and less as a beaten drum was carried farther and farther out of the range of hearing. This condition is probably associated with the other well-known symptom produced by the drug; namely, the prolongation of time.
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