Cannabinoid CB ₁ allosteric ligands suppress inflammatory pain in male mice without tolerance, motor impairment, memory deficits or respiratory depression

Background and Purpose Positive allosteric modulators (PAMs) engage sites distinct from the orthosteric CB 1 cannabinoid receptor binding site. GAT211, a racemic ligand, contains GAT228 ( R ) and GAT229 ( S ) enantiomers. Whether enantiomer‐mediated differences in allosteric activation or positive allosteric modulation translate into differences in therapeutic efficacy or unwanted cannabimimetic effects remain unknown. Experimental Approach We evaluated therapeutic efficacy of the pure CB 1 allosteric agonist, GAT228 ( R ), and the PAM, GAT229 ( S ), in inflammatory pain induced by complete Freund's adjuvant (CFA) in male mice. We assessed whether these allosteric ligands would spare tolerance, memory deficits, motor impairment and respiratory depression associated with the orthosteric CB 1 /CB 2 agonist CP55,940. Key Results GAT228 and GAT229 attenuated CFA‐induced mechanical hypersensitivity in a CB 1 ‐dependent manner without producing tolerance or hypothermia associated with the orthosteric CB 1 /CB 2 agonist CP55,940. CP55,940 also produced memory deficits, motor impairment, and robust respiratory depression. GAT228 and GAT229 failed to do so. Unlike CP55,940, allosteric ligands did not produce motor impairment or notable respiratory depression in the presence or absence of CFA‐induced inflammation. Allosteric ligands increased novel object recognition memory, whereas CP55,940 decreased time spent exploring the novel object. Intraplantar CFA increased immobility time in the tail suspension test, indicative of pain‐related behavioural despair, which was normalized by allosteric ligands and exacerbated by CP55,940. Conclusion and Implication CB 1 allosteric ligands represent promising, safer therapeutic strategies for pain management compared to direct CB 1 orthosteric agonists. Overall, this work contributes to offering a novel pathway for pain management that minimizes the risk of adverse effects.