LEI‐101 produces broad‐spectrum analgesia in preclinical pain models

Background and Purpose A promising method for managing pain without the negative effects on the central nervous system linked to CB 1 receptor activation or opioid analgesics is the selective activation of the cannabinoid CB 2 receptor. Nevertheless, the pharmacological profiles of the available CB 2 agonists vary and in certain instances they depend on endogenous opioid signalling. We investigated the pharmacology of the selective CB 2 receptor agonist LEI‐101 in vitro and in vivo in rodent pain models. Experimental Approach Radioligand binding, cAMP inhibition and calcium mobilization at cannabinoid receptors in humans and rats were employed to characterize LEI‐101. Rat models of osteoarthritis, neuropathic, postoperative and chronic inflammatory pain were used to assess analgesic efficacy. Selective CB 1 , CB 2 and μ ‐opioid antagonists were used to measure receptor selectivity. To evaluate potential central nervous system side effects, locomotor activity was measured. Key Results With significant selectivity over CB 1 receptors, LEI‐101 had high affinity and functional agonist efficacy at human and rat CB 2 receptors. Systemic administration of LEI‐101 produced dose‐dependent antihyperalgesic and antiallodynic effects across all pain models. These effects were abolished by CB 2 ‐selective antagonists but not by CB 1 or μ antagonists. LEI‐101 did not impair locomotor activity at analgesic doses and showed no evidence of opioid‐like tolerance following repeated administration. Conclusions and Implications These findings demonstrate that selective CB 2 receptor activation by LEI‐101 produces robust analgesia across diverse pain states, with a predominantly CB 2‐ dependent and opioid‐independent pharmacological profile. CB 2 ‐selective agonists such as LEI‐101 represent a promising non‐opioid therapeutic strategy for the treatment of chronic pain.