The cannabinoid CB₂ agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats

Cannabinoid CB₂ agonists show promise as analgesics because they lack unwanted side effects associated with direct activation of CB₁ receptors. CB₂ receptor activation suppresses pathological pain in animal models, but the types of pain that best respond to CB₂ agonists are incompletely understood. This gap in knowledge may contribute to failures in clinical translation. We previously showed that the G protein-biased CB₂ receptor agonist LY2828360 attenuated the maintenance of neuropathic pain behavior in mouse models of inflammatory and neuropathic pain. Whether this finding generalizes to neuropathic pain induced by traumatic nerve injury or occurs in multiple rodent species remains unknown. Here we show that LY2828360 (3 and 10 mg/kg i.p.), administered acutely, reversed paclitaxel-induced mechanical hypersensitivity in male rats. By contrast, LY2828360 (10 mg/kg i.p.), administered acutely, attenuated mechanical hypersensitivity in a spared nerve injury (SNI) rat model, whereas the low dose (3 mg/kg i.p.) was ineffective. In both models, efficacy of LY2828360 was sustained following 10 days of repeated dosing. LY2828360 (3 mg/kg i.p.) also prevented development of tolerance to the opioid analgesic morphine (6 mg/kg i.p.) in rats with SNI when co-administered. LY2828360 (3 mg/kg i.p.) did not produce preference or aversion in the conditioned place preference (CPP) test in rats when administered alone but blocked CPP to morphine (6 mg/kg i.p.). Lastly, LY2828360 (3 mg/kg i.p.) did not alter the acquisition of i.v. morphine self-administration under fixed ratio 1 (FR1) and 3 (FR3) or motivation to work for morphine under a progressive ratio (PR) schedule of reinforcement.