PM289, a synthetic CB2 in vitro receptor agonist, modulates morphine-induced antinociceptive effect and withdrawal syndrome in an animal model of osteoarthritic pain.

Osteoarthritis is a common condition, and the associated pain is a leading cause of disability. One main challenge in its management stems from the complexity of the disease and the limited efficacy of current analgesic treatments. Although evidence-based clinical guidelines provide valuable recommendations, they often prove inadequate. Opioids, while effective, are not considered first-line therapies due to adverse effects, particularly with long-term use. A promising strategy for chronic pain involves the coadministration of opioid and cannabinoid receptor agonists. This study investigates the efficacy of combining morphine with PM289, a novel and selective CB2 in vitro receptor agonist, in a rat model of knee osteoarthritis-associated pain, including both sexes. Effects on tactile allodynia, movement-evoked pain, analgesic tolerance, locomotor impairment, conditioned reward and anxiety-like behaviours, and naloxone-precipitated withdrawal symptoms were assessed. Additionally, protein levels of μ-opioid receptor and clusterin-a recognised biomarker of substance abuse-were analysed. PM289 alone produced sustained anti-allodynic and antinociceptive effects without inducing tolerance. When coadministered with morphine, it enhanced analgesia and attenuated opioid withdrawal symptoms, particularly in females. However, it did not reduce morphine-induced conditioned reward in this group. Chronic treatment also increased plasma clusterin levels in both sexes, with enhanced expression in the nucleus accumbens of males. These findings support the potential of PM289 as an adjuvant to chronic opioid therapy, highlighting the importance of sex-specific considerations in its efficacy and safety profile.