THE BENZOMORPHAN-BASED LP1 IS A CENTRAL-ACTING MULTITARGET OPIOID LIGAND FOR CHRONIC PAIN TREATMENT

The simultaneous targeting of opioid receptors could produce an improved antinociception with fewer incidence of undesirable effects, such as tolerance. Opioid ligands characterized by MOR/DOR profile represent potential valuable analgesics. We previously reported that LP1, a benzomorphan-based compound, acted as a MOR-DOR ligand and produced a valid antinociception that was longer lasting than morphine. In this study we determined whether the antinociceptive effect produced by LP1 was central or peripheral using the quaternary opioid antagonist naloxone methiodide (NX-M). To assess which opioid receptor subtypes are involved in LP1 effects, we used the selective MOR, DOR and KOR antagonists, naloxonazine, naltrindole and nor-binaltorphimine, respectively. We also investigated LP1 effect on the antinociception DPDPE-induced to characterize its DOR profile better. In light of its MOR/DOR activity, we evaluated and compared the induction of tolerance to antinociceptive effects of LP1 respect to morphine. Data obtained by radiant tail flick test showed that LP1 acts prevalently in the CNS as a suitable MOR agonist able to counteract DPDPE analgesia. Moreover, LP1, in chronic regimen, showed a low tolerance-inducing capability consistent with its multitarget opioid profile.