The multitarget opioid ligand LP1's effects in persistent pain and in primary cell neuronal cultures

Persistent pain states, such as those caused by nerve injury or inflammation, areassociated with altered sensations, allodynia and hyperalgesia, that areresistant to traditional analgesics. A contribution to development andmaintenance in altered pain perception comes from nociceptive processing anddescending modulation from supraspinal sites. A multitarget ligand seems to beuseful for pain relief with a decreased risk of adverse events and a considerableanalgesic efficacy. The multitarget MOR agonist-DOR antagonist LP1,(3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benazocin-3(2H)-yl]-N-phenylpropanamide, is a central acting antinociceptive agent withlow potential to induce tolerance. LP1 was tested in models of neuropathic pain -induced by chronic constriction injury (CCI) of the left sciatic nerve - andinflammatory pain - produced by intraplantar injection of carrageenan. In CCIrats, subcutaneous (s.c.) LP1 (3 mg/kg) showed a significant antiallodyniceffect, measured with von Frey filaments, and antihyperalgesic effect, evoked in response to a radiant heat stimulus with plantar test. Analogously, LP1significantly reduced allodynic and hyperalgesic thresholds in a model ofinflammatory pain induced by carrageenan. To evaluate the contribution of opioid receptor subtypes in LP1 antinociceptive effects, the multitarget LP1 profile wasassessed using selective opioid antagonists. Moreover, functionalelectrophysiological in vitro assays, using primary cortical and spinal cordnetworks, allowed to define the "pharmacological fingerprint" of LP1. The EC50values in this functional screening seem to confirm LP1 as a potent opioid ligand(EC50 = 0.35 fM and EC50 = 44 pM in spinal cord and frontal cortex,respectively). Using a NeuroProof data-base of well characterised referencecompounds, a similarity profile of LP1 to opioid and non-opioid drugs involved inpain modulation was detected. Our studies seem to support that multitarget ligandapproach should be useful for persistent pain conditions in which mechanicalallodynia and thermal hyperalgesia are significant components of the nociceptive response.