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

Neuropharmacology. 2013 Aug:71:70-82. doi: 10.1016/j.neuropharm.2013.03.008. Epub 2013 Mar 27.


Persistent pain states, such as those caused by nerve injury or inflammation, are associated with altered sensations, allodynia and hyperalgesia, that are resistant to traditional analgesics. A contribution to development and maintenance in altered pain perception comes from nociceptive processing and descending modulation from supraspinal sites. A multitarget ligand seems to be useful for pain relief with a decreased risk of adverse events and a considerable analgesic 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 with low potential to induce tolerance. LP1 was tested in models of neuropathic pain - induced by chronic constriction injury (CCI) of the left sciatic nerve - and inflammatory pain - produced by intraplantar injection of carrageenan. In CCI rats, subcutaneous (s.c.) LP1 (3 mg/kg) showed a significant antiallodynic effect, measured with von Frey filaments, and antihyperalgesic effect, evoked in response to a radiant heat stimulus with plantar test. Analogously, LP1 significantly reduced allodynic and hyperalgesic thresholds in a model of inflammatory pain induced by carrageenan. To evaluate the contribution of opioid receptor subtypes in LP1 antinociceptive effects, the multitarget LP1 profile was assessed using selective opioid antagonists. Moreover, functional electrophysiological in vitro assays, using primary cortical and spinal cord networks, allowed to define the "pharmacological fingerprint" of LP1. The EC₅₀ values 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 reference compounds, a similarity profile of LP1 to opioid and non-opioid drugs involved in pain modulation was detected. Our studies seem to support that multitarget ligand approach should be useful for persistent pain conditions in which mechanical allodynia and thermal hyperalgesia are significant components of the nociceptive response.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • Benzomorphans / metabolism
  • Benzomorphans / pharmacology
  • Benzomorphans / therapeutic use*
  • Cells, Cultured
  • Chronic Pain / drug therapy*
  • Chronic Pain / immunology
  • Chronic Pain / metabolism
  • Disease Models, Animal*
  • Embryo, Mammalian
  • Frontal Lobe / cytology
  • Frontal Lobe / drug effects
  • Frontal Lobe / immunology
  • Frontal Lobe / metabolism
  • Ligands
  • Male
  • Mice
  • Mice, Inbred Strains
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Neuralgia / drug therapy*
  • Neuralgia / immunology
  • Neuralgia / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / immunology
  • Neurons / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism
  • Spinal Cord / cytology
  • Spinal Cord / drug effects
  • Spinal Cord / immunology
  • Spinal Cord / metabolism


  • 3-((2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl)-N-phenylpropanamide
  • Analgesics, Opioid
  • Benzomorphans
  • Ligands
  • Nerve Tissue Proteins
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu