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, 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 a...

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Published in:Neuropharmacology 2013-08, Vol.71, p.70-82
Main Authors: Parenti, Carmela, Turnaturi, Rita, Aricò, Giuseppina, Gramowski-Voß, Alexandra, Schroeder, Olaf H.-U., Marrazzo, Agostino, Prezzavento, Orazio, Ronsisvalle, Simone, Scoto, Giovanna M., Ronsisvalle, Giuseppe, Pasquinucci, Lorella
Format: Article
Language:English
Subjects:
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
Electrophysiological behaviour
Embryo, Mammalian
Frontal Lobe - cytology
Frontal Lobe - drug effects
Frontal Lobe - immunology
Frontal Lobe - metabolism
Indexing in process
Inflammatory pain
Ligands
LP1
Male
Mice
Mice, Inbred Strains
Micro-electrode array (MEA)
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
Neuropathic pain
Opioid receptors
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
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Summary: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. [Display omitted] •The multitarget opioid ligand LP1 could address signs of persistent pain conditions.•LP1 showed antiallodynic and antihyperalgesic effects in neuropathic pain.•LP1 reduced allodynia and hyperalgesia in inflammatory pain.•Electrophysiological “fingerprint” of LP1 in neuronal networks was defined.•Similarit
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2013.03.008