title: The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment.
abstract: OBJECTIVE
  Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine.
  
  
  METHODS
  Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneously (s.c.) twice per day for 9 days to male Sprague-Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR.
  
  
  RESULTS
  Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cells expressing either the MOR or the DOR.
  
  
  CONCLUSIONS
  LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR.
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. lpasquin@unict.it
authors.forename: Lorella
authors.initials: L
authors.lastname: Pasquinucci
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.forename: Rita
authors.initials: R
authors.lastname: Turnaturi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Aricò
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Zafiroula
authors.initials: Z
authors.lastname: Georgoussi
authors.forename: Danai-Dionysia
authors.initials: DD
authors.lastname: Fourla
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Scoto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001575:Benzomorphans / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy*; D004361:Drug Tolerance / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C569975:3-((2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl)-N-phenylpropanamide; D000701:Analgesics, Opioid; D001575:Benzomorphans; D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu