AIMS: Powerful analgesics relieve pain primarily through activating mu opioidreceptor (MOR), but the long-term use of MOR agonists, such as morphine, islimited by the rapid development of tolerance. Recently, it has been observedthat simultaneous stimulation of the delta opioid receptor (DOR) and MOR limitsthe 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 withantinociceptive 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 oftolerance to antinociceptive effects from treatment with LP1 and morphine.MAIN METHODS: Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4mg/kg subcutaneously (s.c.) twice per day for 9days to maleSprague-Dawley rats. In addition, the LP1 mechanism of action was assessed bymeasurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR.KEY FINDINGS: Data obtained from the radiant heat tail flick test showed that LP1maintained its antinociceptive profile until the ninth day, while tolerance tomorphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cellsexpressing either the MOR or the DOR.SIGNIFICANCE: LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind boththe MOR and DOR.

The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment

PASQUINUCCI, Lorella Giuseppina;PARENTI, Carmela;TURNATURI, RITA;MARRAZZO, Agostino;PREZZAVENTO, Orazio;RONSISVALLE, SIMONE;SCOTO, Giovanna Maria;RONSISVALLE, Giuseppe
2012-01-01

Abstract

AIMS: Powerful analgesics relieve pain primarily through activating mu opioidreceptor (MOR), but the long-term use of MOR agonists, such as morphine, islimited by the rapid development of tolerance. Recently, it has been observedthat simultaneous stimulation of the delta opioid receptor (DOR) and MOR limitsthe 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 withantinociceptive 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 oftolerance to antinociceptive effects from treatment with LP1 and morphine.MAIN METHODS: Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4mg/kg subcutaneously (s.c.) twice per day for 9days to maleSprague-Dawley rats. In addition, the LP1 mechanism of action was assessed bymeasurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR.KEY FINDINGS: Data obtained from the radiant heat tail flick test showed that LP1maintained its antinociceptive profile until the ninth day, while tolerance tomorphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cellsexpressing either the MOR or the DOR.SIGNIFICANCE: LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind boththe MOR and DOR.
Bifunctional drugs; Antinociceptive tolerance; [35S]GTPγS binding studies
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/41140
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