Successful management of pain with opioid analgesics is based on use of a drug at its effective dose with lower adverse effects incidence.[1] Powerful opioid analgesics relieve pain primarily through activating mu:opioid peptide (MOP) receptor, but its long:term stimulation with MOP receptor’s selective agonists induces a rapid development of tolerance. Recently, it has been observed that simultaneous MOP and DOP receptors activation produce analgesia with reduced tolerance.[2] The aim of this work was to investigate the tolerance:inducting capability of our new benzomorphan:based ligand 3:[(2R,6R,11R):8:hydroxy:6,11:dimethyl:1,4,5,6:tetrahydro: 2,6:methano:3:benzazocin:3(2H):yl]:N:phenylpropanamide (named LP1). In previous studies LP1 displayed a nanomolar affinity for MOP and delta:opioid peptide (DOP) receptors (Ki = 0.83 nM, Ki = 29 nM, respectively). Moreover, LP1 acted as a mixed MOP/DOP receptors agonist in adenylyl cyclase assay (IC50 = 4.8 nM, IC50 = 12.0 nM, respectively), and exhibited an analgesic potency similar to morphine in the tail flick test (ED50 2.03 and 2.7 mg/kg for LP1 and morphine, respectively).[3] Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneous (100% antinociception in acute administration after 20min) twice per day for 9 days to Male Sprague:Dawley rats. The LP1 mechanism of action was assessed by measurement of LP1:induced [35S]GTPγS binding to the MOP and DOP receptors. In addition, the agonist properties on DOP receptor of LP1 was further investigated through the mitogen activated protein (MAP) kinase assay. Data obtained from the radiant heat tail flick test showed that LP1 maintained its analgesic profile until the ninth day, while tolerance to morphine (10 mg/kg s.c. twice per day) was observed on day 3. Moreover, in vitro LP1 significantly enhanced [35S]GTPγS binding in the membranes of HEK293 cells expressing either the MOP or the DOP receptors and was able to elicited ERK1,2 phosphorilation. In conclusion, LP1 together with an analgesic potency similar to morphine in acute administration, displayed low incidence on the development of tolerance. LP1 low tolerance:inducing capability may be correlated with its ability to bind and activate both the MOP and DOP receptors. Summarizing in vitro and in vivo data, LP1 seems to be a novel analgesic agent for chronic pain treatment.

The benzomorphan-based LP1 ligand is a suitable MOP/DOP receptors agonist for chronic pain treatment

PASQUINUCCI, Lorella Giuseppina;PARENTI, Carmela;
2011

Abstract

Successful management of pain with opioid analgesics is based on use of a drug at its effective dose with lower adverse effects incidence.[1] Powerful opioid analgesics relieve pain primarily through activating mu:opioid peptide (MOP) receptor, but its long:term stimulation with MOP receptor’s selective agonists induces a rapid development of tolerance. Recently, it has been observed that simultaneous MOP and DOP receptors activation produce analgesia with reduced tolerance.[2] The aim of this work was to investigate the tolerance:inducting capability of our new benzomorphan:based ligand 3:[(2R,6R,11R):8:hydroxy:6,11:dimethyl:1,4,5,6:tetrahydro: 2,6:methano:3:benzazocin:3(2H):yl]:N:phenylpropanamide (named LP1). In previous studies LP1 displayed a nanomolar affinity for MOP and delta:opioid peptide (DOP) receptors (Ki = 0.83 nM, Ki = 29 nM, respectively). Moreover, LP1 acted as a mixed MOP/DOP receptors agonist in adenylyl cyclase assay (IC50 = 4.8 nM, IC50 = 12.0 nM, respectively), and exhibited an analgesic potency similar to morphine in the tail flick test (ED50 2.03 and 2.7 mg/kg for LP1 and morphine, respectively).[3] Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneous (100% antinociception in acute administration after 20min) twice per day for 9 days to Male Sprague:Dawley rats. The LP1 mechanism of action was assessed by measurement of LP1:induced [35S]GTPγS binding to the MOP and DOP receptors. In addition, the agonist properties on DOP receptor of LP1 was further investigated through the mitogen activated protein (MAP) kinase assay. Data obtained from the radiant heat tail flick test showed that LP1 maintained its analgesic profile until the ninth day, while tolerance to morphine (10 mg/kg s.c. twice per day) was observed on day 3. Moreover, in vitro LP1 significantly enhanced [35S]GTPγS binding in the membranes of HEK293 cells expressing either the MOP or the DOP receptors and was able to elicited ERK1,2 phosphorilation. In conclusion, LP1 together with an analgesic potency similar to morphine in acute administration, displayed low incidence on the development of tolerance. LP1 low tolerance:inducing capability may be correlated with its ability to bind and activate both the MOP and DOP receptors. Summarizing in vitro and in vivo data, LP1 seems to be a novel analgesic agent for chronic pain treatment.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/110247
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