Successfull management of pain with opioid analgesics is based on use of a drug at its minimal effective dose with lower adverse effects incidence.[1] Powerful analgesics relieve pain primarily through agonism on mu-opioid peptide (MOP) receptor. Unfortunately, the clinical utility in chronic treatment of MOP receptor agonists, such as morphine, is limited by the development of tolerance and physical dependence. Recently, it has been observed that simultaneous MOP and DOP receptors activation produce analgesia with reduced tolerance.[2] So, the aim of this work was to investigate the tolerance-inducting capability of our new benzomorphan-based ligand LP1 which showed a mixed MOP/DOP receptors agonist profile in vivo and in vitro assays. In fact, 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 effect of LP1 administered at the dose of 4mg/kg s.c. (100% antinociception in acute administration after 20min) twice per day for 9 consecutive days to Male Sprague-Dawley rats. Data obtained by the radiant heat tail flick test showed that LP1 maintained its analgesic profile until the ninth day, while the same experimental protocol with morphine (10mg/kg s.c. twice a day) triggered a strong tolerance effect by day 3. In conclusion, LP1 together with an analgesic potency similar to morphine in acute administration, displayed low incidence on the development of tolerance. Due to these findings, the mixed MOP/DOP receptors agonist LP1 seems to be an useful analgesic agent for chronic pain treatment.
NEW BENZOMORPHAN-BASED LP1 LIGAND AS SUITABLE MIXED MOP/DOP RECEPTORS AGONIST FOR CHRONIC PAIN TREATMENT
PASQUINUCCI, Lorella Giuseppina;TURNATURI, RITA;PARENTI, Carmela;
2011-01-01
Abstract
Successfull management of pain with opioid analgesics is based on use of a drug at its minimal effective dose with lower adverse effects incidence.[1] Powerful analgesics relieve pain primarily through agonism on mu-opioid peptide (MOP) receptor. Unfortunately, the clinical utility in chronic treatment of MOP receptor agonists, such as morphine, is limited by the development of tolerance and physical dependence. Recently, it has been observed that simultaneous MOP and DOP receptors activation produce analgesia with reduced tolerance.[2] So, the aim of this work was to investigate the tolerance-inducting capability of our new benzomorphan-based ligand LP1 which showed a mixed MOP/DOP receptors agonist profile in vivo and in vitro assays. In fact, 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 effect of LP1 administered at the dose of 4mg/kg s.c. (100% antinociception in acute administration after 20min) twice per day for 9 consecutive days to Male Sprague-Dawley rats. Data obtained by the radiant heat tail flick test showed that LP1 maintained its analgesic profile until the ninth day, while the same experimental protocol with morphine (10mg/kg s.c. twice a day) triggered a strong tolerance effect by day 3. In conclusion, LP1 together with an analgesic potency similar to morphine in acute administration, displayed low incidence on the development of tolerance. Due to these findings, the mixed MOP/DOP receptors agonist LP1 seems to be an useful analgesic agent for chronic pain treatment.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
