Synthesis and pharmacological analysis of a morphine/substance P chimeric molecule with full analgesic potency in morphine-tolerant rats.

Background: We have previously explored the functional role of the tachykinin substance P (SP) in the mediation of opioid-dependent antinociception and now describe the formulation, synthesis, and initial pharmacological characterization of a hybrid chimeric molecule, designated MSP9, containing the mu opioid receptor (MOR) agonist morphine covalently attached through a succinic acid linker to the SP receptor (SPR) agonist domain SP3-11.

Material/methods: Pharmacological characterization of MSP9, administered by the intramuscular route, was achieved in naive and morphine-tolerant male rats utilizing the tail-flick test.

Results: MSP9 produced significant antinociceptive responses across a wide concentration range and displayed an atypical bell-shaped analgesic dose response relationship with peak effect of 40+/-10% reached at 0.