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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.Pharmacological characterization of MSP9, administered by the intramuscular route, was achieved in naive and morphine-tolerant male rats utilizing the tail-flick test.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 0.2 mg/kg. The antinociceptive responses achieved by very low concentrations of MSP9 were not obtained by administration of equivalent low doses of morphine, suggesting that kinetic and dynamic parameters may contribute to its unusual analgesic properties. Importantly, MSP9 produces a strong antinociceptive response when administered to morphine-tolerant rats, suggesting a significant activation of kappa and/or delta receptors (KORs and DORs, respectively) in the presence of functionally down regulated MORs.Analyses employing selective, blood brain barrier (BBB) permeable, opioid and SP antagonists administered alone or in combination, indicate an obligate requirement for coincident activation of populations of CNS opioid and SP receptors. These combined data suggest that MSP9 activates multiple opioid- and SPR-expressing systems functionally linked to CNS analgesic responses, designating this class of hybrid chimeric molecules as prime candidates for therapeutic development for a wide range of clinical indications.