Substance P-(1-7), a substance P metabolite, inhibits withdrawal jumping in morphine-dependent mice

Substance P has been previously shown to inhibit the intensity of the morphine abstinence syndrome in mice. In view of the rapid degradation of substance P after its release from nerve terminals, we hypothesized that this inhibition is mediated by the N-terminus of substance P and its metabolites rather than via the C-terminus interacting with neurokinin receptors. Intrathecal injection of substance P-(1-7) (1 nmol) 30 min prior to naloxone challenge, in mice that had received 25 μg of morphine sulfate intrathecally once daily for three days, caused a dose-related attenuation of withdrawal jumping. In contrast, administration of the substance P-(1-7) antagonist, [D-Pro²,D-Phe⁷]substance P-(1-7), 15 min prior to naloxone increased withdrawal jumping behaviors. Equimolar doses of morphine and naloxone at 30 min had no effect. From these data, it appears that substance P N-terminal metabolites modulate withdrawal behaviors in morphine-dependent mice.