Acute opioid tolerance and dependence develop within hours of a single injection of morphine. We tested the hypothesis that substance P (SP) amino-terminal metabolites, originating in the periphery, affect the development of tolerance and dependence just as they modulate opioid dependence when injected intrathecally. The SP amino-terminal fragment SP(1-7) (1, 3 or 30 nmol), injected i.p. 30 min before 100 mg/kg morphine, attenuated the development of acute tolerance (5 hr) to the analgesic effect of morphine (5 mg/kg) when tested in the tail-flick assay. Injection of the D-isomer of SP(1-7), [D-Pro2, D-Phe7]SP(1-7), did not alter tolerance development but antagonized the effect of SP(1-7). Neither SP(1-7) nor [D-Pro2,D-Phe7]SP(1-7) reversed tolerance when injected 30 min before challenge with 5 mg/kg morphine. Pretreatment with SP(1-7) i.p. 30 min before 100 mg/kg morphine treatment also increased the number of withdrawal jumps induced by naloxone 3.5 hr later. In contrast, SP(1-7) given 30 min before naloxone inhibited withdrawal. [D-Pro2,D-Phe7]SP(1-7) induced an effect opposite that of SP(1-7) and antagonized the effect of SP(1-7) when coadministered. Thus, SP amino-terminal fragments have the unique characteristic of inhibiting the development of tolerance and potentiating the development but inhibiting the expression of withdrawal. These results suggest a possible mechanism by which pain-evoked release of SP may sustain opioid analgesia by attenuating the development of tolerance and inhibiting the expression of withdrawal.