The substance P amino-terminal metabolite substance P(1-7), administered peripherally, prevents the development of acute morphine tolerance and attenuates the expression of withdrawal in mice

JS Kreeger and AA Larson

Department of Veterinary PathoBiology, University of Minnesota, St. Paul, USA.

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.

Volume 279, Issue 2, pp. 662-667, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics