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.
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.
Kreeger
J S
JS
Department of Veterinary PathoBiology, University of Minnesota, St. Paul, USA.
Larson
A A
AA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000188:drug therapy*; D009270:Naloxone / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D013237:Stereoisomerism; D013373:Substance P / Q000008:administration & dosage / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D013373:Substance P; D009270:Naloxone; C036877:substance P (1-7)