Intrathecal substance P augments morphine-induced antinociception: possible relevance in the production of substance P N-terminal fragments.
The present study sought to examine the mechanism of substance P to modulate the antinociceptive action of intrathecal (i.t.) morphine in paw-licking/biting response evoked by subcutaneous injection of capsaicin into the plantar surface of the hindpaw in mice. The i.t. injection of morphine inhibited capsaicin-induced licking/biting response in a dose-dependent manner. Substance P (25 and 50 pmol) injected i.t. alone did not alter capsaicin-induced nociception, whereas substance P at a higher dose of 100 pmol significantly reduced the capsaicin response. Western blots showed the constitutive expression of endopeptidase-24.11 in the dorsal and ventral parts of lumbar spinal cord of mice. The N-terminal fragment of substance P (1-7), which is known as a major product of substance P by endopeptidase-24.11, was more effective than substance P on capsaicin-induced nociception. Combination treatment with substance P (50 pmol) and morphine at a subthreshold dose enhanced the antinociceptive effect of morphine. The enhanced effect of the combination of substance P with morphine was reduced significantly by co-administration of phosphoramidon, an inhibitor of endopeptidase-24.11. Administration of D-isomer of substance P (1-7), [D-Pro(2), D-Phe(7)]substance P (1-7), an inhibitor of [(3)H] substance P (1-7) binding, or antisera against substance P (1-7) reversed the enhanced antinociceptive effect by co-administration of substance P and morphine. Taken together these data suggest that morphine-induced antinociception may be enhanced through substance P (1-7) formed by the enzymatic degradation of i.t. injected substance P in the spinal cord.
Komatsu
Takaaki
T
First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, Japan.
Sasaki
Mika
M
Sanai
Kengo
K
Kuwahata
Hikari
H
Sakurada
Chikai
C
Tsuzuki
Minoru
M
Iwata
Yohko
Y
Sakurada
Shinobu
S
Sakurada
Tsukasa
T
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006020:Glycopeptides / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement / Q000187:drug effects*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D000906:Antibodies; D006020:Glycopeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C087218:substance P (1-7), Pro(2)-Phe(7)-; D013373:Substance P; C031661:substance P (5-11); C036877:substance P (1-7); D009020:Morphine; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon