Intrathecal substance P (1-7) prevents morphine-evoked spontaneous pain behavior via spinal NMDA-NO cascade.
Previous research has shown that injection of high-dose of morphine into the spinal lumbar intrathecal (i.t.) space of rats elicits an excitatory behavioral syndrome indicative of severe vocalization and agitation. Substance P N-terminal fragments are known to inhibit nociceptive responses when injected i.t. into animals. In this study, we investigated the effect of i.t. substance P (1-7) on both the nociceptive response and the extracellular concentrations of glutamate and nitric oxide (NO) metabolites (nitrite/nitrate) evoked by high-dose i.t. morphine (500 nmol). The induced behavioral responses were attenuated dose-dependently by i.t. pretreatment with the substance P N-terminal fragment substance P (1-7) (100-400 pmol). The inhibitory effect of substance P (1-7) was reversed significantly by pretreatment with [d-Pro2, d-Phe7]substance P (1-7) (20 and 40 nmol), a d-isomer and antagonist of substance P (1-7). In vivo microdialysis analysis showed a significant elevation of extracellular glutamate and NO metabolites in the spinal cord after i.t. injection of high-dose morphine (500 nmol). Pretreatment with substance P (1-7) (400 pmol) produced a significant reduction on the elevated concentrations of glutamate and NO metabolites evoked by i.t. morphine. The reduced levels of glutamate and NO metabolites were significantly reversed by the substance P (1-7) antagonist (40 nmol). The present results suggest that i.t. substance P (1-7) may attenuate the excitatory behavior (vocalization and agitation) of high-dose i.t. morphine by inhibiting the presynaptic release of glutamate, and reducing NO production in the dorsal spinal cord.
First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan. tsukasa@daiichi-cps.ac.jp
Tsukasa
T
Sakurada
Takaaki
T
Komatsu
Hikari
H
Kuwahata
Chizuko
C
Watanabe
Toru
T
Orito
Chikai
C
Sakurada
Minoru
M
Tsuzuki
Shinobu
S
Sakurada
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000378:metabolism*; D009566:Nitrates / Q000134:cerebrospinal fluid; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000134:cerebrospinal fluid; D010146:Pain / Q000188:drug therapy*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013373:Substance P / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors
D000700:Analgesics; D009566:Nitrates; D009573:Nitrites; D010446:Peptide Fragments; C087218:substance P (1-7), Pro(2)-Phe(7)-; D009569:Nitric Oxide; D013373:Substance P; D018698:Glutamic Acid; D016202:N-Methylaspartate; C036877:substance P (1-7); D009020:Morphine