Intrathecal substance P (1-7) prevents morphine-evoked spontaneous pain behavior via spinal NMDA-NO cascade.

Abstract

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.

• Authors: Tsukasa Sakurada, Takaaki Komatsu, Hikari Kuwahata, Chizuko Watanabe, Toru Orito, Chikai Sakurada, Minoru Tsuzuki, Shinobu Sakurada
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 74 Issue 5 Pg. 758-67 (Sep 01 2007) ISSN: 1873-2968 [Electronic] England
• PMID: 17658485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Nitrates
• Nitrites
• Peptide Fragments
• substance P (1-7), Pro(2)-Phe(7)-
• Nitric Oxide
• Substance P
• Glutamic Acid
• N-Methylaspartate
• substance P (1-7)
• Morphine

Topics

• Analgesics (administration & dosage, pharmacology)
• Animals
• Dose-Response Relationship, Drug
• Glutamic Acid (cerebrospinal fluid)
• Male
• Morphine (administration & dosage, pharmacology)
• N-Methylaspartate (metabolism)
• Nitrates (cerebrospinal fluid)
• Nitric Oxide (metabolism)
• Nitrites (cerebrospinal fluid)
• Pain (drug therapy)
• Peptide Fragments (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (metabolism)
• Substance P (administration & dosage, analogs & derivatives, pharmacology)
• Time Factors