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.
AuthorsTsukasa Sakurada, Takaaki Komatsu, Hikari Kuwahata, Chizuko Watanabe, Toru Orito, Chikai Sakurada, Minoru Tsuzuki, Shinobu Sakurada
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 74 Issue 5 Pg. 758-67 (Sep 1 2007) ISSN: 1873-2968 [Electronic] England
PMID17658485 (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
  • 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

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