Upregulation of neurokinin-1 receptor expression in rat spinal cord by an N-terminal metabolite of substance P.
Chronic inflammatory conditions are associated with an upregulation of both substance P (SP) and neurokinin-1 (NK-1) receptors in the dorsal spinal cord. These receptors have been implicated in hyperalgesia as well as stress-induced analgesia. On the basis of the release of SP during chronic pain, and its rapid metabolism, we tested the hypothesis that SP metabolites regulate the synthesis of either SP or NK-1 receptors in the spinal cord. We measured expression of preprotachykinin mRNA and NK-1 receptor mRNA following intrathecally administered substance P(1-7) (SP1-7), the major metabolite of SP in rat, and following capsaicin, a compound known to induce release of endogenous SP. SP(1-7) and capsaicin each increased NK-1 receptor mRNA in the spinal cord (6 h) followed by an increase in NK-1 receptor-immunoreactivity (24 h and 1 week). D-SP(1-7), a D-isomer and antagonist of SP(1-7), did not mimic the effect of SP(1-7), indicating stereoselectivity. Instead, D-SP(1-7) prevented the upregulation of NK-1 receptor immunoreactivity that was induced by capsaicin injected intrathecally, suggesting that the effect of capsaicin is also mediated by SP N-terminal metabolites. In contrast, the decrease in SP synthesis produced by capsaicin was not dependent on SP metabolites as SP(1-7) failed to decrease either preprotachykinin mRNA content in dorsal root ganglia (6 h) or SP immunoreactivity in the lumbar spinal cord (24 h and 1 week). In addition, the effects of capsaicin on SP synthesis were not prevented by D-SP(1-7). Thus, SP metabolites, at times and doses that are antinociceptive, appear to enhance SP-mediated signal transduction by upregulating NK-1 receptor expression without affecting SP synthesis.
Velázquez
Rubén A
RA
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
McCarson
Kenneth E
KE
Cai
Yongjiu
Y
Kovács
Katalin J
KJ
Shi
Qiuying
Q
Evensjö
Maria
M
Larson
Alice A
AA
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007536:Isomerism; D008297:Male; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology; D015320:Tachykinins / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; C036877:substance P (1-7); D002211:Capsaicin