Leucine at the carboxyl-terminal of endokinins C and D contributes to elicitation of the antagonistic effect on substance P in rat pain processing.
Endokinins are tachykinin peptides designated from a human preprotachykinin C (PPT-C, TAC4) gene and consist of endokinin A (EKA), endokinin B (EKB), endokinin C (EKC) and endokinin D (EKD). A representative of mammalian tachykinins is substance P (SP), which functions as a neurotransmitter or modulator in the pain system; however, little is known about the role of these endokinins, especially EKC and EKD, in pain processing. Therefore, we evaluated the effects of EKC/D (using the common carboxyl-terminal duodecapeptide in EKC and EKD) on pain processing in rats. Pretreatment with EKC/D prevented induction of scratching behavior and thermal hyperalgesia by intrathecal administration of EKA/B (using the common C-terminal decapeptide in EKA and EKB) and SP and c-Fos expression in laminae I/II and V/VI of the spinal cord by noxious thermal stimulation. A prominent difference between EKC/D and SP is the presence of leucine instead of methionine at the carboxyl-terminal of EKC/D. Thus, to clarify whether leucine at the carboxyl-terminal of EKC/D plays an important role in determining the inhibitory effect of this peptide, we intrathecally administered [Met(12)]-EKC/D in which only leucine of EKC/D is replaced by methionine. This peptide did not exhibit the inhibitory effect on SP-induced scratching behavior or thermal hyperalgesia but conversely caused thermal hyperalgesia. Taken together, these findings indicate that EKC/D has an inhibitory effect on pain processing in the rat spinal cord, and the effect is due to leucine at the carboxyl-terminal of EKC/D.
Naono
Rumi
R
Division of Neurobiology, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Nakayama
Tomohiro
T
Ikeda
Tetsuya
T
Matsushima
Osamu
O
Nishimori
Toshikazu
T
D000818:Animals; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006593:Hexokinase; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D007930:Leucine / Q000378:metabolism*; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000008:administration & dosage; D010812:Physical Stimulation; D011498:Protein Precursors / Q000737:chemistry / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors*; D015320:Tachykinins / Q000737:chemistry / Q000627:therapeutic use*
D010455:Peptides; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D006593:Hexokinase; D007930:Leucine