Direct evidence for the ongoing brain activation by enhanced dynorphinergic system in the spinal cord under inflammatory noxious stimuli.
BACKGROUND
Dynorphin A in the spinal cord is considered to contribute to nociceptive stimuli. However, it has not yet been determined whether activation of the spinal dynorphinergic system under nociceptive stimuli plays a role in direct acceleration of the ascending nociceptive pathway. In this study, the authors investigated the role of spinal dynorphinergic transmission in ongoing brain activation under noxious stimuli in mice.


METHODS
The changes in prodynorphin messenger RNA expression and dynorphin A (1-17)-like immunoreactivity in the mouse spinal cord were determined after the intraplantar injection of complete Freund's adjuvant in mice. The signal intensity in different brain regions after the intraplantar injection of complete Freund's adjuvant or intrathecal injection of dynorphin A (1-17) was measured by a pharmacological functional magnetic resonance imaging analysis.


RESULTS
Complete Freund's adjuvant injection produced pain-associated behaviors and induced a dramatic increase in signal intensity in the mouse cingulate cortex, somatosensory cortex, insular cortex, and thalamic nuclei. These effects were not seen in prodynorphin knockout mice. Prodynorphin messenger RNA expression and dynorphin A (1-17)-like immunoreactivity on the ipsilateral side of the spinal cord were markedly increased in complete Freund's adjuvant-injected mice. Furthermore, intrathecal injection of dynorphin A (1-17) at relatively high doses caused pain-associated behaviors and a remarkable increase in the activities of the cingulate cortex, somatosensory cortex, insular cortex, and medial and lateral thalamic nuclei in mice.


CONCLUSIONS
These findings indicate that spinally released dynorphin A (1-17) by noxious stimuli leads to the direct activation of ascending pain transmission.
Taketa
Yasuko
Y
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Niikura
Keiichi
K
Kobayashi
Yasuhisa
Y
Furuya
Masaharu
M
Shimizu
Toshikazu
T
Narita
Michiko
M
Imai
Satoshi
S
Kuzumaki
Naoko
N
Maitani
Yoshie
Y
Yamazaki
Mitsuaki
M
Inada
Eiichi
E
Iseki
Masako
M
Suzuki
Tsutomu
T
Narita
Minoru
M
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics; D005620:Freund's Adjuvant; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000523:psychology; D011498:Protein Precursors / Q000235:genetics; D012313:RNA / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D004745:Enkephalins; D011498:Protein Precursors; D016194:Receptors, N-Methyl-D-Aspartate; D012313:RNA; D004399:Dynorphins; D005620:Freund's Adjuvant; C033660:preproenkephalin