Involvement of stem cell factor and its receptor tyrosine kinase c-kit in pain regulation.
The c-kit receptor tyrosine kinase is expressed in a subpopulation of small- and medium-sized neurons of the dorsal root ganglia (DRG) and in the superficial layer of the spinal cord. Stem cell factor (SCF), a ligand of the c-kit receptor, induces neurite outgrowth from DRG and supports the survival of c-kit-expressing neurons. To clarify the possible function of the SCF/c-kit receptor system in the adult animal, we investigated the expression of c-kit receptor in the spinal cord and DRG in relation to pain by using H2C7, a newly developed anti-c-kit monoclonal antibody. S.c. and intrathecal injection of SCF markedly reduced the paw withdrawal threshold to mechanical stimuli and intrathecal SCF at 10 pg maximally induced mechanical allodynia in conscious mice. Intrathecal SCF also reduced the paw withdrawal latency to heat stimuli significantly but transiently. The c-kit receptor was co-expressed in 58.4% of calcitonin gene-related peptide (CGRP) -positive, but only 5.1% of isolectin B4-positive, DRG neurons. In the spinal cord, the c-kit receptor was detected in the superficial layer of the dorsal horn and co-localized there with CGRP in central terminals of DRG neurons. Selective elimination of unmyelinated C-fibers by neonatal capsaicin treatment resulted in marked reduction of the c-kit receptor and CGRP expression in the superficial layer of the spinal cord. Cell-size profiles showed that c-kit receptor expression was significantly up-regulated and down-regulated in medium-sized DRG neurons after neonatal capsaicin treatment and nerve injury, respectively. These results suggest that the c-kit receptor is mainly expressed in peptidergic small-sized DRG neurons and may be involved in pain regulation both peripherally and centrally.
Takagi
K
K
Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi, Japan.
Okuda-Ashitaka
E
E
Mabuchi
T
T
Katano
T
T
Ohnishi
T
T
Matsumura
S
S
Ohnaka
M
M
Kaneko
S
S
Abe
T
T
Hirata
T
T
Fujiwara
S
S
Minami
T
T
Ito
S
S
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D016900:Neurofilament Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D019089:Stem Cell Factor; D013997:Time Factors
D006023:Glycoproteins; C121001:NR2B NMDA receptor; D016900:Neurofilament Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D019089:Stem Cell Factor; C473590:isolectin B4-binding glycoprotein, mouse; C051774:neurofilament protein H; D019009:Proto-Oncogene Proteins c-kit; D015740:Calcitonin Gene-Related Peptide