Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain.
Since neuropathic pain is resistant to conventional analgesics such as opiates and non-steroidal anti-inflammatory drugs, the development of new types of drugs for its treatment has been awaited. Several key molecules associated with nociception have been suggested as potential targets for new analgesics. Glial cell line-derived neurotrophic factor (GDNF) has a variety of functions affecting the survival and development of specified neural cell populations, mediated via transmission of intracellular signals through binding to its high-affinity receptor, GFR*1, and subsequent activation of a tyrosine receptor kinase, RET, neural cell adhesion molecule (NCAM), or other signaling molecules. GDNF also exhibits analgesic effects in rodent models of neuropathic pain, although the underlying mechanisms are still largely unknown, including the intracellular signal transduction involved. We report here that NCAM signaling plays a role in mediating the analgesic effect of GDNF in rats with chronic constrictive injury (CCI). We found that NCAM was expressed in intrinsic neurons in the spinal dorsal horn and in dorsal root ganglion neurons with small cell bodies. Reduction of NCAM expression by NCAM antisense oligodeoxynucleotide administration to CCI rats abolished the analgesic effect of GDNF without affecting RET signaling activation. An NCAM mimetic peptide, C3d, partially reduced the chronic pain induced by CCI. These findings suggest that NCAM signaling plays a critical role in the analgesic effect of GDNF and that development of new drugs activating GDNF-NCAM signaling may represent a new strategy for the relief of intractable pain.
Sakai
Atsushi
A
Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Shizuoka 411-8731, Japan.
Asada
Minoru
M
Seno
Naoki
N
Suzuki
Hidenori
H
D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D008026:Ligation; D008297:Male; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D019006:Neural Cell Adhesion Molecules; D020320:Oligoribonucleotides, Antisense; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat